Part 4: Treatment and Prevention of Infectious Diseases

INTRODUCTION

Childhood immunizations represent one of the great public health achievements of the 20th and 21st centuries. According to the World Health Organization, immunization prevented at least 2 million child deaths in 2003 alone. Less than 250 years after Edward Jenner reported that inoculation with cowpox protected against smallpox, immunization against 15 different diseases before age 2 is routinely recommended in the United States. The individual, societal, and economic benefits of disease prevention resulting from the childhood and adult immunization programs in the United States are without question. A report from the Centers for Disease Control and Prevention (CDC) describing the benefits of vaccination of the 2009 birth cohort through 18 years of age estimated that 20 million cases of vaccine-preventable disease will not occur, 42,000 early deaths related to these diseases will be avoided, and $76 billion in direct and indirect costs will be averted. This economic benefit stands in stark contrast to the comparatively small cost for vaccine purchases. The estimated vaccine purchasing cost for a similar birth cohort based on 2015 pricing is $7.8 billion based on CDC cost and $11.6 billion at private sector pricing. The benefit from the reduction in suffering because of vaccine-preventable disease avoidance cannot be quantified.

IMMUNE RESPONSE

Many vaccines can be categorized as live or inactivated vaccines. Live vaccines contain organisms that have been attenuated or weakened so that the vaccine strain replicates in the host but rarely causes disease. The cowpox vaccine administered by Jenner in 1796 to prevent smallpox is an example of a live vaccine. In the late 19th century, Louis Pasteur and others discovered methods to attenuate both viruses and bacteria through chemical means, leading to the development of early vaccines. In the 1940s, John Enders and his colleagues perfected viral culture techniques that enabled the attenuation of viruses through serial passage in cell culture, paving the way for vaccines against polio, measles, mumps, and rubella. Some of the newest live vaccines are the products of genetic engineering. For example, one available rotavirus vaccine is produced by reassortment: the vaccine strains are derived from viral cultures co-infected with both human and bovine rotaviruses and contain genes from both “parent” viruses.

The immune response elicited by live attenuated vaccines is similar to that produced with natural infection. Live attenuated vaccines stimulate both humoral and cell-mediated immunity. Most live attenuated vaccines produce immunity in recipients after a single dose. Because a small number of recipients do not respond to the first dose of an injected live vaccine (such as measles, mumps, and rubella [MMR], or varicella), a second dose is recommended routinely to ensure a high level of immunity in the population (herd immunity). Although live attenuated vaccine strains replicate in the vaccinee, they usually do not cause disease such as may occur with the “wild” form of the organism. When a live attenuated vaccine does cause symptoms, it is usually much milder than the natural disease. At times, active immunity from a live attenuated viral vaccine may not develop because of interference from previously acquired circulating antibody to the virus. Antibody from any source (eg, transplacental, transfusion) can interfere with replication of a live attenuated vaccine strain and lead to a poor immune response. Currently available live attenuated viral vaccines include MMR, varicella, zoster, and rotavirus. Oral polio vaccine is a live viral vaccine but is no longer available in the United States, having been replaced by an inactivated polio vaccine. Licensed live attenuated bacterial vaccines include oral typhoid vaccine, oral cholera vaccine, and bacillus Calmette-Guérin (BCG), a cutaneous vaccine against tuberculosis.

In contrast to the immune response to a live vaccine, the immune response to an inactivated vaccine is mostly humoral. Inactivated vaccines cannot replicate and therefore require multiple doses to stimulate a protective immune response. In general, the first dose primes the immune response but does not produce protective immunity. A protective immune response develops after the second or third dose. Antibody titers against inactivated antigens diminish with time. As a result, some inactivated vaccines require periodic supplemental doses to maintain protective antibody titers. The immune response to inactivated antigens is less affected by circulating antibody than that of live agents, so they may be given when antibody is present in the blood. Currently available whole-cell inactivated vaccines include the whole viral vaccines (polio, hepatitis A, and rabies). Inactivated whole virus influenza vaccine and whole inactivated bacterial vaccines (pertussis, typhoid, cholera, and plague) are no longer available in the United States.

Vaccines can also be composed of fractions of bacteria or viruses. Fractional vaccines can be either protein-based or polysaccharide-based. Protein-based vaccines include toxoids (inactivated bacterial toxin) and subunit or subvirion products. Fractional subunit vaccines include hepatitis B, influenza, acellular pertussis, and human papillomavirus (HPV). A subunit vaccine for Lyme disease is no longer available in the United States.

Polysaccharide-based vaccines are composed of pure cell wall polysaccharide from bacteria. Conjugated polysaccharide vaccines contain polysaccharide that is chemically linked to a protein. In the late 1980s, it was demonstrated that the limited immunogenicity associated with polysaccharide vaccines could be overcome through conjugation. Conjugation changes the immune response from T-cell independent to T-cell dependent, leading to increased immunogenicity in infants and antibody booster response to subsequent doses of vaccine. The first conjugated polysaccharide vaccine was Haemophilus influenzae type b (Hib), licensed in 1989. A conjugated vaccine for pneumococcal disease was first licensed in 2000. A meningococcal conjugated vaccine was licensed in 2005. A pure polysaccharide vaccine is still available for pneumococcus, but pure polysaccharide vaccines for Hib or meningococcus are no longer available in the United States.

As noted, vaccine antigens may be produced by genetic engineering. Some are recombinant vaccines: hepatitis B and HPV vaccines are produced by insertion of a segment of the respective viral gene into the gene of a yeast cell or an insect virus that infects a susceptible cell line. The modified yeast cell or insect cell line produces pure hepatitis B surface antigen or HPV capsid protein. Live attenuated influenza vaccine has been engineered to replicate more effectively in the cooler temperature of the mucosa of the nasopharynx and less well at the core temperature in the lungs. Live typhoid vaccine (Ty21a) consists of Salmonella typhi bacteria that were genetically modified to not cause illness.

VACCINE LICENSURE

Vaccines are licensed by the US Food and Drug Administration (FDA) based on results of clinical trials submitted by the manufacturer. Recommendations for use of these licensed vaccines are provided by the Advisory Committee on Immunization Practices (ACIP) of the CDC and representatives from participating committees including, the Committee on Infectious Disease (COID) of the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). The addition of new vaccines as well as changes to the existing national immunization schedules for both children and adults are based on numerous factors such as efficacy, safety, burden of disease that may be prevented, equity, compatibility with existing vaccines, and cost. Recommendations for the immunization of children and adolescents are updated annually, including catch-up schedules for children who start their immunizations late or who fall 1 month or more behind, and can be located at the CDC Web site (http://www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf).

VACCINE ADMINISTRATION

Recommendations from the CDC and from manufacturers regarding transport and storage, schedule, dose, route, and site of administration should be followed for each vaccine. Most routinely recommended childhood vaccines are administered intramuscularly or subcutaneously. Failure to administer a vaccine as recommended may result in decreased vaccine effectiveness or increased adverse effects.

In general, intramuscular injections are administered in the anterolateral thigh in infants and the deltoid muscle of older children and adolescents. For toddlers, either the anterolateral thigh or the deltoid may be used. The buttock should be avoided as a site of injection because of the potential for sciatic nerve damage and the presence of varied amounts of subcutaneous fat which impairs absorption. Changing needles after withdrawing a vaccine dose from a vial but before administration to a patient is not necessary, nor is pulling back on the vaccine plunger after insertion of the needle but before administration. The route of administration of injectable vaccines is determined in part by the presence of an adjuvant. Inactivated vaccines containing an adjuvant should be injected into a muscle because subcutaneous administration may cause local irritation, induration, skin discoloration, inflammation, or granuloma formation. Unlike intramuscular injections, subcutaneous injections are administered at a 45-degree angle to the skin. The preferred needle length will vary with age. Guidance for selection of proper needle length is available at http://www.immunize.org/catg.d/p3085.pdf.

When vaccines are administered according to the recommended schedule, a child may receive 3 or more injections in a single visit. The pain associated with the administration of immunizations may be a source of distress and anxiety for patients and their families. Parents can be coached to present a calm, matter-of-fact demeanor. They may be taught distraction techniques to minimize the discomfort experienced by their children. Sucrose water (12–50% or 1 packet of sugar in 10 mL of water) may decrease pain in children younger than 6 months when administered shortly before a procedure. When a child needs multiple injections at a single visit, simultaneous administration (multiple staff members injecting separate sites at the same time) is preferred to sequential administration (one after the other). Combination vaccines represent one solution to the issue of increased numbers of injections during single clinic visits and generally are preferred over separate injections of equivalent component vaccines. Combination vaccines can be administered instead of separately administered vaccines if licensed and indicated for the patient’s age. Considerations should include provider assessment, patient/guardian preference, and the potential for adverse events. Different vaccines should not be mixed in the same syringe unless specifically licensed for use in this manner. Partial doses of vaccines should never be administered, as this may result in decreased immunogenicity and inadequate protection.

Topical anesthetic agents applied to the skin may help to reduce the pain of an injection by blocking transmission of pain signals. EMLA (lidocaine 2.5%/prilocaine 2.5%) is approved by the FDA for patients greater than 37 weeks of gestational age and should be applied 60 minutes in advance of the injection. Lidocaine 4% is approved by the FDA for children older than 2 years and should be applied 30 minutes before the injection. Available data indicate no known adverse effect of topical anesthetics on the immune response. Evidence does not support the routine use of oral analgesics before or at the time of vaccination. Reduced immunogenicity of some vaccines may be associated with prophylactic use of acetaminophen. An oral analgesic may be used for treatment of fever and local discomfort following immunization. Studies of children with previous febrile seizures have not demonstrated antipyretics to be effective in the prevention of febrile seizures.

The timing and spacing of vaccine doses are 2 of the most important issues in the appropriate use of vaccines. All age appropriate vaccines can be administered at the same visit, with rare exceptions. In those with functional or anatomic asplenia, the Menactra (Sanofi Pasteur) meningococcal conjugate vaccine should not be given until at least 4 weeks after all doses of pneumococcal conjugate vaccine (PCV13) have been administered. PCV13 and pneumococcal polysaccharide vaccine (PPSV23) should be separated by at least 8 weeks. Live MMR and varicella vaccines, if not administered on the same day, should be separated by at least 4 weeks. Otherwise, in order to facilitate completion of the vaccine schedule and minimize the period during which a child is susceptible to vaccine-preventable disease, all vaccines for which a child is eligible at a given visit should be administered.

There are no minimum intervals between doses of different inactivated vaccines or between administration of live parenteral or oral vaccines and any other vaccine. Likewise, there are no maximum intervals between doses of routinely recommended vaccines. When there is a lapse in the administration of sequential doses of vaccines in a given series, the series need not be restarted but may simply be continued. There is no increase in risk of an adverse event from immunizing an individual who already has had the disease.

There are minimum ages for the administration of all routinely recommended vaccines except hepatitis B vaccine. Likewise, there are minimum intervals between the doses of the same vaccine. Because vaccine administration before the recommended age or interval can result in decreased immunogenicity, doses administered more than 4 days early (“grace period”) should not be considered valid doses and should be repeated at the appropriate interval.

Antibody-containing products, including whole blood, packed red blood cells, plasma, hyperimmune globulin, and intravenous immune globulin, can interfere with the immune response to some live viral vaccines. Measles and varicella vaccines must be deferred for a minimum of 3 or more months after the receipt of an antibody-containing product. The interval varies with the amount of antigen-specific antibody in the product received (Table 239-1).

ADVERSE EVENTS

All vaccines undergo rigorous safety testing before licensure. However, no vaccine is completely risk free. The value of a given vaccine depends on the prevalence and severity of the disease targeted, the vaccine’s ability to prevent or modify disease, and the incidence and severity of vaccine-related morbidity. Although most adverse events after vaccination are minor and self-limited, some vaccines have been associated with rare but serious side effects.

A vaccine adverse event refers to any medical event that occurs following vaccination. An adverse event could be a true adverse reaction or just a coincidental event, with further research needed to distinguish between them. Acute vaccine adverse reactions fall into 3 general categories: local, systemic, and allergic. The most common type of adverse reactions are local reactions, such as pain, swelling, and redness at the site of injection. Local reactions may occur with up to 80% of vaccine doses, depending on the type of vaccine. Local adverse reactions generally occur within a few hours of the injection and are usually mild and self-limited. On rare occasions, local reactions may be exaggerated or severe. Systemic adverse reactions may occur following receipt of live attenuated vaccines. Live attenuated vaccines must replicate in order to produce immunity. The adverse reactions that follow live attenuated vaccines, such as fever or rash, represent symptoms produced from viral replication and are similar to a mild form of the natural disease. Systemic adverse reactions following live vaccines occur 3 to 21 days after the vaccine is administered (ie, after an incubation period of the vaccine virus). The third type of acute vaccine adverse reactions is allergic reactions. Allergic reactions may be caused by the vaccine antigen itself or some other component of the vaccine, such as cell culture material, stabilizer, preservative, or antibiotic used to inhibit bacterial growth. Severe allergic reactions (anaphylaxis) occur at a rate of 1 case per 1–2 million doses administered.

Thimerosal is a mercury-containing organic compound used for decades in the United States and other countries as a preservative in vaccines and other biologic products. Thimerosal prevents contamination of multidose vials, primarily by bacteria and fungi, during repeated entry of the vial. In humans, thimerosal is metabolized to ethyl mercury and thiosalicylate. Ethyl mercury is cleared quickly via excretion in stool without an opportunity to accumulate to harmful levels. In contrast, methyl mercury is formed in the environment when mercury metal is metabolized by bacteria. Consumption of fish is a common source of methyl mercury. Methyl mercury is not cleared from the body quickly, thereby allowing the chemical to reach neurotoxic levels. Ethyl mercury has not been associated with the neurotoxic effects seen with methyl mercury accumulation. Despite the absence of evidence of harm, in 1999, the AAP and the US Public Health Service recommended removal of thimerosal from vaccines. By 2001, thimerosal was removed or reduced to trace amounts in all vaccines routinely recommended for children 6 years of age or younger in the United States. In January 2003, the last vaccine containing thimerosal as a preservative expired. Thimerosal is present in some multidose vials of influenza vaccine.

CONTRAINDICATIONS AND PRECAUTIONS

Contraindications and precautions to vaccination generally dictate circumstances when vaccines should not be given. Many contraindications and precautions are temporary, and the vaccine can be given at a later time. A contraindication is a condition that increases the likelihood of a serious adverse reaction to a vaccine for a patient with that condition. Administration of the vaccine could result in harm to the recipient. For instance, administering MMR vaccine to a person with a true anaphylactic allergy to gelatin could cause serious illness or death in the recipient. In general, vaccines should not be administered when a contraindication condition is present. A precaution is a condition in a recipient that might increase the chance or severity of a serious adverse reaction or that might compromise the ability of the vaccine to produce immunity (such as administering measles vaccine to a person with passive immunity to measles from a blood transfusion). The chance of injury or adverse event is less than with a contraindication. In general, vaccines are deferred when a precaution condition is present. However, situations may arise when the benefit of protection from the vaccine outweighs the risk of an adverse reaction, and a provider may decide to give the vaccine. Contraindications and precautions for routinely used vaccines are available at http://www.bhsj.org/Clinic/immz/contraindications-guide-508.pdf.

Any clinically significant adverse event that occurs after the administration of any vaccine licensed in the United States should be reported to the Vaccine Adverse Event Reporting System (VAERS). Providers should report a clinically significant adverse event even if they are unsure whether a vaccine caused the event. Questions regarding VAERS are addressed at the VAERS Web site at https://vaers.hhs.gov/index.

In the United States, the National Vaccine Injury Compensation Program (VICP) was created by the National Childhood Vaccine Injury Act (NCVIA) of 1986. A no-fault alternative to civil litigation, the VICP was created to adjudicate vaccine injury claims and compensate individuals found to be injured by certain vaccines. Claimants alleging injury from vaccines must file with the VICP before pursuing any legal action against vaccine manufacturers or healthcare providers. They are not required to prove negligence by the manufacturer or healthcare provider in order to receive compensation. Rather, settlements are based on a Vaccine Injury Table (available at http://www.hrsa.gov/vaccinecompensation/vaccineinjurytable.pdf), which summarizes adverse events associated with vaccines. The Vaccine Injury Table is updated by a panel of experts as new research on vaccine adverse events becomes available. VICP settlements are funded by an excise tax on each covered vaccine.

The VICP has reduced legal claims against manufacturers and healthcare providers, helped ensure national vaccine supplies, and stabilized vaccine costs. Providers who administer covered vaccines in both the public and private sectors have specific responsibilities defined by the NCVIA. For example, patients and/or their parents or guardians must be informed of the risks and benefits of vaccines. A current version of the Vaccine Information Statement (VIS) for each covered vaccine must be provided each time the vaccine is administered (available at http://www.cdc.gov/vaccines/hcp/vis/current-vis.html). Providers must also document key components of the vaccination process, including the date of administration, the manufacturer, the lot number, the VIS version date, and the date the VIS was given.

PARENTAL REFUSAL

Concerns about vaccine safety have eroded parental confidence in immunizations, leading to antivaccine movements in some countries and occasionally a resurgence of vaccine-preventable diseases due to the lack of immunization. Increasingly, pediatric healthcare providers encounter families who refuse 1 or more immunizations for their children. The AAP Committee on Bioethics has published guidance for pediatricians faced with vaccine refusal. Despite education of parents about the effectiveness of vaccines and the low chance of vaccine-associated adverse events, some parents will decline to have their children vaccinated. This often results from families misinterpreting or misunderstanding information presented by the media and on unmonitored and biased Web sites, causing substantial and often unrealistic fears. Providing parents with an opportunity to ask questions about their concerns regarding recommended childhood immunizations, attempting to understand parents’ reasons for refusing 1 or more vaccines, and maintaining a supportive relationship with the family are all part of a good risk management strategy. Physicians are encouraged to explain what is known about the risks and benefits of vaccines, helping parents consider the risks of a given vaccine with the risks of remaining unimmunized.

Continued parental refusal of vaccines should be respected unless a child faces serious harm, as might be the case during an outbreak. However, communication about vaccines should continue at each subsequent healthcare visit. To facilitate the process of informed refusal, the AAP has developed a refusal waiver (https://www.aap.org/en-us/Documents/immunization_refusaltovaccinate.pdf). This “Refusal to Vaccinate” form outlines potential risks of vaccine refusal, including severe illness, death, and the transmission of disease to others. It is suggested that this information be reviewed with the parent and a signature obtained at each medical encounter. This form is not a legal document, however, and should not be presumed to provide immunity from liability if a patient develops a vaccine-preventable disease or transmits a vaccine-preventable disease to others. The AAP encourages physicians to attempt to avoid discharging families who refuse vaccines from their practice unless a “significant level of distrust develops” or there are “significant differences in the philosophy of care.”

DIPHTHERIA–TETANUS–ACELLULAR PERTUSSIS VACCINES

Routine childhood immunization has virtually eliminated once-common diseases such as diphtheria and tetanus and significantly reduced cases of pertussis. Although cases of pertussis have been on the rise for the past 2 decades, the 20,762 reported cases in 2015 reflect a significant decrease from the more than 200,000 cases reported annually in the 1930s. Pertussis is one of the few vaccine-preventable disease that is not at record low levels.

Diphtheria–tetanus–whole cell pertussis (DTwP) vaccines were introduced in the 1940s. These vaccines combined diphtheria and tetanus toxoids (toxin from Corynebacterium diphtheriae and Clostridium tetani treated with formaldehyde) with a suspension of whole cell, inactivated Bordetella pertussis. Although effective in reducing disease, these vaccines were associated with local and systemic reactions. Febrile seizures, for example, were observed in 6 to 9 per 100,000 vaccinees, usually on the day of immunization. Rare systemic reactions included inconsolable crying lasting 3 hours or longer (up to 3%), fever ≥ 104.9°F (0.3%), and an unusual, high-pitched cry (0.1%). Hypotonic-hyporesponsive episodes were observed in 1 in 1750 immunizations.

Since the 1990s, because of less reactogenicity than with DTwP vaccines, only diphtheria–tetanus–acellular pertussis (DTaP) vaccines have been used. They contain diphtheria and tetanus toxoids combined with 3 or more purified B pertussis antigens. Licensed DTaP vaccines and combination vaccines that include DTaP all contain pertussis toxin (PT), a cell wall protein that promotes attachment to respiratory epithelial cells, and filamentous hemagglutinin (FHA). Pertactin (PRN) and fimbrial proteins (FIM) are included in some DTaP vaccines. DTaP and DTaP-containing vaccine products and their pertussis antigen components are listed in Table 239-2. Two pediatric acellular pertussis vaccines are currently available for use in the United States. Both vaccines are combined with diphtheria and tetanus toxoids as DTaP and are approved for children 6 weeks through 6 years of age (until the 7th birthday).

In 2002, the FDA approved Pediarix (GlaxoSmithKline), the first pentavalent (5-component) combination vaccine licensed in the United States. Pediarix contains DTaP (Infanrix), hepatitis B (Engerix-B), and inactivated polio vaccine (IPV). Pentacel (Sanofi-Pasteur) is a combination vaccine that contains lyophilized Hib (ActHIB) vaccine and is reconstituted with a liquid DTaP-IPV solution. Pentacel is licensed by the FDA for doses 1 through 4 of the DTaP series among children 6 weeks through 4 years of age. Kinrix (GlaxoSmithKline) is a combination vaccine that contains DTaP and IPV. Kinrix is licensed only for the fifth dose of DTaP and fourth dose of IPV in children 4 through 6 years of age whose previous DTaP vaccine doses have been with Infanrix and/or Pediarix for the first 3 doses and Infanrix for the fourth dose.

Despite differences in antigen content, licensed DTaP vaccines are considered equally effective, although estimates of effectiveness vary. More than 95% of infants develop protective antibody against diphtheria after 4 doses of vaccine, and clinical effectiveness is estimated at 97%. Essentially 100% of vaccinated infants develop protective antibody against tetanus. There are no widely accepted serologic correlates of protection for pertussis, but point estimates of clinical effectiveness range from 80% to 85%.

Children ages 2 months to 6 years should receive 5 doses of DTaP vaccine. Each 0.5-mL dose is administered intramuscularly. The primary series consists of 4 doses typically given at ages 2 months, 4 months, 6 months, and 15 to 18 months, although the first dose may be given as early as age 6 weeks. The minimum interval between each of the first 3 doses is 4 weeks. The fourth dose must be given at least 6 months after the third, and not before age 12 months. The fifth dose of DTaP is not necessary if the fourth dose is administered at 4 years or older. When feasible, the same brand of DTaP vaccine should be used for all doses in the immunization series. If the brand of DTaP vaccine used previously is not available or is not known, any brand may be used. Adverse reactions—both mild and severe—are significantly less common with DTaP vaccines than with DTwP vaccines. Mild reactions include injection site reactions such as redness, tenderness, and swelling; fever < 101°F (2–7%); and irritability (12–30%). Swelling of an entire limb has been reported in children receiving 4 or 5 doses of DTaP vaccine. The swelling resolves without sequelae and does not preclude further doses of vaccine.

Until 2005, no pertussis-containing vaccines were licensed for use in individuals older than 7 years of age. Immunity from pediatric DTwP/DTaP vaccines wanes after approximately 5 to 10 years, leaving adolescents susceptible to infection. Although the majority of deaths from pertussis occur among babies younger than 3 months of age, they acquire the infection from contacts, often adolescents. In 2005, 2 different tetanus–diphtheria–acellular pertussis (Tdap) vaccines were licensed for use in adolescents. One product, licensed for persons 10 years and older (Boostrix [GlaxoSmithKline]) contains 3 different pertussis antigens and is similar to the infant product Infanrix but with reduced quantities of antigen. A second product (Adacel [Sanofi Pasteur]) is licensed for adolescents and adults ages 10 through 64 years and, like the infant product Daptacel, contains 5 different pertussis antigens. However, Adacel contains less diphtheria toxoid and detoxified pertussis toxin than Daptacel.

Both Tdap vaccines result in immune responses to tetanus and diphtheria similar to those observed after immunization with tetanus-diphtheria (Td) vaccine. Immunity to pertussis antigens is similar to that observed in infants following 3 doses of the respective DTaP vaccine.

A single dose of Tdap vaccine is recommended for all adolescents at age 11 to 12, replacing the previously recommended Td booster. A dose of 0.5 mL is given intramuscularly. Tdap may be administered to adolescents whether or not they completed a childhood immunization series with DTwP or DTaP. Those not immunized at age 11 or 12 may be immunized later. Adolescents who received a dose of Td at age 11 or 12 may be subsequently immunized with Tdap in order to provide protection against pertussis. Tdap can be administered regardless of the interval since the last tetanus- or diphtheria toxoid–containing vaccine. A single lifetime dose of Tdap is recommended except during pregnancy when a repeat dose is recommended during each pregnancy, as the immunity provided by Tdap vaccines is short lived. Booster vaccination of a pregnant woman and subsequent transplacental antibody may protect her infant during the first few months of life when most at risk of serious complications from pertussis including death.

Local injection site reactions may occur after Tdap vaccination. Pain at the injection site occurs in 75% of vaccinees; 20% to 30% experience some redness and swelling. Headache and fatigue are the most frequent systemic side effects. Precautions and contraindications can be found at http://www.bhsj.org/Clinic/immz/contraindications-guide-508.pdf.

POLIO VACCINES

Polio incidence reached a peak in the United States in 1952, with more than 21,000 paralytic cases annually. Following introduction of effective vaccines, polio incidence declined rapidly. The last case of wild-virus polio acquired in the United States was in 1979. Global polio eradication possibly may be achieved within the next decade.

Both live attenuated and inactivated poliovirus vaccines (IPVs) are used worldwide. In the United States, IPV was licensed in 1955 and was used extensively from that time until the early 1960s. In 1963, trivalent live attenuated oral poliovirus vaccine (OPV) was licensed. Trivalent OPV was the vaccine of choice in the United States and most other countries after its introduction in 1963. Advantages of OPV include the stimulation of intestinal as well as systemic immunity. In addition, fecal shedding of the vaccine strains occurs for several weeks after immunization, leading to indirect immunization of contacts. Rarely, however, OPV causes paralytic disease in vaccine recipients or their contacts. Between 1980 and 1996, an average of 8 cases of vaccine-associated paralytic polio (VAPP) were reported annually in the United States. In an effort to eliminate VAPP, exclusive use of IPV vaccine in the United States was recommended in 2000. An enhanced-potency IPV was licensed in 1987. It contains formaldehyde-inactivated poliovirus types 1, 2, and 3 and 2-phenoxyethanol as a preservative. The vaccine is immunogenic, with at least 90% of vaccinees developing protective antibody after 2 doses and 99% after 3 doses. IPV is also available as part of combination vaccines.

All children in the United States should receive 4 doses of IPV. The primary series consists of 3 doses, with the first 2 doses administered at ages 2 and 4 months. The third dose is given at age 6 to 18 months. Children who receive 3 doses of IPV before their fourth birthday should receive a fourth dose at school entry (age 4–6). If the fourth dose is given before age 4, a fifth dose should be administered at 4 through 6 years and at least 6 months after the previous dose. Each 0.5-mL dose can be administered subcutaneously or intramuscularly.

Like other injectable vaccines, IPV causes minor local reactions such as pain and redness at the injection site. Allergic reactions attributed to trace amounts of streptomycin, neomycin, and polymyxin B in the vaccine have been reported. No serious adverse events have been attributed to IPV.

HEPATITIS B VACCINES

An estimated 850,000 to 2.2 million people in the United States are chronically infected with hepatitis B virus. Before immunization of infants with hepatitis B vaccine became routine, up to 30% to 40% of chronic infections were thought to have resulted from perinatal or early childhood transmission of the virus. Infants infected perinatally have a 90% risk of chronic infection, and up to 25% die of chronic liver disease as adults. Key components of a national immunization strategy to eliminate hepatitis B transmission via infant immunization are based on prevention of mother-to-infant transmission of hepatitis B and, importantly, subsequent prevention of acquisition of hepatitis B later in life associated with high-risk activities.

Two recombinant hepatitis B vaccines (Recombivax HB [Merck] and Engerix B [GlaxoSmithKline]) are licensed in the United States. Both vaccines contain hepatitis B surface antigen (HBsAg) protein synthesized in Saccharomyces cerevisiae (common baker’s yeast) and then purified and adsorbed onto aluminum hydroxide. Each is available in pediatric and adult formulations (Table 239-3). A combination vaccine for the prevention of hepatitis B infection in children consists of DTaP–hepatitis B–IPV (Pediarix [GlaxoSmithKline]). A combination hepatitis A–hepatitis B vaccine (Twinrix [GlaxoSmithKline]) is licensed only for use in adults age 18 or older. Hepatitis B vaccines are efficacious, inducing a protective antibody response in over 95% of infant recipients after 3 doses.

Three doses of hepatitis B vaccine are recommended for all infants. A dose of 0.5 mL is administered intramuscularly. Only monovalent hepatitis B vaccine is indicated and all newborn infants should receive the first of 3 doses within 24 hours of birth. Infants born to HBsAg-positive mothers should receive the vaccine within 12 hours of birth plus 0.5 mL of hepatitis immune globulin (HBIG) administered at a separate site. When a mother’s HBsAg is unknown, infants should receive hepatitis B vaccine within 12 hours of birth and HBIG no later than age 1 week if the mother is subsequently found to be HBsAg-positive. Either monovalent vaccine or a combination hepatitis B vaccine may be used to complete the series with subsequent doses given at age 1 to 2 months and 6 to 18 months (give at 6 months for those born to HBsAg-positive mothers). Monovalent vaccine may be administered as early as at birth, but the combination vaccine containing hepatitis B (DTaP-HepB-IPV) cannot be given before age 6 weeks. Some infants will receive 4 doses of hepatitis B vaccine (birth dose and 3 subsequent doses) when combination vaccine is used to complete the vaccine series.

Infants born to HBsAg-positive mothers should be tested for HBsAg and antibody to HBsAg sometime between 9 and 18 months, or between 1 and 2 months after completion of the series if the series was delayed. HBsAg-negative infants with nonprotective levels of anti-HBs (< 10 mIU/mL) should be reimmunized with 3 doses of hepatitis B vaccine. Serologic testing is not required for infants born to HBsAg-negative mothers.

Diminished immune responses have been noted in infants weighing less than 2000 g who receive hepatitis B vaccine before age 1 month. The immunization strategy for these infants depends on the HBsAg status of the mother. When the maternal HBsAg status is positive or unknown, hepatitis B vaccine is administered within 12 hours of birth, but this dose is not counted in the 3-dose series; routine 3-dose hepatitis B immunization should begin at 1 month of age. For infants weighing less than 2000 g born to HBsAg-negative mothers, the first dose of hepatitis B vaccine is postponed until age 1 month or hospital discharge.

Hepatitis B vaccination is contraindicated for persons with a history of hypersensitivity to yeast or any other vaccine component. Despite a theoretic risk for allergic reaction to vaccination in persons with allergy to S cerevisiae (baker’s yeast), no evidence exists to document adverse reactions after vaccination of persons with a history of yeast allergy. Persons with a history of serious adverse events (eg, anaphylaxis) after receipt of hepatitis B vaccine should not receive additional doses. As with other vaccines, vaccination of persons with moderate or severe acute illness, with or without fever, should be deferred until illness resolves.

HAEMOPHILUS INFLUENZAE TYPE B CONJUGATE VACCINES

Before licensure of vaccines for the prevention of Hib infection, 1 in 200 children developed invasive Hib disease (see Chapter 258). This organism was the most common cause of childhood meningitis in the United States and a frequent cause of other invasive diseases (eg, bacteremia, pneumonia, septic arthritis, facial cellulitis, epiglottitis). With universal childhood immunization, initially with polysaccharide Hib vaccine followed by the licensure of the conjugated vaccine in 1989, cases of invasive Hib disease decreased more than 99%.

Three single-antigen conjugate Hib vaccines are available in the United States (Hiberix, GlaxoSmithKline; ActHIB, Sanofi Pasteur; PedvaxHIB, Merck). All vaccines contain Hib capsular polysaccharide (PRP) conjugated to either tetanus toxoid (PRP-T: ActHIB, Hiberix) or an outer membrane protein (PRP-OMP) from Neisseria meningitidis serogroup B (PedvaxHIB). Two combination vaccines are available that contain conjugated Hib polysaccharide: Pentacel with DTaP and IPV; and MenHibRix with N meningitidis serotypes C and Y (also conjugated).

All Hib conjugate vaccines are highly immunogenic, inducing protective antibody against Hib polysaccharide in > 95% of children after a primary series. Effectiveness against invasive disease is estimated at 95% to 100%. However, PRP-OMP is unique in its ability to elicit high levels of antibody in young children with the first dose of vaccine. Therefore, a PRP-OMP–containing vaccine (PedvaxHIB) is preferred for children at high risk of invasive Hib disease, including American Indian and Alaskan Native children. Hib vaccines do not elicit protective antibody against the carrier protein and do not protect against non–type B strains of H influenzae, including nontypeable strains.

The schedule for Hib vaccine differs by the product used and the age at initiation of the series. The primary series of ActHIB or Hiberix consists of 3 doses of vaccine given at ages 2 months, 4 months, and 6 months. The primary series of PedvaxHIB consists of 2 doses given at ages 2 months and 4 months. The vaccines are considered interchangeable for the primary series, but when at least 1 dose of ActHIB or Hiberix is used, 3 doses are required. The first dose of the primary series should not be given to infants younger than age 6 weeks because of the risk of inducing immunologic tolerance against subsequent doses. A booster dose of Hib vaccine is given at age 12 to 15 months. For those not immunized during the first 6 months of life, catch-up schedules can be found in the recommendations of the AAP COID as published in the Red Book.

Generally, healthy children not immunized before age 59 months do not require immunization with Hib vaccine. However, previously unvaccinated individuals older than age 59 months who are at increased risk for invasive Hib disease, including those with functional or anatomic asplenia or human immunodeficiency virus (HIV) infection, should be given 1 dose of Hib vaccine. Recipients of hematopoietic stem cell transplant require 3 doses regardless of prior vaccine history. Adverse reactions following Hib conjugate vaccines are not common. Swelling, redness, or pain has been reported in 5% to 30% of recipients and usually resolves within 12 to 24 hours. Systemic reactions such as fever and irritability are infrequent. Serious reactions are rare.

PNEUMOCOCCAL CONJUGATE VACCINES

Streptococcus pneumoniae is a common cause of invasive and noninvasive infection in children worldwide. The organism colonizes the upper respiratory tract, and disease results from local spread (otitis media, sinusitis) or hematogenous dissemination (eg, bacteremia, pneumonia, meningitis). Before the licensure of a 7-valent pneumococcal conjugate vaccine (PCV7, Prevnar, Wyeth) in 2000, pneumococci accounted for 17,000 cases of invasive disease in the United States each year in children under age 5, including 500 deaths. The highest rates of disease were seen in children age 6 to 11 months and in Alaska Natives, African Americans, and specific American Indian populations. With universal immunization of young children, cases of invasive pneumococcal disease in children younger than age 5 decreased by 77%.

PCV7 contained purified capsular polysaccharide from S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, conjugated to CRM 197 (a nontoxic mutant of diphtheria toxin) and, in prelicensure trials involving approximately 40,000 children, was 97% effective in reducing invasive pneumococcal disease due to vaccine serotypes. However, serotypes not included in the vaccine (eg, 19A) then began to increase in incidence, so in 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) was licensed in the United States. PCV13 contains the 7 serotypes included in PCV7 plus serotypes 1, 3, 5, 6A, 7F, and 19A.

As with PCV7, a 4-dose series of PCV13 is recommended at ages 2, 4, 6, and 12 to 15 months of age. The 0.5-mL dose is administered intramuscularly. When initiation of the series is delayed, the total number of recommended doses depends on the age at the first dose of vaccine.

A 23-valent pneumococcal polysaccharide vaccine (PPSV23) is also licensed in the United States. This vaccine is used for those at least 2 years of age who are at high risk of invasive pneumococcal disease. When both vaccines are indicated, PCV13 should be administered first and PPSV23 should be given at least 8 weeks after the last dose of PCV13.

Local reactions (such as pain, swelling, or redness) following PCV13 occur in up to half of recipients. Approximately 8% of local reactions are considered to be severe (eg, tenderness that interferes with limb movement). Local reactions are generally more common with the fourth dose than with the first 3 doses. In clinical trials of pneumococcal conjugate vaccine, fever (> 100.4°F [38°C]) within 7 days of any dose of the primary series was reported for 24% to 35% of children. High fever was reported in less than 1% of vaccine recipients. Nonspecific symptoms such as decreased appetite or irritability were reported in up to 80% of recipients.

MEASLES, MUMPS, AND RUBELLA VACCINES

Since the licensure of an effective vaccine against measles, mumps, and rubella (MMR) in the 1960s, the incidences of measles, mumps, rubella, and congenital rubella syndrome have decreased more than 90%. Sporadic outbreaks of disease occur mostly among unvaccinated or incompletely vaccinated populations.

MMR vaccine (MMR II [Merck]) contains 3 live attenuated viruses. Vaccine strains of measles and mumps are grown in chick embryo cell culture; rubella is grown in human diploid cell culture. A combination measles, mumps, rubella, varicella vaccine (MMRV; ProQuad [Merck]) is also available. Each vaccine contains small quantities of neomycin to prevent bacterial overgrowth.

A single dose of MMR vaccine confers protection to measles and rubella in more than 95% of vaccine recipients age 12 months or older. Individuals who do not develop serologic evidence of immunity after the first dose of vaccine (primary vaccine failure) typically respond to the second dose. The duration of protective immunity is long lasting and probably lifelong. Postlicensure studies indicate that 1 dose of mumps or MMR vaccine is approximately 78% effective against disease caused by mumps virus. Two-dose mumps vaccine effectiveness is approximately 88%.

Two doses of MMR vaccine are recommended for all children. The dose is 0.5 mL and is administered subcutaneously. The first dose is administered at age 12 to 15 months, and the second dose at age 4 to 6 years. The second dose may be administered earlier as long as 4 weeks have elapsed since the first dose. During measles outbreaks or when the risk of exposure to measles is high because of travel outside the United States, children as young as age 6 months should receive the vaccine, but doses administered before age 12 months are not counted in the 2-dose series. These children should be revaccinated with 2 additional doses of MMR with the first dose administered at age 12 through 15 months. The persistence of maternal measles antibody in young infants may modify the immune response to the vaccine. MMRV may be used instead of separate injections of MMR and varicella in healthy children ≥ 12 months to 12 years.

MMR vaccine may be administered on the same day with any other live or inactivated childhood vaccines as long as the vaccines are given in separate syringes at separate sites. Injected live virus vaccines not given on the same day as MMR vaccine should be deferred for at least 4 weeks. Measles vaccination may temporarily suppress tuberculin skin test reactivity for 4 to 6 weeks after immunization but will not interfere with the accuracy of a test placed on the same day. MMR vaccine must be deferred for 3 or more months after the receipt of an antibody-containing product (including immune globulin, whole blood, packed red blood cells, and intravenous immune globulin) because passively transferred antibody interferes with the immune response (see Table 239-1). The interval varies with the amount of antigen-specific antibody in the product received.

Redness, induration, or soreness at the injection site may occur after MMR vaccine. Local hypersensitivity consisting of wheal-and-flare reactions or urticaria is occasionally seen. Fever and rash are the most common systemic side effects, with 5% to 15% of vaccinees developing a fever ≥ 39.4°C (103°F) 6 to 12 days after immunization (among seronegative vaccinees) and 5% developing a morbilliform rash. Higher rates of fever as well as a slight increase in febrile seizures have been reported with the first dose of combination MMRV vaccine in comparison to children who receive separate injections of MMR and varicella vaccines on the same day. For children age 12 to 23 months, the rate of febrile seizures after MMR vaccine is 4 cases per 10,000 vaccinations. In contrast, the rate of febrile seizures after MMRV vaccination is 9 per 10,000 vaccinations. Neither vaccine is associated with the development of chronic seizure disorders. The above should be discussed with parents, as should the benefit of receiving only a single injection when MMRV is used. When the first dose is given at ≥ 48 months of age or for dose 2 at 15 months to 12 years, MMRV is preferred over separate MMR and varicella vaccine injections. Transient thrombocytopenia occurring within 2 months of MMR immunization has been observed in less than 1 in 30,000 vaccinees and is presumably due to the measles component of the vaccine. Because of the risk of vaccine-induced thrombocytopenia, a history of thrombocytopenia is considered a precaution to MMR immunization. It should be noted, however, that the risk of thrombocytopenia with vaccination is less than that observed with natural measles infection. Arthralgias occur in up to 25% of adult women given rubella-containing vaccines, including MMR, but joint complaints in children are much less common. Although the measles and mumps viruses are grown in chick embryo cell culture, MMR does not contain significant quantities of cross-reacting egg protein (ovalbumin) to elicit an allergic reaction, and children with egg allergy may safely be vaccinated. Skin testing for egg allergy is not predictive of adverse reactions to vaccine and is not recommended.

Live virus vaccines including MMR are generally contraindicated in individuals known or suspected to be immunodeficient. However, HIV-infected children who are not severely immunocompromised (defined by age-specific quantitation of CD4 lymphocytes) should receive MMR because the risk associated with the vaccine is much less than that associated with wild-type measles infection. MMRV vaccine should not be used in place of MMR vaccine for immunization of HIV-infected children because the MMRV vaccine contains a higher concentration of varicella vaccine virus. Other precautions and contraindications can be found at http://www.bhsj.org/Clinic/immz/contraindications-guide-508.pdf.

In 1998, a connection between receipt of MMR vaccine and autism was postulated. This theory was based on a case series of 12 children, 8 of whom developed regressive neurologic symptoms 1 to 14 days after receipt of MMR vaccine. The paper published in The Lancet describing this association contained methodologic flaws and has subsequently been retracted by the journal. In addition, a number of well-controlled epidemiologic studies involving thousands of children have failed to find evidence that MMR causes autism. Both the AAP and the Institute of Medicine have concluded that there is no association between MMR vaccine and autism.

MMR is contraindicated in pregnant women because of a theoretical risk to the fetus. However, because the attenuated viruses in the MMR vaccine are not transmitted from person-to-person after immunization, household contacts of either pregnant women or immunosuppressed individuals can and should be immunized to prevent introducing natural virus into the household. Breastfeeding mothers immunized with rubella-containing vaccines may occasionally transmit rubella vaccine virus to their infants via breast milk. Because transmission results only in a mild rash illness and does not interfere with response to MMR vaccine administered at age 12 months, breastfeeding is not a contraindication to receipt of rubella-containing vaccines.

VARICELLA VACCINES

Before the licensure of varicella vaccine in 1995, approximately 4 million cases of chickenpox occurred annually in the United States. Although most infections were self-limited, secondary complications including pneumonia, encephalitis, and secondary bacterial infections (usually soft tissue infections) that occasionally were quite severe (eg, necrotizing fasciitis), resulted in more than 10,000 hospitalizations and 100 deaths each year.

Two live attenuated varicella-zoster virus–containing vaccines are available for use in children. A monovalent varicella vaccine (Varivax [Merck]) is licensed for children older than age 12 months, adolescents, and adults. A combination measles, mumps, rubella, varicella vaccine (ProQuad [Merck]) is approved for use in children ages 12 months to 12 years. Both vaccines contain live attenuated varicella-zoster virus (Oka strain), although the combination vaccine contains a higher concentration of varicella vaccine virus, with a minimum of 10,000 plaque-forming units (PFUs) compared to 1350 PFUs in the monovalent product. Both vaccines contain minute quantities of neomycin and gelatin.

A single dose of varicella vaccine is approximately 72% to 85% effective against varicella disease, with even higher protection against severe varicella disease. Because primary vaccine failure (failure to make protective antibodies) after 1 dose of varicella vaccine occurs and frequent school-based outbreaks of varicella have been observed in populations with high single-dose vaccination rates, 2 doses of varicella-containing vaccine are recommended for all children. Recipients of 2 doses of varicella vaccine are 3.3 times less likely to have breakthrough varicella compared to recipients of 1 dose (2.2% vs 7.3%; P < .001). Following the recommendation for 2 doses instead of 1 varicella vaccine dose, varicella cases declined 97% between 1995 and 2010 in areas of active surveillance.

The first dose is administered at age 12 to 15 months, and the second dose is generally administered at age 4 to 6 years, although it can be given as early as 3 months after the first dose (if inadvertently given between 28 days and 3 months after the first dose, the second dose need not be repeated). A dose of 0.5 mL is administered subcutaneously. Catch-up immunization is recommended for susceptible older children not previously immunized or those immunized with a single dose of vaccine.

Varicella vaccine is associated with few side effects. Approximately 20% of monovalent varicella vaccine recipients experience transient pain and tenderness at the site of injection. A mild varicelliform eruption develops at the injection site in 3% of children within 1 month of immunization, and 5% of children may develop a generalized rash. Transmission of the attenuated vaccine virus from immunocompetent individuals who develop a rash soon after vaccination to susceptible individuals has been reported but is extremely rare (1 case of transmission per 10 million doses).

Precautions and contraindications can be found at http://www.bhsj.org/Clinic/immz/contraindications-guide-508.pdf. Varicella-containing vaccines should not be administered to individuals with a history of anaphylactic reaction to neomycin or gelatin. Monovalent varicella vaccine does not contain egg protein and thus may be safely administered to individuals with egg allergy. Although the measles and mumps vaccine viruses in MMRV are grown in chicken-embryo cell culture, the amount of egg protein is not significant, and children with egg allergy may receive MMRV.

Specific recommendations have been published for immunization of individuals with altered immunity. Varicella-containing vaccines are not recommended for children receiving treatment for leukemia, lymphoma, or other malignancies affecting the bone marrow or lymphatic systems; children receiving long-term immunosuppressive therapy; or children with most congenital or acquired T-cell immunodeficiencies. Immunodeficiency should be excluded in children with a family history of hereditary immunodeficiency before a varicella-containing vaccine is administered. For individuals receiving high-dose systemic corticosteroids (≥ 2 mg/kg/d of prednisone or its equivalent or 20 mg/d of prednisone) for ≥ 14 days, immunization should be deferred with a minimum interval of 1 month between the last dose of steroids and subsequent vaccination. Monovalent varicella vaccine may be administered to children with certain humoral immune deficiencies and HIV-infected children defined by age specific CD4+ lymphocyte counts. Household contacts of immunocompromised hosts should be vaccinated to decrease the likelihood of introducing wild varicella into the household. However, those vaccinees who then develop rash should avoid contact with immunocompromised persons who are not immune to varicella for the duration of the rash.

Varicella vaccine is contraindicated in pregnant women, but children living in the same household may be vaccinated. Caution is advised when vaccinating children taking salicylates. No adverse events associated with salicylate use and varicella vaccine have been reported. However, the manufacturer recommends that salicylates be avoided for 6 weeks after vaccine administration because of the well-established relationship between Reye syndrome and use of salicylates during natural varicella infection. According to the ACIP, varicella vaccine with subsequent close monitoring should be considered for children requiring chronic salicylate therapy because the risk of aspirin-associated complications is likely to be greater with natural varicella infection.

HEPATITIS A VACCINES

Before the implementation of a targeted hepatitis A immunization program in the United States, there were 180,000 infections reported annually, resulting in approximately 100 deaths (see Chapter 303). The highest incidence of infection occurred in children ages 5 to 14 years. Children younger than age 6 years frequently developed asymptomatic (anicteric) infection and were a source of transmission of the virus to others. Native Americans, Alaska Natives, and Hispanics were at increased risk for disease.

National recommendations for hepatitis A immunization have evolved from a targeted strategy focused on groups of individuals at increased risk for infection to one that includes universal immunization of infants. Beginning in 1996, routine hepatitis A immunization was recommended for children age 2 years or older living in communities with high rates of hepatitis A infection or periodic outbreaks, namely children living in Alaska Native villages or Native Americans. In 1999, the recommendations were expanded to include children ages 2 to 18 years living in states, counties, or communities with annual hepatitis A infection rates that were at least twice the national average or ≥ 20 cases per 100,000 population. Locales with hepatitis A infection rates of at least 10 cases per 100,000 population were encouraged to “consider” immunization of children ages 2 to 18 years.

In 2005, hepatitis A vaccine was licensed for children as young as age 12 months, and the CDC amended recommendations to include all children beginning at 1 year of age, regardless of state of residence. Two doses of hepatitis A vaccine are currently recommended for all children in the second year of life, with at least 6 months between doses. Anyone aged 2 to 18 years old and not previously immunized may be vaccinated if immunity against hepatitis A is desired. States, counties, and communities with existing programs for immunization of children ages 2 to 18 are encouraged to maintain these programs.

Two hepatitis A vaccines are currently licensed for use in children age 12 months or older (Havrix [GlaxoSmithKline] and Vaqta [Merck]). Both contain whole hepatitis A virus propagated in human fibroblasts, formalin-inactivated and adsorbed to aluminum hydroxide adjuvant. More than 95% of children and adults will have protective antibody 4 weeks after the first dose, and nearly 100% seroconvert after a second dose. A combination hepatitis A–hepatitis B vaccine (Twinrix [GlaxoSmithKline]) is licensed for use in those age 18 years or older. A dose of 0.5 mL is administered intramuscularly. Although administration of the same hepatitis A vaccine is preferable for both doses, either single-antigen hepatitis A vaccine may be used to complete the series, regardless of what product was given for the first dose. Local injection site reactions, including erythema, swelling, and tenderness, occur in approximately 20% of children immunized with hepatitis A vaccine. These reactions are generally mild and resolve within 24 hours. Decreased appetite and fatigue occur less commonly. Serious adverse events have not been associated with hepatitis A vaccine. Contraindications and precautions are found at http://www.bhsj.org/Clinic/immz/contraindications-guide-508.pdf.

INFLUENZA VACCINES

Annual epidemics of influenza result in 50 million to 60 million infections, with the highest attack rates in school-age children. The risks for serious disease, hospitalization, and death from influenza are highest among children age 2 years and younger, adults age 65 and older, and individuals of any age with underlying medical conditions that place them at increased risk for complications from influenza (Table 239-4).

The effectiveness of influenza vaccines varies by vaccine type, the number of doses administered, the age and immune status of the vaccinee, and the match between circulating strains of influenza and those contained in the vaccine. Inactivated vaccines typically are protective in about 60% of healthy vaccinated people less than 65 years of age. The role of high dose or adjuvanted influenza vaccine in persons > 65 years of age is not yet determined.

Both live attenuated and inactivated influenza vaccines were used in previous years. A live attenuated influenza vaccine (LAIV) containing 2 influenza A viruses and 2 influenza B viruses previously was recommended for use in the United States. The viruses in this vaccine were reassortants that contained genes encoding for the surface proteins hemagglutinin and neuraminidase from circulating wild-type influenza viruses and genes from master influenza A and B viruses that confer cold adaption and temperature sensitivity. The vaccine strains were designed to replicate in the cooler temperature of the nasopharynx in order to simulate the route of infection by wild-type virus, but because of their temperature sensitivity, vaccine strains were designed not to replicate in the lower airway. The CDC and the AAP recommend that LAIV not be offered in any setting during the 2016 to 2017 and 2017 to 2018 seasons because of lack of effectiveness during the 3 prior influenza seasons.

The trivalent inactivated vaccine (IIV3) contains 2 inactivated influenza A viruses (types H1N1 and H3N2) and 1 influenza B virus. The quadrivalent inactivated vaccine (IIV4) contains 2 inactivated influenza A viruses and 2 influenza virus B strains representing each lineage. The composition of the vaccine changes annually based on circulating influenza types. Most vaccine strains are grown in chicken eggs and then inactivated by formaldehyde or β-propiolactone treatment. Organic solvents or detergents are then used to disrupt the viruses into viral subunits or subvirions. Other influenza vaccines are prepared using strains grown in continuous cell lines or using recombinant technology. In general, IIV vaccines are approved for use in individuals age 6 months or older, including those with underlying medical conditions. Unlike other vaccines routinely recommended for children, influenza vaccines contain thimerosal if a multidose vial is used.

Annual influenza immunization is recommended for all people 6 months of age and older (Table 239-5 lists schedules and doses). No influenza vaccine is licensed for use in children younger than 6 months; therefore, immunization of household and other close contacts is the preferred way to protect these children from influenza. Similarly, other groups at high risk of complications from influenza infection (and their close contacts) are especially targeted for influenza vaccination (see Table 239-4). Vaccination of pregnant women with IIV can protect them and their infant. Annual vaccination of healthcare workers should be mandatory. Inactivated influenza vaccines can be administered as soon as the vaccine is available in late summer or early fall.

Transient, local reactions, including tenderness, erythema, and induration at the injection site, occur in 15% to 20% of IIV3 vaccine recipients. Systemic reactions such as fever and myalgias occur in 1% or less. Hypersensitivity reactions including anaphylaxis are rare. Precautions and contraindications can be found at http://www.bhsj.org/Clinic/immz/contraindications-guide-508.pdf.

ROTAVIRUS VACCINES

In the prevaccine era in the United States, rotavirus gastroenteritis resulted in 55,000 to 70,000 hospitalizations annually with 20 to 60 deaths (see Chapter 231). Because of the effectiveness of the rotavirus vaccines, norovirus has replaced rotavirus as the most common cause of severe gastroenteritis in this country.

The first vaccine for the prevention of rotavirus gastroenteritis was licensed in the United States in 1998. However, this live attenuated tetravalent rhesus reassortant vaccine was withdrawn from the market in 1999 because a slight increase in risk of intussusception was noted in vaccine recipients, particularly after the first dose of vaccine.

Currently, 2 oral live attenuated rotavirus vaccines are licensed in the United States. A pentavalent rotavirus vaccine (RV5, RotaTeq [Merck]) contains 5 reassortant viruses derived from human and bovine rotavirus strains. A monovalent vaccine is also available (RV1, Rotarix [GlaxoSmithKline]). RV1 contains live attenuated human rotavirus. In clinical trials, RV5 demonstrated 74% efficacy against all rotavirus gastroenteritis and 98% efficacy against severe rotavirus gastroenteritis. RV1 performs similarly.

The schedule for rotavirus immunization depends on the product used. RV5 is administered as a 3-dose series for infants at age 2 months, 4 months, and 6 months. RV1 is administered as a 2-dose series with doses given at ages 2 months and 4 months. The first dose of either vaccine can be administered as early as age 6 weeks, but not later than age 14 weeks, 6 days. The minimum interval between vaccine doses is 4 weeks, and the last dose should be administered no later than age 8 months, 0 days. All doses in the series should be completed with the same product, but immunization should not be delayed if the product used for previous doses is unknown or not available. If any dose in the series is RV5 or an unknown product, 3 total doses should be given. Redosing is not indicated when an infant spits out or vomits the vaccine, and subsequent doses should be administered at recommended intervals.

In 2010, rotavirus vaccination was temporarily suspended because DNA sequences from porcine circovirus type 1 were found in vaccine lots. Subsequently, live porcine circovirus type 1 was identified in RV1, and porcine circoviruses types 1 and 2 were identified in RV5. The FDA ultimately determined that these viruses pose no risk to humans, and at present, both vaccines are available for administration.

Precautions and contraindications for rotavirus vaccine are available at http://www.bhsj.org/Clinic/immz/contraindications-guide-508.pdf. Altered immunocompetence should be considered a precaution to vaccine administration; however, severe combined immunodeficiency is a contraindication to immunization. Postmarketing studies have identified a minimal risk of intussusception after any available rotavirus vaccine. A history of intussusception is a contraindication to vaccination. Premature infants who are at least 6 weeks of age and clinically stable are eligible for immunization and should be vaccinated using the same schedule as term infants. The vaccine should be administered at or after discharge from the hospital nursery.

MENINGOCOCCAL VACCINES

In the United States in 2016, a total of 375 cases of invasive disease due to N meningitidis were reported. This is a historically low rate, and the reason for the falling rates of disease is not known. The highest rates of disease occur in children younger than age 1 year, but 62% of cases occur in individuals age 11 years or older. Rates of meningococcal disease due to serogroups A, C, W, and Y (included in the quadrivalent vaccines) among adolescents exceed those of the general population. Other individuals at increased risk of meningococcal disease include those with functional or anatomic asplenia and those with deficiencies of properdin and terminal complement components.

Two meningococcal conjugated vaccines are licensed for use in infants at increased risk of meningococcal infection: MenHibrix (GlaxoSmithKline), licensed for use at 6 weeks through 18 months of age; Menactra (Sanofi Pasteur), for 9 months through 55 years of age; and Menveo (Novartis), for 2 months through 55 years of age. These 2 meningococcal quadrivalent vaccines (MCV4s) are active against serogroups A, C, W, and Y: Menactra employs a diphtheria toxoid carrier protein, while Menveo contains a nontoxic mutant diphtheria toxin. These 2 vaccines are given intramuscularly. Like all protein conjugate vaccines, they elicit immune responses from T cells as well as B cells, resulting in some degree of immunologic memory.

Routine vaccination using MCV4 should be administered at 11 or 12 years of age with a booster dose at 16 years of age. Individuals 13 through 18 years of age who were not previously immunized should be immunized, and those receiving the first dose at 13 to 15 years of age should receive a booster dose at 16 to 18 years of age. College freshmen living in dormitories who have not previously received a dose of MCV4 should also be immunized. Those at least 2 months of age who are at increased risk for invasive meningococcal disease should be immunized with a meningococcal conjugate vaccine, but the different products are given at different schedules. Because vaccine-induced antibodies against N meningitidis wane over time, children initially vaccinated with MCV4 who remain at increased risk for meningococcal disease require revaccination. Local reactions, including redness, tenderness, and swelling at the injection site, are common after MCV4 administration but generally resolve within 1 to 2 days. Systemic reactions, including headache and malaise, are observed in up to 60% of vaccinees.

Two serogroup B meningococcal protein vaccines were recently licensed by the FDA. Although these vaccines are not recommended for routine use, the ACIP recommends vaccination of people age 10 years and older who are at increased risk for serogroup B meningococcal disease including: during outbreaks of serogroup B disease, those with functional or anatomic asplenia including those with sickle cell disease, those with persistent deficiencies in the complement pathway, persons receiving eculizumab, and microbiologists who routinely work with isolates of N meningitidis. The vaccines are administered in either a 2- or a 3-dose series. The efficacy of serogroup B meningococcal vaccines at disease prevention is unknown, as licensure was based on a serologic response using a presumed measure of immunity. Neither vaccine is expected to provide protection against all circulating serogroup B strains, and the duration of immunity is likely to be limited to a few years.

HUMAN PAPILLOMAVIRUS VACCINES

HPV is the most common sexually transmitted disease in the United States (see Chapter 228). Seventy-four percent of the 6.2 million new infections each year occur in individuals age 15 to 24 years. Although most infections are asymptomatic and self-limited, persistent infection may cause genital warts and, more worrisome, cancers of the anogenital region and cervix. Two HPV types, 16 and 18, account for 70% of all cases of cervical cancer.

The vaccine is composed of noninfectious virus-like particles (VLPs) prepared from recombinant L1 viral capsid protein are available in the United States. Previously, 2 vaccines were FDA-approved. A bivalent vaccine (2vHPV; Cervarix [GlaxoSmithKline]) including oncogenic HPV types 16 and 18, licensed for females 9 through 25 years of age, has been shown to be highly effective in preventing cervical cancer due to the HPV types contained in the vaccine. A quadrivalent vaccine (4vHPV; Gardasil [Merck]) contains types 6 and 11, which are common causes of genital warts, is licensed for males and females 9 through 26 years of age, and has been shown to protect against genital warts in males and females, as well as vaccine type cervical cancer and anal precancers in males. Neither vaccine is available in the United States. A 9-valent HPV vaccine (9vHPV; Gardasil 9, Merck) includes types 6, 11, 16, 18, 31, 33, 45, 52, and 58 and is currently available. 9vHPV is recommended for females 9 through 26 years of age and for males 9 through 21 years of age for prevention of vulvar, vaginal, cervical, and anal cancer and anogenital warts (condyloma acuminata), as well as precancerous and dysplastic lesions caused by serotypes contained in the vaccine. Males aged 22 through 26 years also may be vaccinated with 9vHPV.

Females and males age 11 or 12 years should be vaccinated with HPV vaccine routinely, although the series may be started as early as age 9 years. Each 0.5-mL dose is administered intramuscularly. If the first dose is administered before the 15th birthday, only 2 doses are necessary with the second dose 6 to 12 months after the first dose. If the series is begun on or after the 15th birthday, 3 doses are recommended with the second dose 1 to 2 months after the first dose and the third dose at least 6 months after the first dose. The HPV vaccine should be administered before the onset of sexual activity because the vaccine has no efficacy against an established infection, and HPV infection is acquired soon after sexual activity begins.

Local injection site reactions, including pain, swelling, and erythema, are common after vaccination with HPV vaccine but are generally mild. Systemic symptoms such as headache, fatigue, and myalgias are also observed. Because syncope may occur as with adolescents administered any vaccine, vaccine recipients should be observed sitting or lying down for 15 minutes following vaccination. Precautions and contraindications are available at http://www.bhsj.org/Clinic/immz/contraindications-guide-508.pdf.

SUGGESTED READINGS

INTRODUCTION

The deployment of antiviral therapy typically requires the clinician to strike a delicate balance between targeting virally encoded functions required for production of progeny viruses and avoiding toxicity to the host cellular functions subverted by the viral replication machinery. Accordingly, as a part of the trade-off for eliciting antiviral effect, many antivirals historically have induced considerable toxicity in the host cell as well. A watershed moment in the history of antiviral drug discovery was the development of the drug acyclovir, one of a series of drugs that was developed that blocked nucleic acid synthesis only in virally infected cells without damaging the uninfected host cells (because a viral enzyme, thymidine kinase, is required to phosphorylate the compound to its active form). This discovery resulted in the awarding of a Nobel Prize to Dr. Gertrude Elion in 1988.

Today, a number of effective antivirals currently are licensed and available, and are important in the management of infections caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), hepatitis B and C viruses, influenza A and B viruses, and human immunodeficiency virus (HIV). To maximize therapeutic effectiveness, treatment should generally be initiated as early as possible in the course of infection. Under some circumstances, antivirals may be effective in prophylaxis against acquisition or reactivation of infection. The advent and increased utilization of rapid-diagnosis molecular platforms for viral infections has enabled the more timely use of antiviral therapy in many clinical settings, so a working knowledge of available antivirals in pediatric practice is essential.

Although most early experience with antivirals in pediatric practice was accrued in the inpatient setting, structural and biochemical modifications of antiviral compounds have led to the development of many agents with excellent bioavailability after oral administration. Many of these drugs are now used extensively in the outpatient setting (Table 240-1). However, severe viral infections, especially in immunocompromised hosts, still require aggressive parenteral therapy, usually in the inpatient setting (Table 240-2).

HERPESVIRUSES

Herpes Simplex Virus and Varicella-Zoster Virus

Acyclovir is the most useful agent for the treatment of HSV and VZV infections. Acyclovir is a synthetic purine nucleoside analog that, as noted above, has specificity for the HSV thymidine kinase, which phosphorylates the drug to the monophosphate form. The drug is then further phosphorylated by host cell thymidine kinases to the triphosphate form, which inhibits viral DNA polymerase. This initial dependence upon a viral, not a cellular, enzyme is the basis for acyclovir’s selectivity and favorable safety profile. Acyclovir is most active against HSV-1 and HSV-2. It also has substantial activity against VZV but requires approximately 10-fold higher concentrations to inhibit replication of VZV compared to HSV. Typically in pediatric practice, acyclovir should be administered by parenteral or oral routes.

Acyclovir is available in oral formulations; however, less than 20% of an orally administered dose is absorbed. Therefore, oral administration is not appropriate for serious or life-threatening infections. Valacyclovir is the l-valyl ester of acyclovir, and after oral administration, it is rapidly converted to acyclovir by hepatic first-pass metabolism. Its bioavailability after oral administration exceeds 50%. Although valacyclovir has been used in adults for the treatment and suppression of genital herpes infections, there is currently no oral suspension available for children, and pediatric pharmacokinetic data are limited. Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500-mg capsules for use in pediatric patients for whom a solid dosage form is not appropriate (Table 240-1).

Alternatives to acyclovir for HSV infections include penciclovir, a nucleoside antiviral agent, and its oral diacetyl ester prodrug, famciclovir. Both drugs have the same spectrum of activity as acyclovir. Following oral administration, famciclovir is converted by the liver into the active drug, penciclovir. Its bioavailability is approximately 70%. Famciclovir has been used in the suppression of genital herpes. Penciclovir is available for topical use and is licensed by the US Food and Drug Administration (FDA) for herpetic gingivostomatitis but should not be used in neonates or young infants with mucocutaneous herpetic infections.

Other topical antivirals are available for HSV infection. These are occasionally used to treat keratoconjunctivitis caused by HSV and include trifluorothymidine, iododeoxyuridine, and vidarabine ophthalmic drops. Parenteral vidarabine was formerly used in the treatment of HSV encephalitis, but is no longer available in an intravenous formulation.

Acyclovir is safe and generally well tolerated, although patients should be monitored for potential side effects. Neurotoxicity (paresthesias and other neurologic symptoms such as tremor, ataxia, and hallucinations) can occur in patients receiving acyclovir, particularly in the setting of renal insufficiency. Doses should be adjusted for patients with impaired creatinine clearance. Serum creatinine should be monitored in patients treated with acyclovir, especially if more than 5 to 7 days of therapy is anticipated. Acyclovir therapy can induce neutropenia, particularly in the context of long-term suppressive therapy following neonatal HSV infection, but this side effect is reversible with dose reduction or discontinuation. Acyclovir also can cause gastrointestinal symptoms, including anorexia, nausea, vomiting, and diarrhea.

The decision to treat HSV-1, HSV-2, and VZV infections depends on whether the infection is primary or recurrent; the clinical presentation; and host factors, such as age and underlying conditions. Primary infections are more often treated than recurrent infections because of the absence of viral-specific immunity. Because neonates and other immunodeficient hosts infected with HSV or VZV can experience substantial morbidity and mortality, parenteral antiviral therapy for these patients is recommended.

The diagnosis of infection caused by HSV-1 or HSV-2 in neonates is an indication for intravenous antiviral therapy. The use of high-dose intravenous acyclovir (60 mg/kg/day) is indicated for all clinical presentations of neonatal HSV infection (Chapters 225 and 304). Further, following such parenteral therapy, 6 months of oral suppressive treatment has been shown to improve outcomes. Intravenous acyclovir is also indicated for HSV encephalitis at any age and regardless of immune status. Antiviral therapy also is indicated for immunocompromised children with primary HSV-1 or HSV-2 infection. Although the risk of life-threatening dissemination is low even among severely immunocompromised patients, severe local symptoms can persist for 2 weeks or longer.

Acyclovir also can be considered for treatment of serious HSV infections in other patients in whom the indications are less well established. Examples of such patients include otherwise healthy children with severe herpetic gingivostomatitis and children with eczema herpeticum. If the patient is hospitalized, intravenous acyclovir may be used, but if the patient is not, oral therapy may be appropriate. Acyclovir in the oral capsule formulation is FDA-approved for treating primary and recurrent genital HSV virus infection, usually caused by HSV-2. The recommended dosage for adults and adolescents is 200 mg 5 times per day. Sexually active teenagers or sexually abused children may present with this infection and should be treated if the clinical symptoms are significant and the child is able to take capsules. Severe primary genital HSV, particularly in pregnant women, should be treated with intravenous acyclovir.

HSV isolates resistant to acyclovir, on the basis of mutations in the viral thymidine kinase or viral DNA polymerase genes, have been reported. Although these isolates have demonstrated diminished virulence in animal models, they have been associated with progressive mucosal infections in immunocompromised hosts. Alternative antiviral agents to consider for the therapy of patients infected with acyclovir-resistant isolates include foscarnet and cidofovir (Table 240-2). Foscarnet is an inorganic pyrophosphate analog that has activity against all human herpesviruses. It is only available in an intravenous formulation. Side effects of foscarnet include nephrotoxicity and electrolyte disturbances, including symptomatic derangements of both calcium and phosphate. Cidofovir is an acyclic phosphonate nucleotide analog that does not require viral thymidine kinase to convert it to its active form. Therefore, it is well suited to treat viruses that are resistant to acyclovir due to alterations in viral thymidine kinase. Cidofovir has a very long half-life because it accumulates intracellularly; it can be given once per week. Cidofovir therapy is associated with significant nephrotoxicity. Co-administration with probenecid and pre-hydration with crystalloid can ameliorate nephrotoxicity. Experience with these agents in pediatric patients is limited.

Acyclovir has good activity in vitro against VZV, but its use in acute varicella should be limited to patients at high risk for severe disease, such as children older than age 12 or immunocompromised individuals. If acyclovir is administered within 24 hours of the onset of rash, a more rapid decrease in fever and a modest reduction in the total number of lesions can be expected. Acyclovir also is effective in the treatment of reactivated VZV (herpes zoster, shingles). For immunocompromised patients with herpes zoster who have a high risk of dissemination, high-dose intravenous acyclovir should be administered. In healthy individuals with herpes zoster, treatment with oral acyclovir can decrease acute pain but may not have an impact on the development of postherpetic neuralgia. Oral valacyclovir or famciclovir is approved for the treatment of herpes zoster in adults, but no pediatric recommendations are available for this indication.

Cytomegalovirus

Ganciclovir was the first effective antiviral agent available for the treatment of infections due to CMV. Ganciclovir is an acyclic analog of the nucleoside guanosine, which is phosphorylated by a CMV-specific viral kinase, the UL97 gene product. It is subsequently triphosphorylated by host kinases. The triphosphate form of the drug has high affinity for CMV DNA polymerase and can inhibit viral replication. Ganciclovir has been used extensively in bone marrow and solid organ transplant recipients in prophylactic, preemptive, and treatment regimens. It also has been shown to be effective in the treatment of CMV retinitis in patients infected with HIV. In addition, ganciclovir has been demonstrated to be of benefit in newborns with symptomatic congenital CMV infection, improving both audiologic and neurodevelopmental outcomes. Ganciclovir has very poor oral bioavailability and should only be administered intravenously. Valganciclovir, the l-valine ester of ganciclovir, has excellent bioavailability after oral administration and has been used to prevent CMV disease in transplant patients, and to treat symptomatic congenital CMV infection in which 6 months of therapy has been shown to improve outcomes.

The main side effects of ganciclovir include myelosuppression (primarily neutropenia and, to a lesser extent, anemia and thrombocytopenia) and nephrotoxicity. Therefore, blood counts and serum creatinine should be monitored during treatment. Liver function tests should also be monitored in infants on long-term therapy for symptomatic congenital CMV infection. Because viral shedding in urine and oropharyngeal secretions is common in the context of CMV infection, care should be taken by the clinician to consider the goals of antiviral therapy, and not commence ganciclovir or valganciclovir therapy solely in response to a positive laboratory test for CMV. CMV isolates that are resistant to ganciclovir (most commonly because of mutations in the UL97 phosphotransferase) have been described. Infection due to CMV isolates that are resistant to ganciclovir can be treated with either foscarnet or cidofovir.

INFLUENZA VIRUSES

Although influenza vaccination remains the best strategy to reduce morbidity and mortality attributable to influenza virus infection, antiviral drugs are also effective for both prophylaxis and treatment. Two main classes of antivirals are available—adamantanes and neuraminidase inhibitors.

Amantadine and rimantadine are the two adamantanes that historically have been used for both prevention and treatment of influenza A virus infections. The mechanism of action of these drugs involves binding to the M2 ion channel, preventing acidification of host endosomes, a step that is essential for virus uncoating. Unfortunately, because of the high prevalence of resistance among circulating strains of influenza A virus, the use of adamantanes is no longer generally recommended.

The neuraminidase inhibitors, oseltamivir, zanamivir, and peramivir, are active against both influenza A and B viruses and act by inhibiting the release of the newly formed influenza virus from host cells. Oseltamivir or zanamivir, given to household contacts of influenza-infected individuals as prophylaxis, has been shown to reduce the incidence of proven influenza infections by 68% to 89%. Treatment with either drug, if initiated within 2 days of onset of symptoms, has been shown to shorten the duration of fever and other symptoms by 1 to 2 days. Oseltamivir may be used in children older than 2 weeks for treatment and older than 3 months as prophylaxis. Further, treatment with these drugs has been shown to improve the outcome in those severely ill (and should be given to all hospitalized for influenza) and those at risk for severe illness, which includes all children under 2 years of age. See Table 240-1 for dosing. For further recommendations for the use of these drugs for treatment or prophylaxis of high-risk people and their contacts, see the Centers for Disease Control and Prevention (CDC) Web site.

Oseltamivir is available as a suspension or tablet. Nausea and vomiting are the most common side effects. Zanamivir is administered by aerosol and its primary side effects include bronchospasm. It is approved for treatment of influenza in children 7 years and older, and for prophylaxis in children 5 years and older (Table 240-1). Peramivir is an intravenous neuraminidase inhibitor. It is not FDA-approved for use in children, but case reports have described its use in critically ill patients with influenza who have deteriorated following enterally administered oseltamivir therapy or those unable to tolerate enteral therapy. Resistant viruses have been identified, but they are not widespread.

RESPIRATORY SYNCYTIAL VIRUS

Primary respiratory syncytial virus (RSV) infection often causes pneumonia or bronchiolitis, which can be particularly severe in children with chronic lung disease, congenital heart disease, or immunodeficiency, and in infants younger than 6 weeks. Recommendations for the use of the RSV-specific monoclonal antibody, palivizumab, for prophylaxis against RSV infection in high-risk infants are revised periodically by the American Academy of Pediatrics (AAP).

Ribavirin is a nucleoside analog that inhibits a wide spectrum of RNA and DNA viruses including RSV. It is approved by the FDA for administration as an aerosol to treat lower respiratory tract infections caused by RSV. Because the improvement associated with ribavirin use in studies has been limited to a small increase in oxygen saturation; because it must be given by aerosol, which causes concern about exposure of healthcare workers and pregnant women to ribavirin; and because of its high cost, the AAP suggests that therapy with ribavirin be considered for use in selected patients with documented, potentially life-threatening RSV infection.

HEPATITIS B AND HEPATITIS C VIRUSES

Currently, seven antiviral agents have been approved by the FDA for treatment of adults with chronic hepatitis B infection. These agents, categorized as either interferons (IFN-α2b and pegylated interferon-α2a/α2b) or nucleoside or nucleotide analogues (eg, lamivudine, adefovir, entecavir, tenofovir, telbivudine), are used as monotherapy or in combination. Lamivudine is now considered the first-line therapy in adults, eclipsing interferon. Experience with and indications for antiviral therapy for chronic hepatitis B infection in children are limited. IFN-α, lamivudine, and adefovir were the first drugs approved for treatment of chronic hepatitis B infection in children, but success is widely variable. In September 2012, tenofovir was FDA-approved for children 12 years or older weighing over 35 kg with chronic hepatitis B infection. More recently, entecavir was approved for use in children 2 years and older with chronic hepatitis B infection and evidence of active viral replication and disease activity, and, with IFN-α, entecavir is emerging as a first-line antiviral regimen for children with chronic hepatitis B infection who are candidates for antiviral therapy.

For chronic hepatitis C infection, IFN-α therapy combined with oral ribavirin has been shown to be effective and is the only approved therapy for use in children (approved for children older than 3 years). The main adverse effects seen are an influenza-like illness, which usually resolves with continued therapy; neuropsychiatric problems, occurring in 10% to 20% of patients; and bone marrow suppression. Until recently, only IFN-α and ribavirin were approved by the FDA to treat adults and children with chronic hepatitis C infection. The recent development of novel and highly effective antivirals for hepatitis C virus has revolutionized the care of adults, but unfortunately these drugs are not yet licensed for pediatric use. Novel drugs include ledipasvir, sofosbuvir, daclatasvir, elbasvir, beclabuvir, grazoprevir, paritaprevir, ombitasvir, velpatasvir, and dasabuvir. Ledipasvir, ombitasvir, daclatasvir, elbasvir, and velpatasvir inhibit the virally encoded phosphoprotein, NS5A, which is involved in viral replication, assembly, and secretion, while sofosbuvir is metabolized to a uridine triphosphate mimic, which functions as an RNA chain terminator when incorporated into the nascent RNA by the NS5B polymerase enzyme. Dasabuvir and beclabuvir are also NS5B inhibitors. Paritaprevir and grazoprevir inhibit the nonstructural protein 3 (NS3/4) serine protease, a viral nonstructural protein that is the 70 kDa cleavage product of the hepatitis C virus polyprotein. It is hoped that these compounds will soon be licensed for pediatric use.

SUGGESTED READINGS

INTRODUCTION

Antibacterial therapy in infants and children presents many unique challenges not faced in other clinical specialties. A major problem is the paucity of pediatric data regarding efficacy, pharmacokinetics, and optimal dosages; pediatric recommendations are therefore often extrapolated from studies in adults. Age-appropriate antibiotic dosing and toxicities must also be considered, taking into account the developmental status and physiology of children. The clinician must consider important differences among various age groups with respect to the pathogenic bacterial species responsible for pediatric infections. Specific antibiotic therapy is optimally driven by a microbiologic diagnosis, predicated on isolation of the pathogenic organism from a normally sterile body site, and supported by antimicrobial susceptibility testing. Given the inherent difficulties that can arise in collecting specimens from pediatric patients and given the increased risk of serious bacterial infection in young infants, much of pediatric infectious diseases practice is based on clinical diagnosis with empirical use of antibacterial agents before or even without eventual identification of the specific pathogen.

Several key considerations must be incorporated in decisions about the appropriate empirical use of antibacterial agents in infants and children. Recommendations for therapy often are dictated by the clinical syndrome and/or anatomic site of infection and the age of the child (Table 241-1). This information affects the choice of antimicrobial agent(s) and also the dose, dosing interval, route of administration (oral vs parenteral), and degree of urgency. The vaccination history may reflect reduced risk for some invasive infections but not necessarily elimination of risk of them. The risk of serious bacterial infection in pediatrics is also affected by the child’s immunologic status, which may be compromised by immaturity (neonates), underlying disease (immunodeficiency), or treatment of underlying diseases with chemotherapy (malignancy) or immune modulators (rheumatologic disease). Infections in immunocompromised children often result from bacteria that are not considered pathogenic in immunocompetent children. The possibility of central nervous system (CNS) involvement must be considered in pediatric patients, because some bacteremic infections in childhood carry a significant risk for hematogenous spread to the CNS including Haemophilus influenzae type b, pneumococcus, and meningococcus.

Potential causative pathogens being empirically treated and patterns of antimicrobial resistance in the community must also be considered. Resistance to penicillins and cephalosporins (Table 241-2) is common among strains of Streptococcus pneumoniae and Staphylococcus aureus (ie, methicillin-resistant S aureus [MRSA]), often necessitating the use of other classes of antibiotics.

Although empirical broad-spectrum antibiotics are often employed in pediatric practice, empiricism must be balanced against the risk of potentiating selection of resistant microorganisms. Overuse of antibiotics is a major contributing factor to antimicrobial resistance, and the indiscriminate use of antibiotics alters the drug-resistance patterns of isolates not only from the individual being treated but also the community in general. Particular care should be taken not to treat viral diseases with antibiotics. Although overuse of antibiotics is often driven by the sincere desire to help patients, antibiotics do carry a significant risk, including side effects.

GENERAL PRINCIPALS OF ANTIBIOTIC THERAPY

ANTIBIOTIC SELECTION

The decision to prescribe an antibiotic is generally based on proof or strong suspicion that the patient has a bacterial infection. In the febrile neonate or in the critically ill patient in whom there is some chance that bacterial infection may be a contributing factor, it is prudent to administer antibiotics effective against the most likely pathogens. If more than 1 antibiotic is active against the most likely pathogen(s), the antimicrobial agents should be chosen on the basis of relative toxicity and other factors. An important tenet of the use of antibiotic therapy is that once the pathogen is identified, the antibiotic with the narrowest spectrum of activity, lowest cost, and most convenient administration should be used.

Age- and Risk-Specific Use of Antibiotics in Children

Neonates

The causative pathogens of neonatal infections are typically acquired around the time of delivery from the maternal birth canal. Thus, empirical antibiotic selection must take into account the importance of these pathogens in neonates. Among the causes of neonatal sepsis in infants, group B Streptococcus (GBS) is the most common, although intrapartum antibiotic prophylaxis has greatly decreased the incidence of neonatal disease due to this agent. Gram-negative enteric organisms, in particular Escherichia coli, are other common causes of neonatal sepsis. Although rare, Listeria monocytogenes is also an important pathogen, insofar as it is intrinsically resistant to cephalosporin antibiotics, which are often used as empirical therapy in young children. All of these organisms can be associated with meningitis in the neonate; therefore, lumbar puncture should always be considered in the setting of bacteremic infections in this age group, and, if meningitis cannot be excluded, antibiotic management should include agents capable of crossing the blood-brain barrier.

Older Children

Antibiotic choices in toddlers and young children were once driven by the high risk of this age group for invasive disease caused by H influenzae type b, but since the advent of conjugate vaccines, invasive disease due to this agent has declined dramatically. It is still appropriate to consider the use of antimicrobials that are active against this pathogen, particularly if meningitis is a consideration. The unfortunate refusal by some parents to accept immunizations in their children means that these agents must continue to be considered in the differential diagnosis of serious bacterial infections especially if vaccine compliance cannot be assured. Particularly important pathogens to be considered in this age group include S pneumoniae, Neisseria meningitidis, and S aureus. Antimicrobial resistance is commonly exhibited by S pneumoniae and S aureus. Strains of S pneumoniae that are resistant to penicillin and cephalosporin antibiotics are frequently encountered in clinical practice. Similarly, MRSA is highly prevalent in many regions. Resistance of S pneumoniae and that of MRSA is due to mutations that confer alterations in penicillin-binding proteins (PBPs), the molecular targets of penicillins and cephalosporins (see Table 241-2).

Depending on the specific clinical diagnosis, other pathogens that are commonly encountered include Moraxella catarrhalis, nontypeable strains of H influenzae, and Mycoplasma pneumoniae, which cause respiratory tract infections including pneumonia; group A Streptococcus (GAS), which causes pharyngitis, skin and soft tissue infections, osteomyelitis, septic arthritis, and, rarely, bacteremia with toxic shock syndrome; Kingella kingae, which causes bone and joint infections in young children; Salmonella, which causes enteritis, bacteremia, osteomyelitis, and septic arthritis; and viridans streptococci and Enterococcus, which cause endocarditis. This complexity underscores the importance of formulation of a clear clinical diagnosis, including an assessment of the severity of the infection, in concert with knowledge of local susceptibility patterns in the community.

Immunocompromised and Hospitalized Patients

It is important to consider the risks associated with immunocompromising conditions (eg, malignancy, solid organ or hematopoietic stem cell transplantation) and the risks conferred by conditions leading to prolonged hospitalization (eg, intensive care, trauma, burns). Immunocompromised children are predisposed to develop a wide range of bacterial, viral, fungal, or parasitic infections. Prolonged hospitalization can lead to nosocomial infections, often associated with indwelling lines and catheters and commonly caused by gram-negative enteric organisms. In addition to the usual bacterial pathogens, Pseudomonas aeruginosa and enteric organisms, including E coli, Klebsiella pneumoniae, Enterobacter, and Serratia, are important considerations as opportunistic pathogens in these settings.

Selection of appropriate antimicrobials is challenging because of the diverse causes and scope of antimicrobial resistance exhibited by these organisms. Many strains of enteric organisms have resistance due to extended-spectrum β-lactamases (ESBLs). P aeruginosa encodes proteins that function as efflux pumps to eliminate multiple classes of antimicrobials from the cytoplasm or periplasmic space. In addition to these gram-negative pathogens, infections caused by Enterococcus faecalis and Enterococcus faecium are inherently difficult to treat. These organisms may cause urinary tract infection or infective endocarditis in immunocompetent children and may be responsible for a variety of syndromes in immunocompromised patients, especially in the setting of prolonged intensive care. The emergence of infections caused by vancomycin-resistant Enterococcus (VRE) has further complicated antimicrobial selection in high-risk patients and has necessitated the development of newer antimicrobials that target these highly resistant gram-positive infections. Although experience with many of these newer agents in the management of complex hospitalized pediatric patients is limited, they are important agents to be aware of.

A special situation affecting antibiotic use is the presence of an indwelling medical device, such as a venous catheter, ventriculoperitoneal shunt, stent, or other catheter. In these patients, in addition to S aureus, coagulase-negative staphylococci are also a major consideration. Coagulase-negative staphylococci seldom cause serious disease without a predisposing risk factor such as an indwelling medical device. Empirical antibiotic regimens must take this risk into consideration. In addition to appropriate antibiotic therapy, removal or replacement of the colonized prosthetic material is commonly required for cure.

ROUTE OF ADMINISTRATION

The route chosen for the administration of antibiotics depends on a number of factors, including the severity of infection, pharmacokinetics, logistics of administration, and anticipated patient compliance. In some situations, intramuscular administration of antibiotics is appropriate. These situations include settings where parenteral administration of a long-acting agent, such as ceftriaxone, is desirable (eg, in the emergency department where a child is not ill enough to justify hospital admission).

A common practice, particularly for pediatric bone and joint infections, is to commence therapy by an intravenous route and then transition to oral therapy for completion of the treatment course. A number of prerequisites are desirable. The child should be demonstrating a positive clinical response with improvement on intravenous therapy, and a downward trend should be noted in elevated acute-phase reactants such as C-reactive protein, erythrocyte sedimentation rate, serum procalcitonin, or platelet count. Importantly, parental compliance must be assured. Oral antibiotic therapy, resulting in decreased costs and reduction of the risks attendant to maintenance of an indwelling venous catheter for long-term treatment of infections, is underused and should be considered if the above criteria can largely be met.

DURATION OF THERAPY

With only rare exception, the duration of antibiotic administration recommended for specific infections is often based on uncontrolled experience, not on controlled trials. Guidelines concerning the duration of therapy for common pediatric infections are provided in this chapter. Clinicians should not commit patients to a rigid duration of therapy when the infection is initially identified; rather, therapy should be guided by clinical and laboratory response rather than by an arbitrary number of days.

Clinical monitoring usually involves sequential physical examinations with special reference to body temperature and the site originally infected. Fever and signs of inflammation should resolve within several days after appropriate antibiotics are initiated. Laboratory monitoring may include repeat bacterial cultures (eg, blood) to ensure sterilization, and for severe infections, it may be useful to monitor the peripheral white blood cell count and acute-phase reactants. Serial imaging studies may be valuable in some situations. An important principle to bear in mind is that the persistence of fever is not necessarily indicative of “antibiotic failure.” Some infections (eg, pyelonephritis or empyema) are characterized by persistence of fever even in the setting of successful therapy. Unrelenting fever beyond that expected for the illness in question, lack of anticipated clinical improvement, a lack of sustained improvement in laboratory markers, and continued culture positivity from the focus of infection are appropriate reasons to consider changes in antibiotic therapy. In some settings, persistence of fever can indicate a focus of infection that may require surgical drainage.

CLASSIFICATION OF ANTIBIOTICS

Antibiotics typically target unique gene products important in bacterial physiology and replication that fundamentally differ from those found in human cells. Four of the most common sites of antibacterial action that provide the molecular basis for antimicrobial therapeutics are: (1) inhibition of the synthesis of the bacterial cell wall; (2) inhibition of nucleic acid replication; (3) inhibition of protein synthesis; and (4) interference with folate metabolism (Table 241-3). The mechanism of action of an antibiotic impacts whether that agent is “bacteriostatic” (prevents the growth of the organism or maintains it in a stationary phase of growth) or “bactericidal” (kills the bacteria). Cell wall–active agents (eg, the penicillins, cephalosporins, carbapenems) are typically bactericidal, since disruption of cell wall integrity rapidly leads to lysis of the organism.

ANTIBIOTIC RESISTANCE

The development of microbial drug resistance results from the widespread use of the growing array of antimicrobial agents, coupled with the ability of bacteria to acquire and spread resistance in addition to the capacity of humans to spread bacteria. There are, unfortunately, a large number of mechanisms by which bacteria develop resistance to antibiotics. Recent years have seen the emergence of ESBLs, β-lactamases that hydrolyze extended-spectrum cephalosporins that have an oxyimino side chain. Agents that are subject to hydrolysis include cefotaxime, ceftriaxone, and ceftazidime, as well as the oxyimino-monobactam agent aztreonam. ESBLs are frequently encoded by plasmids carrying genes encoding resistance to other drug classes, including aminoglycosides. Therefore, antibiotic options in the treatment of ESBL-producing organisms are sparse but generally include carbapenems. Another emerging class of resistant organisms in the United States demonstrates resistance mediated by the K pneumoniae carbapenemases (KPCs). These organisms are resistant to all β-lactam, cephalosporin, and carbapenem antibiotics, and reconsideration (and use) of agents developed many decades ago and not used for a long time until recently, such as colistin, needs to be considered in some cases.

Table 241-2 lists several of the resistance mechanisms relevant to β-lactam antibiotics. These include the production of enzymes that inactivate or modify the antibiotic, mutations that lead to decreased antibiotic uptake or an active efflux system, and alterations in molecular targets of antibiotic activity. Mechanisms differ across different species of bacteria, and this knowledge in turn impacts clinical decision making. For example, a bacterial strain that is resistant based on β-lactamase production may be treated with an antibiotic combined with a β-lactamase inhibitor, such as ampicillin-sulbactam. A bacteria that is resistant to β-lactamase based on modified PBPs (eg, S pneumoniae), on the other hand, will be impervious to treatment with a β-lactam/β-lactamase inhibitor combination.

SPECIFIC ANTIBIOTICS

Table 241-4 provides a summary of currently licensed antibiotics in the United States that may be useful in clinical practice. For some agents, data on drug dosage in children are limited.

PENICILLINS

Penicillin G is the “natural” or “native” penicillin; all other penicillins are semisynthetic compounds. The basic structure of penicillin consists of a 6-aminopenicillanic acid (6-APA) nucleus. A variety of side chains have been added to penicillin to produce the semisynthetic penicillins. The 6-APA nucleus has a thiazolidine ring connected to a β-lactam ring. The integrity of the β-lactam ring is necessary for antibacterial activity. Hence, organisms that produce β-lactamases, which break the ring configuration, render the drug inactive.

The penicillins are divided into 3 groups on the basis of their antibacterial spectrum as detailed in the following discussion.

Narrow-Spectrum, β-Lactamase–Sensitive Penicillins

The prototype of this group is penicillin G. Penicillin G is active against GAS, GBS, and many other streptococci, most Neisseria species, some Gram-negative anaerobes, and Treponema pallidum. Penicillin G is not active against most gram-negative aerobic organisms. Bacteria sensitive to penicillin generally have a minimal inhibitory concentration (MIC) less than 0.05 mg/L.

A 100,000-IU/kg dose of penicillin G (1 IU = 0.6 μg) administered intravenously results in serum concentrations in excess of 10 mg/L, 200-fold higher than the MIC of most sensitive bacteria. This antibiotic also diffuses widely, attaining therapeutic concentrations in most body tissues. For example, up to 25% of serum concentrations are attained in the cerebrospinal fluid (CSF) during the treatment of bacterial meningitis. The terminal half-life (t_1/2) of penicillin G is less than 1 hour, and penicillin G is eliminated primarily by renal tubular secretion. This secretion can be inhibited by co-administration of probenecid. Because renal dysfunction will compromise the elimination of penicillin, dosages may need to be reduced in patients with renal insufficiency. This is necessary only in the most severe renal insufficiency owing to the low toxicity of penicillin.

Penicillin V, the phenoxymethyl analog of penicillin G, is much more stable than is its parent compound and therefore better absorbed from the gastrointestinal tract. A 250-mg dose of this preparation results in concentrations roughly equivalent to those attained after twice the dose of orally administered penicillin G. Procaine penicillin is a commonly used intramuscular preparation that produces low (3 mg/L) concentrations of drug sustained over several days. It is best suited to the single-dose outpatient treatment of very sensitive organisms. Benzathine penicillin is another preparation given intramuscularly. Serum concentrations of less than 0.1 mg/L, sustained for as long as 3 to 4 weeks, are attained with this formulation. It is used to prevent recurrent GAS infections in patients with rheumatic fever when compliance with oral therapy may be an issue.

Broad-Spectrum, β-Lactamase–Sensitive Penicillins

Aminopenicillins

Examples of aminopenicillins include (parenteral) ampicillin and (oral) amoxicillin. The activity of the aminopenicillins against most gram-positive bacteria is similar to that of penicillin. Aminopenicillins are, however, more active than penicillin against enterococci, L monocytogenes, and non-β-lactamase–producing H influenzae. They also are active against some E coli, Shigella, Salmonella, and indole-negative Proteus species. Amoxicillin is a drug of choice for the treatment of acute otitis media. It is also available in a formulation combined with the β-lactamase inhibitor clavulanate, which is also recommended for treatment of otitis media and sinusitis. Similarly, ampicillin is available in combination with the β-lactamase inhibitor sulbactam.

The serum concentration of ampicillin after a 1-g intravenous dose is approximately 40 mg/L; after a 500-mg dose taken orally, it is approximately 4 mg/L. Concentrations of amoxicillin are usually twice those of ampicillin after an equivalent oral dose. The distribution, t_1/2, and excretion characteristics of the aminopenicillins are similar to those of penicillin.

Ureidopenicillins

Ureidopenicillins include piperacillin, azlocillin, and mezlocillin. These antibiotics have a broader spectrum of gram-negative activity than do the aminopenicillins and include activity against most strains of P aeruginosa. The usual MICs of P aeruginosa range from 12 to 25 mg/L, with piperacillin consistently being the most active agent. Maximum serum concentrations of these agents are usually in excess of 150 mg/L after a 3- to 5-g parenteral dose. These antibiotics are used almost exclusively in the treatment of urinary tract, lung, and bloodstream infections caused by ampicillin-resistant enteric gram-negative pathogens. Piperacillin is also available combined with the β-lactamase inhibitor tazobactam in a proprietary formulation to enhance activity against β-lactamase–producing bacteria.

β-Lactamase–Resistant Penicillins

These penicillins include parenteral agents (methicillin, nafcillin, and oxacillin) and oral agents (cloxacillin, dicloxacillin, and flucloxacillin). The principal bacteriologic advantage of this group of antibiotics is their activity against β-lactamase–producing staphylococci. Most isolates of methicillin-sensitive S aureus have MICs of 0.25 to 0.5 mg/L. These antibiotics are less active than penicillin G against other gram-positive bacteria, and they are inactive against gram-negative enteric organisms and anaerobes. Maximum serum concentrations after a 1-g intravenous dose of methicillin, nafcillin, or oxacillin range from 20 to 40 mg/L, whereas after a 500-mg oral dose of cloxacillin, they range from 4 to 8 mg/L. Dicloxacillin and flucloxacillin have enhanced absorption after oral administration. Thus, serum concentrations of these agents are twice those of cloxacillin after an equivalent oral dose. This group of penicillins is used almost exclusively for the treatment of mild, moderate, and severe infections caused by methicillin-sensitive S aureus, including cellulitis, pyomyositis, septic arthritis, osteomyelitis, pneumonia, and septicemia.

Toxicity of Penicillins

The adverse reactions of all penicillins are similar. In general, these agents are well tolerated; however, suspension formulations tend to have an unpleasant taste and aftertaste and, as a result, may be poorly accepted. All penicillins have a wide toxic-to-therapeutic ratio, although they can cause hypersensitivity reactions, neurotoxicity, nephrotoxicity, and hematologic toxicity.

Hypersensitivity reactions are relatively common and include rashes, serum sickness, anaphylaxis, nephritis, and drug fever. Urticarial skin reactions and anaphylaxis, which occur within 20 to 30 minutes after a dose, are termed immediate reactions. These are the most dangerous reactions and constitute absolute contraindications to future treatment with a penicillin derivative. Fortunately, the incidence of anaphylaxis is only 0.01% to 0.02% of individual courses of therapy.

Nonurticarial skin eruptions that occur several days after the initiation of a course of penicillin are relatively common. Many such eruptions represent the rash of a viral infection for which an antibiotic has been inappropriately prescribed. Patients manifesting these sorts of reactions should not be labeled “penicillin-allergic.”

Convulsions and other forms of CNS irritation may occur when high doses of a penicillin have been administered, particularly to patients with compromised renal function. Such reactions are also more likely when high CSF concentrations of drug are attained, such as in patients with meningeal inflammation.

Interstitial nephritis can occur during therapy with any penicillin, although it is most frequently associated with the administration of methicillin. Hypokalemia is another side effect of high-dose penicillin therapy.

Coombs-positive hemolytic anemia may occur with any of the penicillins, as may neutropenia. Neutropenia is most common among patients receiving a β-lactamase–resistant penicillin and usually resolves when the antibiotic is stopped. Decreased platelet aggregation, which may precipitate bleeding, has been noted at high concentrations of most penicillins.

In addition to the reactions noted above, which are common to all of the penicillins, ampicillin or amoxicillin can cause a characteristic nonurticarial maculopapular rash that does not appear to have an allergic etiology. This rash usually appears 3 to 4 days after the onset of therapy and is classically described with ampicillin when given during intercurrent infectious mononucleosis.

CEPHALOSPORINS

The cephalosporins are currently divided into 5 “generations,” with original agents being referred to as first-generation cephalosporins and the most recent agents being fourth or fifth generation (Table 241-5). In general, the spectrum of activity of the cephalosporins increases with each generation (ie, enhanced activity against many gram-negative organisms). Cephalosporins should not be used to treat infections due to L monocytogenes or Enterococcus.

These agents may also be useful in patients who are intolerant to penicillins. Although cephalosporins and penicillins share the β-lactam ring structure, the true incidence of cross-reactivity to cephalosporins in skin test–confirmed penicillin-allergic patients is less than 5%. Cephalosporins should not be administered to patients with a history of immunoglobulin (Ig) E–mediated hypersensitivity reactions to penicillins, as similar reactions to cephalosporins may be observed.

First-Generation Cephalosporins

These cephalosporins are active against most staphylococci (excluding MRSA), pneumococci, and streptococci. MICs against sensitive gram-positive organisms are usually less than 0.5 mg/L. Their activity against aerobic gram-negative bacteria and against anaerobes is limited. Maximum serum concentrations after a 500-mg dose of oral cephalexin are approximately 20 mg/L, whereas they are 100 mg/L after 1-g intravenous doses of cefazolin. These antibiotics distribute widely throughout the body but do not penetrate well into CSF. Therefore, they must not be used to treat meningitis. Their t_1/2 ranges from 30 minutes to 1.5 hours, and they are eliminated unchanged in the urine. Doses may need adjustment in the presence of renal insufficiency, although these agents have a wide toxic-to-therapeutic ratio.

The first-generation cephalosporins are rarely drugs of first choice, although they are useful in outpatient management of skin and soft tissue infection not due to MRSA. Liquid suspensions are more palatable than those prepared for dicloxacillin or clindamycin, which has implications for compliance in young children. These antibiotics are useful in the perioperative prophylaxis of surgical procedures that carry a high risk of postoperative infections caused by staphylococcal species, such as those involving the cardiovascular system and bones.

Second-Generation Cephalosporins

These cephalosporins have a broader bacteriologic spectrum than do the first-generation agents. For example, cefuroxime is not only more active against gram-negative enteric bacteria but is active against both β-lactamase-negative and -positive strains of H influenzae, generally at concentrations below 2 mg/L. The major bacteriologic advantage of the cephamycins cefoxitin and cefotetan is their activity against a broad range of anaerobic pathogens, with most anaerobes being inhibited by less than 16 mg/L. Maximum serum concentrations of cefuroxime and cefoxitin after a 1-g intravenous dose are approximately 100 mg/L. The half-lives of the second-generation agents are similar to those of the first-generation agents. Also, like the first-generation, excretion of second-generation cephalosporins is primarily renal, and they distribute widely but do not attain sufficient concentrations in CSF to warrant their use in the treatment of bacterial meningitis.

Second-generation cephalosporins, like the first-generation agents, are rarely drugs of first choice. Cefuroxime, available in intravenous and oral forms, has been actively promoted because of its activity as a good agent for the treatment of a variety of infections in children, including cellulitis, osteomyelitis, septic arthritis, and pneumonia. The most common use of cefuroxime is in respiratory tract infections and occasionally in acute otitis media and sinusitis. Cefoxitin and cefotetan are effective agents in the prevention and treatment of intra-abdominal or pelvic infections.

Third-Generation Cephalosporins

Third-generation cephalosporins retain much of the gram-positive activity of the first 2 generations, although their antistaphylococcal activity is reduced 5- to 10-fold. They are remarkably active against most gram-negative enteric isolates, with MICs usually less than 0.5 mg/L. Ceftazidime is also active against most isolates of P aeruginosa. Maximum serum concentrations of the third-generation agents range from 50 to 150 mg/L after a 1-g intravenous dose. In healthy subjects, their half-lives range from 1 hour (cefotaxime) to between 6 and 8 hours (ceftriaxone). These antibiotics diffuse well into most tissues. Cefotaxime and ceftriaxone, in particular, penetrate well into the CSF, and they are approved by the Food and Drug Administration (FDA) for the therapy of bacterial meningitis in children. Excretion of these agents is primarily renal.

Settings in which third-generation cephalosporins are recommended include empiric therapy of suspected bacterial meningitis, pyelonephritis, and suspected infections in certain immunocompromised hosts. Ceftriaxone also is the drug of choice for infections caused by N gonorrhoeae.

Although these antibiotics show excellent activity against a wide variety of Enterobacteriaceae, their widespread use has led to the development of antibiotic resistance. Bacteria containing plasmid-encoded ESBLs are considered resistant to all cephalosporins and have rapidly spread over the past decades, especially among strains of E coli and K pneumoniae. Although their prevalence has been low in US pediatric populations, clinicians should continue to be judicious in their use of third-generation cephalosporins. All microbiology laboratories should screen Enterobacteriaceae for the presence of ESBL.

Ceftriaxone is eliminated by both renal and biliary clearance. It can cause biliary sludging. It can precipitate if used together with calcium, leading to severe reactions. The FDA specifies that ceftriaxone should not be mixed with calcium-containing products and that ceftriaxone and calcium should not be administered in the same or different infusion lines or sites in any patient within 48 hours of each other. This can be problematic in children requiring total parenteral nutrition. Due to its high level of protein binding with subsequent displacement of bilirubin, ceftriaxone should not be used in neonates with hyperbilirubinemia, due to the theoretical risk of kernicterus.

Ceftazidime/avibactam was approved by the FDA in 2015. This antibiotic is a fixed-dose combination drug containing ceftazidime and a novel non-β-lactam β-lactamase inhibitor avibactam. Current indications include complicated intra-abdominal infections and complicated urinary tract infections. It may also be useful for the treatment of infection due to KPCs. Pediatric experience is limited.

Fourth-Generation Cephalosporins

This generation of cephalosporins combines the antistaphylococcal activity (excluding MRSA) of first-generation agents with enhanced gram-negative spectrum compared with third-generation cephalosporins. Currently, cefepime is the only available fourth-generation cephalosporin in the United States. Cefepime has excellent activity against multidrug-resistant gram-negative bacteria including P aeruginosa, as well as bacteria that produce the AmpC-inducible β-lactamase. Use might include therapy of infections suspected or proved to be caused by multidrug-resistant pathogens or in treating infections in immunocompromised hosts at risk of infections caused by Pseudomonas species and other multidrug-resistant gram-negative rods (eg, cystic fibrosis).

Fifth-Generation Cephalosporins

The first-in-class of the fifth-generation cephalosporins is ceftaroline. This agent exhibits broad-spectrum activity against gram-positive bacteria, including MRSA and more resistant strains of S aureus, such as vancomycin-intermediate S aureus (VISA), heteroresistant VISA (hVISA), and vancomycin-resistant S aureus (VRSA). Ceftaroline is also active against many respiratory pathogens including S pneumoniae, H influenzae, and M catarrhalis. Although pediatric experience is limited, it is indicated in complicated skin and soft tissue infections and community-acquired pneumonia. A second agent from this group, ceftobiprole, is not yet approved for use in the United States.

Another fifth-generation cephalosporin, ceftolozane, is a derivative of ceftazidime with improved activity against Pseudomonas species. It is not stable against most ESBLs or carbapenemases. It is marketed in combination with the β-lactam inhibitor tazobactam to improve its activity against β-lactamase–producing Enterobacteriaceae. Ceftolozane-tazobactam is approved in a dosage of 1 g/0.5 g administered every 8 hours by the intravenous (IV) route. Clinical decisions based on MIC determinations will be essential to make the best use of a specific β-lactam/β-lactamase inhibitor combination in individual patients.

Toxicity of Cephalosporins

Serious adverse reactions due to cephalosporins are uncommon. Allergic reactions are seen in approximately 5% of courses. As with most antibiotics, the full spectrum of hypersensitivity reactions may occur, including rash, fever, eosinophilia, serum sickness, and anaphylaxis. Adverse reactions attributable to irritation at the site of administration are common. Reactions also include local pain after intramuscular injection, phlebitis after intravenous administration, and minor gastrointestinal complaints after oral administration.

Therapy with cephalosporins leads to the development of a positive direct Coombs reaction during approximately 3% of courses. This is, however, not commonly associated with hemolytic anemia. Some of the cephalosporins are associated with dose-related nephrotoxicity, whereas others are associated with interstitial nephritis.

The third-generation drugs may cause transient elevations of liver function tests and blood urea nitrogen. These broad-spectrum cephalosporins also have a profound inhibitory effect on the vitamin K–synthesizing bacterial flora of the gastrointestinal tract.

GLYCOPEPTIDES

Vancomycin

The prototypical member of this class of antibiotics is vancomycin. The primary activity of this cell wall–active antibiotic is against gram-positive bacteria. Despite its introduction several decades ago, vancomycin recently has gained widespread use. The reasons relate to the emergence and increasing prevalence of several important multidrug-resistant pathogens. Most clinical isolates of S aureus and coagulase-negative staphylococci, including those that are methicillin-resistant, are inhibited by less than 1.6 mg/L of this antibiotic. However, recent reports of increasing MICs of S aureus strains to vancomycin have been associated with treatment failure. VRE also are being reported at an increasing rate, especially with hospital-acquired infections. Vancomycin is active against multidrug-resistant pneumococci. Gram-positive bacilli, including Clostridium species, are very sensitive to vancomycin, but gram-negative bacteria are resistant.

Vancomycin is not absorbed from the gastrointestinal tract. Maximum serum concentrations after a 10-mg/kg intravenous dose are approximately 25 mg/L, 6-fold higher than the MICs of the usual bacteria being treated. It diffuses quite widely throughout the body and, during meningeal inflammation, attains concentrations in CSF that are approximately 10% to 20% of serum concentrations. The t_1/2 of vancomycin is approximately 4 to 6 hours in patients with normal renal function. The drug is excreted unmetabolized, almost exclusively in the urine. Doses should be reduced in patients with decreased renal function and levels monitored.

Toxicity

Vancomycin historically has had a reputation for toxicity. Many of its original adverse reactions, including ototoxicity and nephrotoxicity, were probably due to impurities in the formulation. Now that a more purified form is available, these adverse reactions are uncommon, although nephrotoxicity may occur with concomitant administration of other potentially nephrotoxic agents (eg, aminoglycosides). One of the more common side effects is the “red man” syndrome, which occurs during the infusion. It is characterized by fever, chills, and a pruritic rash usually involving the head, neck, and chest. Although more likely to occur after rapid infusion of vancomycin, red man syndrome may also occur after slow infusions and appears to be mediated by histamine. It may be treated or prevented with the use of antihistamines. It is not a contraindication to further vancomycin therapy.

Telavancin

Telavancin is a novel glycopeptide antibiotic recently approved by the FDA. Pediatric experience is limited. It is indicated for skin and skin structure infections caused by S aureus (including MRSA), GAS, and E faecalis (vancomycin-susceptible isolates only). It is also approved for hospital-acquired (including ventilator-associated) pneumonia caused by S aureus. The recommended adult dose is 10 mg/kg IV every 24 hours for 7 to 21 days. It appears to be more nephrotoxic than vancomycin. Telavancin has been associated with prolongation of the QT interval.

Dalbavancin and Oritavancin

Dalbavancin’s unique characteristic is its long half-life (150–250 hours). In adults with normal renal function, the dose is 1000 mg IV, followed 1 week later by 500 mg IV. This agent can be considered when MRSA is confirmed or strongly suggested. Dalbavancin is not active against vancomycin-resistant S aureus. It is approved by the FDA for bacterial skin and soft tissue infections.

Oritavancin is a vancomycin derivative with indications similar to that of dalbavancin. It has a half-life of approximately 250 hours. The dosage for adults is a single 1200-mg dose, administered IV over 3 hours. There is no pediatric experience yet with this agent.

COLISTIN

Colistin, also known as polymyxin E, belongs to the class of polypeptide antibiotics known as polymyxins. It was developed many decades ago but fell out of favor because of its substantial nephrotoxicity. Colistin is effective against most gram-negative bacilli, including strains producing ESBL or KPCs, and so has re-emerged in recent years as a therapeutic option in critically ill patients with infections caused by these highly resistant organisms. Resistance to colistin is rare. Two forms of colistin are available commercially: colistin sulfate and colistimethate sodium. Colistimethate sodium is the formulation marketed in the United States.

AZTREONAM

Aztreonam is the first member of a unique class of antibiotics referred to as monobactams. Although monobactams are β-lactam antibiotics, their structure is so different that cross-reactivity does not appear to be a problem; they can be prescribed for patients with penicillin or cephalosporin allergies. Aztreonam is resistant to a broad range of β-lactamases produced by gram-negative bacteria and therefore is active in vitro against many gram-negative organisms. Activity against gram-positive bacteria is minimal. In comparison with the aminoglycosides, aztreonam appears to be less nephrotoxic and ototoxic. Clinical experience in children is limited.

CARBAPENEMS

Imipenem, meropenem, doripenem, and ertapenem are members of the carbapenem β-lactam antibiotic family. Because imipenem is rapidly metabolized by renal brush-border enzymes, it is administered with cilastatin, a substance that inhibits imipenem metabolism by the kidney. Insofar as they are more stable in vivo to inactivation by human renal dehydropeptidase, meropenem, doripenem, and ertapenem are administered without cilastatin. The carbapenems have activity against gram-negative and gram-positive aerobes and anaerobes. Carbapenems are useful in the treatment of ESBL-producing gram-negative bacteria that are resistant cephalosporins. In addition, they can be used as monotherapy for polymicrobial infections, which potentially include anaerobes such as intra-abdominal infection and necrotizing fasciitis. An important limitation of ertapenem is its lack of activity against P aeruginosa. Doripenem, on the other hand, has exceptional activity against P aeruginosa. These antibiotics diffuse widely throughout the body and have excellent penetration into CSF. Only meropenem has an FDA-approved indication for the therapy of meningitis in children. These agents are all administered by the parenteral route. They appear to have toxicity profiles similar to that of other β-lactam agents. Imipenem is epileptogenic in high doses, whereas meropenem appears to have less neurotoxicity.

RIFAMPIN

Rifampin is active against a wide range of gram-positive and gram-negative bacteria. It also is active against the majority of Mycobacterium tuberculosis strains, with MICs less than 0.5 mg/L. Rifampin is given orally and is well absorbed from the gastrointestinal tract. Maximum serum concentrations of 8 mg/L are usually attained after a 600-mg dose. Rifampin penetrates well into most body tissues and fluids, including tears; saliva; bone; liver; lungs; and other fluids such as pleural, ascitic, and CSF (the latter even in the absence of inflammation). The t_1/2 of rifampin ranges from 2 to 5 hours. It is metabolized in the liver and excreted principally in the bile and, to a lesser degree, in the urine. All patients receiving this antibiotic should be advised that their bodily secretions, including tears, saliva, sweat, and urine will develop a reddish-orange discoloration. This is especially important for patients who wear soft contact lenses, which may be permanently discolored. Important drug interactions with rifampin have been recognized. For example, it enhances the metabolism of fluconazole, oral contraceptives, warfarin, propranolol, and anticonvulsants, all of which are metabolized in the liver. Doses of these concurrently administered agents may need to be increased to maintain therapeutic concentrations.

The use of rifampin as a single agent is limited by the fact that bacteria can rapidly develop resistance. It is, however, one of the first-line agents to be used as part of combination therapy for most forms of tuberculosis. It also is the antibiotic of choice for the prophylaxis of children with exposure to patients with infections caused by H influenzae type b and N meningitidis. Rifampin also has been used to eradicate upper respiratory carriage of GAS. It may also be useful in combination with antistaphylococcal agents in the management of catheter-associated infections due to these organisms.

Hypersensitivity reactions include dermatitis and a flu-like syndrome occasionally with thrombocytopenia, hemolytic anemia, and acute renal failure. Cholestatic hepatitis is another possible adverse reaction.

QUINOLONES

The prototype of the quinolone antibiotics is nalidixic acid. This naphthyridine derivative has been used almost exclusively as a urinary antiseptic. It is as active as ampicillin against gram-negative enteric isolates, but has no useful activity against Pseudomonas species or gram-positive bacteria. Because nalidixic acid is only partially absorbed from the gastrointestinal tract, large doses are necessary to attain therapeutic urinary concentrations. These high doses have caused side effects, including visual disturbances. An additional problem has been the rapid development of bacterial resistance during therapy. These factors have limited the use of this antibiotic.

Research directed at modifying the chemical structure of nalidixic acid resulted in the development of the ever-growing family of fluorinated quinolone derivatives, including ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. The spectrum of activity of these derivatives now includes gram-positive bacteria (including some strains of MRSA) and many enteric organisms. Quinolones may be given IV, and most quinolones are absorbed well after oral administration, and thus represent the first agents available for the oral treatment of systemic infections caused by multidrug-resistant gram-negative enteric isolates. Ciprofloxacin has the most activity against Pseudomonas, and thus, it is often useful for oral therapy of such infections. These agents are also of great value because their activity is unrelated to that of other antibiotics and resistance is not plasmid-borne. In adults, the quinolones may be preferred over alternate agents for treatment of complicated urinary tract infection, suspected bacterial gastroenteritis, osteomyelitis caused by gram-negative bacilli, and invasive external otitis.

Toxicity

In animal studies, the quinolones cause cartilaginous damage in young animals. This limited their use in children to recalcitrant infections for which alternatives were lacking. A body of data emerging over the past 25 years suggests that quinolones may be generally safe for administration to children. However, the American Academy of Pediatrics Committee on Infectious Diseases recommends that the use of quinolones should be limited in children because of high rates of resistance seen with overuse and the theoretical risk of joint injury. There are specific circumstances in which a quinolone may be the most appropriate antibiotic, such as in urinary tract infections due to Pseudomonas species or other multidrug-resistant gram-negative bacteria or if other antibiotics are contraindicated because of allergy.

METRONIDAZOLE

The antibacterial activity of metronidazole is limited to anaerobes, with greatest activity against gram-negative anaerobic bacilli such as Bacteroides and Fusobacterium, most of which have MICs under 3.12 mg/L. Activity against gram-positive anaerobic cocci is less consistent, with about 75% of such strains being inhibited by 12.5 mg/L.

Metronidazole can be administered intravenously, orally, or rectally. Maximum serum concentrations after a 7.5-mg/kg dose administered intravenously are 20 to 25 mg/L. Concentrations after an equivalent oral dose are similar, and those after an equivalent rectal dose are about half. The drug diffuses well into all tissues; therapeutic concentrations can be attained in CSF, bile, bone, and abscesses. The t_1/2 of metronidazole is approximately 8 hours. It is metabolized to acid and hydroxy metabolites. Between 60% and 80% is eliminated by the kidneys, and 6% to 15% is eliminated in the feces. Hepatic insufficiency prolongs the t_1/2 of unchanged metronidazole, and doses usually have to be adjusted. Renal insufficiency usually does not necessitate dose adjustment.

Metronidazole therapy often is associated with a metallic taste and nausea. More serious but less frequent adverse reactions include a reversible peripheral neuropathy, seizures, encephalopathy, and neutropenia. A disulfiram-like reaction can occur when metronidazole is taken with alcohol. Several studies conducted in laboratory animals have indicated that prolonged use of high-dose metronidazole can be carcinogenic; however, there is no evidence that it is carcinogenic in humans.

Metronidazole has been shown to be effective in a wide variety of infections caused by anaerobes. The most common indications for this antibiotic are the treatment of pelvic and intra-abdominal sepsis and brain abscesses. It also is an effective treatment for pseudomembranous colitis caused by C difficile.

AMINOGLYCOSIDES

The aminoglycoside group of antibiotics contains a large number of structurally related compounds. Streptomycin was the first of these agents to be discovered. Agents subsequently developed include neomycin, kanamycin, gentamicin, tobramycin, amikacin, and netilmicin. Streptomycin is primarily used to treat tuberculosis. Gentamicin, tobramycin, and amikacin are the most common aminoglycosides used; they are discussed below as a group, with only their clinically important differences emphasized.

These antibiotics are active primarily against gram-negative and limited numbers of gram-positive aerobes. They are inactive against the vast majority of anaerobes. All 3 of these aminoglycosides are active against most strains of P aeruginosa, with tobramycin consistently demonstrating the greatest activity. Gentamicin is consistently the most active of these agents against strains of Serratia marcescens. Otherwise, their relative antibacterial activities are similar, with most sensitive strains being inhibited by less than 3 to 4 mg/L.

An important aspect of aminoglycoside activity against gram-negative aerobes is the increasing resistance developed since their introduction. Resistance is most often due to antibiotic inactivation by enzymes produced by the bacteria. There are at least 12 such inactivating enzymes. Gentamicin is susceptible to the largest number of these enzymes (9 of 12), and amikacin is susceptible to the smallest number (1 of 12). When widespread bacterial resistance develops to one of the aminoglycosides being used in a particular hospital, changing to an alternate agent usually results in a return to increased sensitivity.

The pharmacokinetics of all the aminoglycosides are similar. They are poorly absorbed from the gastrointestinal tract, but well absorbed after intramuscular or intravenous administration. Maximum serum concentrations of gentamicin and tobramycin are 5 to 8 mg/L after unit doses of 1 to 2.5 mg/kg. Maximum serum concentrations of amikacin range from 15 to 30 mg/L after a unit dose of 7.5 mg/kg. The aminoglycosides are distributed in most extracellular fluids, but do not attain therapeutic concentrations in CSF. The main site of deposition of these drugs is the kidney, which accounts for approximately 40% of the total antibiotic in the body. The renal cortex accumulates approximately 85% of the kidney load, and the resulting concentrations are more than 100-fold greater than serum concentrations. The half-lives of the aminoglycosides range from 1.5 to 2.5 hours, and they are eliminated, primarily unchanged, by glomerular filtration. The doses of the aminoglycosides must be carefully monitored and adjusted in the presence of renal insufficiency. In such cases, the total daily dose is decreased by either prolonging the dosing interval or reducing the unit dose. Nomograms, based on the measured or approximated glomerular filtration rate, are available to guide these adjustments.

Aminoglycosides demonstrate concentration-dependent killing, that is, the bactericidal activity increases with increasing concentration of drug. In addition, aminoglycosides exhibit a substantial postantibiotic effect (ie, aminoglycosides will inhibit growth of bacteria even after the serum level has fallen below the MIC for that antibiotic). Because of these pharmacodynamic characteristics, aminoglycosides may be effective when administered as a single daily dose. Toxicity is not increased using this dosing strategy.

Indications

Aminoglycosides are indicated for treatment of endocarditis due to certain bacteria where they are used for synergy with the primary agent (eg, ampicillin and gentamicin for enterococcal endocarditis). The aminoglycosides also are useful in combination with a cell well–active agent in the empiric therapy of febrile neutropenic episodes in immunocompromised patients. Other indications include treatment of proven or suspected gram-negative infections of the blood or urinary tract. Aminoglycosides are used less frequently since the development of third-generation cephalosporins.

Toxicity

The most important toxicities of the aminoglycosides are ototoxicity and nephrotoxicity. These toxic effects are more common in adults than in children, who generally tolerate this class of drugs well. Ototoxicity may be primarily vestibular or cochlear. The agent most commonly associated with vestibular toxicity is gentamicin, with an estimated incidence in adults of 2%. This ranges from mild vertigo to severe Ménière syndrome. Damage is usually permanent, but symptoms may eventually be reduced by adaptation. The agents most likely to cause cochlear toxicity are amikacin and tobramycin. Although the frequency of hearing loss following treatment with these drugs is low, it may occur without any warning and may be irreversible. Risk factors that seem to predispose to ototoxicity include cumulative dosage, advanced age, and maternal history of preexisting renal compromise or hearing loss. Controlled trials in adult patients have found little difference overall in the incidence of ototoxicity following treatment with gentamicin, tobramycin, or amikacin.

Early manifestations of nephrotoxicity may include hypokalemia, glycosuria, alkalosis, hypomagnesemia, and hypocalcemia. Renal damage is dose-related and generally reversible.

Another less common but important side effect of the aminoglycosides is a competitive type of neuromuscular blockade, seen most often after intraperitoneal administration or after intravenous push. For this reason, aminoglycosides should not be administered to those with infant botulism. Hypersensitivity reactions to systemically administered aminoglycosides are uncommon.

Because of their relatively narrow toxic-to-therapeutic ratio, serum concentrations of the aminoglycosides should be monitored. When using multiple daily dosing, peak concentrations of gentamicin and tobramycin should not exceed 10 mg/L, and trough concentrations should be below 2 mg/L. Amikacin peak and trough concentrations should not exceed 30 mg/L and 10 mg/L, respectively. When using single daily dosing, levels approximately 8 hours after the start of dosing should be in the range of 2 to 5 mg/L for gentamicin and tobramycin and 10 to 15 mg/L for amikacin.

TETRACYCLINES

The tetracyclines are not frequently prescribed for children because of age-related toxicities. The antibiotics in this category include tetracycline, doxycycline, minocycline, and the newer agent tigecycline. The tetracyclines are active against a wide range of gram-positive and gram-negative bacteria, Mycoplasma, Rickettsia, and Chlamydia. They also are active against Treponema pallidum and moderately active against a wide range of anaerobes. All tetracyclines are absorbed adequately, but incompletely, from the gastrointestinal tract. They are chelated by various cations and are absorbed more completely during fasting. These antibiotics distribute widely and attain concentrations in the CSF of 10% to 50% of simultaneous serum concentrations. Most of these agents are excreted primarily by renal glomerular filtration, with lesser amounts being eliminated in the bile. Doxycycline is an exception, with 90% appearing in the feces. The half-lives of the tetracyclines range from 6 hours for tetracycline to approximately 20 hours for doxycycline.

Indications

Indications for tetracycline therapy in adults and children over 8 years of age include infections caused by Mycoplasma pneumoniae, Q fever, psittacosis, brucellosis, and lymphogranuloma venereum. Tetracyclines may be used in children irrespective of age in the treatment of Rocky Mountain spotted fever, ehrlichiosis, and anaplasmosis, since there are no reasonable alternative agents for these infections. Minocycline is frequently prescribed to patients with acne vulgaris. Doxycycline is an effective chemoprophylactic agent against E coli–induced diarrhea and anthrax.

Tigecycline, a semisynthetic derivative of minocycline, is a parenteral agent of a new class of antibiotics (glycylcyclines). It has a broader spectrum of (bacteriostatic) activity than traditional tetracyclines but retains the side effect profile of tetracyclines. Tigecycline is active against tetracycline-resistant gram-positive and gram-negative pathogens, including MRSA, and possibly VRE, but not Pseudomonas. It also may be useful for multidrug-resistant Enterobacteriaceae.

Toxicity

The adverse effects of tetracyclines relate to tooth and bone deposition. Permanent binding to dental calcium can produce a dose-related, brownish, fluorescent discoloration of the teeth when administered during the period of dental calcification (5 months to 8 years). Bone deposition of tetracycline may result in temporary cessation of bone growth. This effect is reversible when the drug is discontinued. Doxycycline is one of the least offensive tetracyclines in relation to bone staining and does not appear to cause teeth staining in children < 8 years of age until the child has consumed over 5 courses of treatment.

Other adverse effects of tetracyclines that are not age-related include gastrointestinal disturbances, photosensitivity, hepatotoxicity, and neurotoxicity. Hypersensitivity reactions to the tetracyclines are rare.

Photosensitivity reactions may be caused by any of the tetracyclines but are most frequent with doxycycline. Unfortunately, doxycycline is sometimes prescribed as a prophylactic agent against diarrhea in individuals traveling to tropical, sunny climates. Hepatotoxic reactions are uncommon, but fatal liver necrosis has been described after large intravenous doses in pregnant women. The pathogenesis of this reaction is unknown.

Manifestations of neurotoxicity are observed frequently and almost exclusively with minocycline. Dizziness, weakness, vertigo, and ataxia appear within the first few days of therapy. Another neurologic side effect of these agents is benign intracranial hypertension that is self-limited and resolves when the therapy is discontinued.

OXAZOLIDINONES

Linezolid is the first member of the recently developed oxazolidinone class of antibiotics. Linezolid binds to the bacterial 50S ribosomal subunit. It has 100% bioavailability after oral administration and has wide distribution throughout the body, including lung extracellular lining fluid and CSF. Maximum serum concentrations of 11 to 16.7 μg/mL are achieved within 1 to 2 hours of an oral dose. Linezolid is cleared primarily by nonrenal mechanisms, with only 30% of the drug eliminated by the kidneys. The t_1/2 is 1.5 to 5 hours; infants and young children clear the medication more rapidly. Linezolid has been approved for the treatment of complicated skin and skin-structure infections and nosocomial pneumonia. It demonstrates activity against gram-positive bacteria such as Staphylococcus, Streptococcus, and Enterococcus, including MRSA and VRE. It also has been used as second-line therapy for both tuberculous and nontuberculous mycobacterial infections. Recommended dosages are 600 mg orally or IV twice daily for children ≥ 12 years of age and 10 mg/kg/dose orally or IV every 8 hours for children < 12 years of age.

Tedizolid is a second-generation oxazolidinone derivative that is 4- to-16-fold more potent against staphylococci and enterococci compared to linezolid. It was approved by the FDA in 2014 for the treatment of acute bacterial skin and skin-structure infections caused by S aureus (including MRSA), GAS, GBS, Streptococcus anginosus, and Enterococcus. The recommended dosage in patients over 18 years of age is 200 mg once daily for 6 days; pediatric studies to date are limited.

Toxicity

Linezolid is generally well-tolerated in children. Most adverse effects occur only with prolonged (> 2 weeks) therapy. These include reversible hepatotoxicity and bone marrow suppression. Linezolid is also a reversible monoamine oxidase inhibitor, so concurrent treatment with selective serotonin reuptake inhibitors is contraindicated as this combination has been associated with serotonin syndrome.

LINCOSAMIDES

The prototype of the lincosamide class of antibiotics is clindamycin. Clindamycin is well absorbed from the gastrointestinal tract. An oral dose of 300 mg results in maximum serum concentrations of 4 to 5 mg/L. It may be prescribed as a capsule or suspension. Maximum serum concentrations after an intravenous dose are 2- to 3-fold higher than after an oral dose. Clindamycin distributes widely but penetrates into CSF poorly. The drug is metabolized primarily in the liver, with less than 25% excreted in the urine. Thus, hepatic insufficiency has a more profound effect on the disposition of this drug than does renal insufficiency. The t_1/2 of clindamycin is 2 to 4 hours.

Clindamycin acts at the 50S subunit of the bacterial ribosome. It is active against most gram-positive bacteria, both aerobic and anaerobic. It also is active against most gram-negative anaerobic rods, but it is inactive against most gram-negative aerobes. Sensitive organisms usually have MICs less than 0.5 mg/L.

An important role for clindamycin has emerged in the management of infections due to MRSA. Because of its outstanding penetration into body fluids (excluding the CSF) as well as tissues and bone, clindamycin can be used for therapy of serious infections caused by S aureus or GAS. Even when using vancomycin or a β-lactam agent for treatment, clindamycin may be co-administered for treatment of serious infection due to S aureus or GAS (toxic shock syndrome or necrotizing fasciitis), as its effect on ribosomes may decrease toxin production by the bacteria. There is a form of inducible clindamycin resistance exhibited by some strains of S aureus; therefore, consultation with the clinical microbiology laboratory or an infectious diseases specialist is necessary before treating a serious infection due to S aureus with clindamycin. Clindamycin is also useful in the management of anaerobic infections. Clindamycin plays an important role in the treatment of malaria and babesiosis (when each is co-administered with quinine), Pneumocystis jirovecii pneumonia (when co-administered with primaquine), and toxoplasmosis.

Toxicity

The most important adverse reactions to clindamycin are gastrointestinal disturbances. Approximately 30% of patients treated with this drug develop diarrhea. This diarrhea is usually self-limited and subsides when therapy is discontinued. It may be associated with nausea, vomiting, and abdominal cramps. A more severe gastrointestinal side effect is pseudomembranous colitis, which was first described in association with this antibiotic. It is caused by gastrointestinal overgrowth of toxin-producing C difficile. Almost every antibiotic has now been implicated in the pathogenesis of pseudomembranous colitis, and clindamycin is not the most frequent culprit. Furthermore, pseudomembranous colitis is much less common in children than in adults.

Minor abnormalities of liver function tests are quite common during clindamycin therapy, and cardiovascular collapse has been observed after rapid intravenous administration.

MACROLIDES

The macrolide antibiotics most commonly used in pediatric practice include erythromycin and the newer agents clarithromycin and azithromycin. This class of antimicrobials exerts its antibiotic effect through binding to the 50S subunit of the bacterial ribosome, producing a block in elongation of bacterial polypeptides. Clarithromycin is metabolized to 14-hydroxy clarithromycin, and interestingly, this active metabolite also has potent antimicrobial activity. Azithromycin has largely replaced erythromycin for use in many infections.

The spectrum of activity of these drugs includes many gram-positive bacteria. Unfortunately, resistance to these agents among S aureus and GAS is fairly widespread, limiting the usefulness of macrolides for many skin and soft tissue infections and for streptococcal pharyngitis. Azithromycin and clarithromycin have demonstrated efficacy for otitis media. Although many S pneumoniae are becoming resistant, members of this class have an important role in the management of pediatric respiratory infections, including atypical pneumonia caused by M pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila, as well as infections caused by Bordetella pertussis. Azithromycin is also useful for the treatment of gastrointestinal disease due to some bacteria (eg, Salmonella, Shigella, and Campylobacter) and is the treatment of choice for traveler’s diarrhea in children.

Azithromycin is an azalide antibiotic that is structurally related to erythromycin. It may be given IV or orally, and its biochemical modifications result in excellent oral bioavailability, greatly extended serum and tissue half-lives (both exceeding 48 hours), and excellent in vivo activity against most of the organisms susceptible to erythromycin. In addition, it has excellent activity against Chlamydia trachomatis, with MICs between 0.03 and 0.5 mg/L. It is particularly well suited for treating genital infections caused by Chlamydia. A single oral dose is as effective as a 7-day course of erythromycin or doxycycline. Similarly, for other infections for which a 10- to 14-day course of other antibiotics is routinely given, a 5-day course of azithromycin may be adequate. Further, an extended-release microsphere formulation has recently been released that allows for single-dose treatment of some infections, such as community-associated pneumonia (CAP).

Clarithromycin is another macrolide antibiotic that is similar to azithromycin. A special feature of clarithromycin is its activity against selected mycobacteria; thus, it is particularly useful in the treatment of atypical mycobacteria infections, especially those caused by Mycobacterium avium-intracellulare.

Toxicity

Oral erythromycin formulations often result in gastrointestinal disturbances, including nausea, vomiting, diarrhea, and abdominal cramps. These adverse effects are likely to occur at high doses. A much more serious adverse reaction, fortunately rare among children, is cholestatic hepatitis. It occurs most commonly with the estolate preparation and is probably due to the propionyl ester linkage. Manifestations can include fever, jaundice, pruritus, rash, increased liver size, and eosinophilia. Resolution usually occurs when the antibiotic is discontinued. Oral erythromycin (and azithromycin) use in neonates has been associated with the development of pyloric stenosis. Intravenous erythromycin is frequently associated with thrombophlebitis. Ototoxicity, manifested as tinnitus and transient deafness, is a rare adverse reaction.

Drug interactions are common with erythromycin and to a lesser extent with clarithromycin. These agents can inhibit the CYP3A4 enzyme system, resulting in increased levels of certain drugs such as astemizole, cisapride, statins, pimozide, and theophylline. Itraconazole may increase macrolide levels, whereas rifampin, carbamazepine, and phenytoin may decrease macrolide levels. There are few reported adverse drug interactions with azithromycin. Clarithromycin has been associated with prolonged QT interval and auditory and visual hallucinations in some recipients of the drug.

SULFONAMIDES AND TRIMETHOPRIM

Sulfonamides were the first group of synthetic antibacterial compounds. They originally had a wide range of activity, but this range is considerably compromised by acquired bacterial resistance. Trimethoprim and the sulfonamides are bacteriostatic agents that inhibit the bacterial folate synthesis pathway, in the process impairing both nucleic acid and protein synthesis. Sulfonamides interfere with the synthesis of dihydropteroic acid from para-aminobenzoic acid, whereas trimethoprim acts at a site further downstream, interfering with synthesis of tetrahydrofolic acid from dihydrofolic acid. The sulfonamides are available in both parenteral and oral formulations. Although there have historically been a large number of sulfonamides developed for clinical use, relatively few remain available for pediatric practice. The most important agent is the combination of trimethoprim-sulfamethoxazole (TMP-SMZ), which is commonly used for treatment of urinary tract infections. TMP-SMZ has also emerged as a commonly prescribed agent for staphylococcal skin and soft tissue infections, since this antibiotic retains activity against MRSA. TMP-SMZ should not be used when infection may be due to GAS. TMP-SMZ also plays a unique role in immunocompromised patients as a prophylactic and therapeutic agent for P jirovecii infection. Bacteria that are usually sensitive to sulfonamides include Nocardia species, many Enterobacteriaceae, H influenzae, and B pertussis, and Chlamydia and nonbacterial pathogens such as Toxoplasma and Plasmodium falciparum are also sensitive to the sulfonamides. Other commonly used sulfonamides include sulfisoxazole, which is useful in the management of urinary tract infections, and sulfadiazine, which is a drug of choice in the treatment of toxoplasmosis.

The sulfonamides are often classified on the basis of their half-lives, which range from 2 to 6 hours with the short-acting sulfonamides, such as sulfanilamide, sulfadiazine, and sulfisoxazole, to 150 to 200 hours with the ultralong-acting sulfonamide sulfadoxine. Most of the sulfonamides are well absorbed from the gastrointestinal tract. Serum concentrations vary somewhat among the different agents, but after the usual recommended orally administered doses, maximum concentrations are typically in the range of 50 to 100 mg/L. Concentrations are higher after intravenous administration. These drugs are distributed widely and attain therapeutic concentrations in CSF. The sulfonamides are acetylated in the liver, and some also undergo glucuronidation. Free and conjugated sulfonamides are excreted by renal glomerular filtration and secretion. The longer-acting sulfonamides undergo more complete tubular resorption than do the shorter-acting agents. Minimal amounts of the sulfonamides are excreted in the bile.

Toxicity

Sulfonamides may cause a variety of hypersensitivity reactions, ranging from mild rashes to life-threatening Stevens-Johnson syndrome. The latter reaction is more common with the longer-acting sulfonamides. Hematologic toxicity also may occur with sulfonamide use. Reactions include agranulocytosis, which is usually reversible on discontinuation of the drug, and hemolytic anemia in patients with deficiency of glucose-6-phosphate dehydrogenase (G6PD). Renal damage was common with the older sulfonamides, which were poorly water soluble. Patients developed crystalluria, which led to urinary obstruction and hematuria. Renal damage may also be a manifestation of a hypersensitivity reaction. Sulfonamides are contraindicated in the neonate and during the latter part of pregnancy, as they may displace bilirubin from protein-binding sites, possibly leading to jaundice and kernicterus. Neonates also seem to be more susceptible to the potential renal toxicity of these agents.

NITROFURANTOIN

Although nitrofurantoin was approved by the FDA in 1953, its exact mechanism of action is still not known. It has a hydantoin ring with a nitro-substituted furanyl side chain that is metabolized by bacteria to activate its bactericidal activity. Nitrofurantoin has broad activity against gram-positive and gram-negative enteric bacteria.

Nitrofurantoin is well absorbed after oral administration and rapidly cleared by the kidneys. It has an extremely short half-life (~30 minutes) and a high volume of distribution, which may be due to both rapid distribution into tissue compartments and enzymatic degradation at those sites. Therefore, serum levels are not maintained, but the antibiotic concentrates in the urine, making it a useful antibiotic for urinary tract infections.

Indications

Because of the high concentrations of nitrofurantoin in urine and its broad spectrum of activity, it has primarily been used as therapy or prophylaxis in urinary tract infections. Some data suggest that nitrofurantoin may be more effective than other antibiotics in preventing recurrent urinary tract infections in children. However, its gastrointestinal side effects may limit its utility.

Toxicity

The primary side effect of nitrofurantoin is nausea and vomiting. These adverse effects are the most common reason for discontinuing therapy. Although there have been reports of acute lung injury and pulmonary fibrosis in adults on long-term nitrofurantoin therapy, similar toxicities have not been seen in children. Hemolysis can occur in patients with G6PD deficiency.

STREPTOGRAMINS

The emergence of highly resistant gram-positive organisms, in particular VRE, has necessitated development of new classes of antibiotics. One such class that is especially useful for resistant gram-positive infections is the streptogramins. The currently licensed agent in this category is dalfopristin-quinupristin, which is available in a parenteral formulation. It is appropriate for treatment of MRSA, methicillin-resistant coagulase-negative staphylococci, and vancomycin-resistant E faecium but not E faecalis. The recommended dose for children and adults is 7.5 mg/kg by intravenous route every 8 hours. This antibiotic is a potent inhibitor of CYP3A4 and so may be associated with substantial drug-drug interactions.

DAPTOMYCIN

Daptomycin is a novel member of the cyclic lipopeptide class of antibiotics. Its spectrum of activity includes virtually all gram-positive organisms, including E faecalis and E faecium (including VREs) and S aureus (including MRSA). The structure of daptomycin is a 13-member amino acid peptide linked to a 10-carbon lipophilic tail, which results in a novel mechanism of action of disruption of the bacterial membrane through the formation of transmembrane channels. These channels cause leakage of intracellular ions, leading to depolarization of the cellular membrane and inhibition of macromolecular synthesis. A theoretical advantage of daptomycin for serious infections is its bactericidal activity against MRSA and enterococci. It is administered IV. Experience in children is limited. Doses ranging from 6 to 10 mg/kg/d have been used in children. Myopathy and elevations in creatine phosphokinase have been described. Daptomycin is inactivated by surfactant and should not be used to treat pneumonia.

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INTRODUCTION

Antifungal agents are available in systemic and/or topical formulations. The choice of antifungal agent(s) and duration of therapy depend not only on the causative pathogen but also the anatomic location and severity of the infection and host immune status. For example, topical antifungal agents are less likely to cause toxicity and should, as a rule, be the first choice for treating skin and mucous membrane infections, whereas tinea capitis and onychomycosis (fungal infection of the nails) are best treated systemically (see Chapter 362). Infections that are severe, are disseminated, or involve the bloodstream should be treated with systemic therapy. In some instances, aggressive initial therapy using more potent antifungal agents with higher toxicity profiles may be warranted as initial therapy for life-threatening invasive fungal diseases in immunocompromised hosts. This aggressive initial therapy may be followed by less aggressive “step-down” therapy until immune reconstitution occurs. It is not uncommon that drug-drug interactions (eg, azole agents with anticancer chemotherapies) limit antifungal options in practice. To guarantee the maximum effectiveness and safety, therapeutic drug monitoring (TDM) is essential, especially for some of the systemic azole agents and flucytosine. In contrast to antibacterial therapy, correlation between in vitro susceptibility test results (eg, minimal inhibitory concentrations [MICs]) and clinical outcome has not been established for each antifungal-pathogen combination except for fluconazole, voriconazole, and echinocandins with Candida species. Organism- and disease-specific antifungal therapies are summarized in Table 242-1.

SYSTEMIC ANTIFUNGAL THERAPY

The most commonly used systemic antifungal agents can be divided into 3 major groups based on their structure and function: polyenes, azoles, and echinocandins.

Polyenes

The polyenes bind to sterols in the fungal cell membrane, causing increased cell membrane permeability followed by leakage of cellular contents and cell death. They have been reported to be both fungistatic and fungicidal, depending on the fungal organism as well as host factors. Currently amphotericin B, available as amphotericin B deoxycholate (AMBD) or its lipid formulations, is the only polyene agent for systemic use. Amphotericin B is active against most fungi, including yeasts such as Candida species, Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and also a variety of molds including but not limited to Aspergillus species and zygomycetes (eg, Rhizopus species and Mucor species). Because of its broad antifungal spectrum, amphotericin B is often used for the empiric treatment of febrile neutropenic cancer patients. It is also indicated for visceral leishmaniasis. Of note, amphotericin B is not active against Scedosporium species, some isolates of Fusarium species, Aspergillus terreus, and Candida lusitaniae. All amphotericin B formulations have poor penetration into the cerebrospinal fluid (CSF), vitreous humor, and amniotic fluid.

AMBD is typically administered as a 1- to 6-hour (usually 2- to 4-hour) daily intravenous infusion of 0.6 to 1.5 mg/kg. The dosage is dependent on the infecting organism and the extent of infection. AMBD is highly protein bound and accumulates in tissues, especially the liver and spleen. Thus, after therapy has been established, some experts opt to administer the drug every other day or 3 times weekly. Common side effects include acute infusion-related reactions and nephrotoxicity (often reversible). Infusion-related fever and chills can be treated with meperidine, antipyretics, slowing the infusion rate, or a combination of these options. Patients who experience severe reactions can be given these agents or a hydrocortisone infusion before AMBD is administered. Neonates and children are less likely than adults to experience infusion-related toxicity. Frequency and severity of infusion-related side effects often diminish with continued treatment. Nephrotoxicity and electrolyte disturbances (hypokalemia and hypomagnesemia) are also common, but usually reversible, side effects. Volume expansion with normal saline prior to administration of AMBD has reduced nephrotoxicity in adults, but there are no comparable data for children.

Amphotericin B has been administered directly into the CSF via intraventricular/intrathecal routes in cases of meningitis; however, no data exist to suggest that this improves the outcome of candidal meningitis, and significant toxicity due to administration has been reported. It has also been used as a bladder irrigant for treating uncomplicated candidal cystitis. However, the availability of new systemic antifungal agents with better penetration into these compartments has almost eliminated the use of intraventricular/intrathecal CSF and bladder administration.

Lipid formulations of amphotericin B result in less infusion-related and renal toxicities compared to AMBD. Thus, these agents can be given at higher doses than AMBD; however, infusion-related symptoms and nephrotoxicity remain the dose-limiting toxic effects. Two lipid formulations are commercially available: liposomal amphotericin B (LAMB, AmBisome) and amphotericin B lipid complex (ABLC, Abelcet). LAMB and ABLC have lower kidney penetration but achieve higher amphotericin B concentrations in the liver and spleen compared to AMBD. LAMB achieves higher amphotericin B concentrations in the brain than the other amphotericin B formulations, whereas ABLC achieves higher amphotericin B concentrations in the lung. Recommended daily dosages are variable and depend on the infecting organism and host susceptibility. Current recommendations are 3 to 5 mg/kg for LAMB and 5 mg/kg for ABLC. In general, most experts recommend 5 mg/kg of either lipid formulation for the treatment of serious fungal infections in pediatric patients. Despite the much higher cost of the lipid formulations and the necessity for higher dosages, utilization of these agents is increasing in pediatric patients because of their improved safety profile.

Azoles

Azoles inhibit the fungal cytochrome P450 enzyme, sterol 14-α-demethylase, thereby impairing fungal ergosterol synthesis and leading to damage in the fungal cell membrane. Azoles are fungistatic in general. The azole family contains 2 classes of drugs: the imidazoles and the triazoles. Although the 2 classes are similar in their spectrum of activity and their mechanism of action, the triazoles are more commonly prescribed, because they are more slowly metabolized (requiring less frequent dosing) and have less effect on human sterol synthesis (and thus are associated with less toxicity). The available systemic azoles include the imidazoles, miconazole and ketoconazole, and the triazoles, fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. Isavuconazole has been recently approved by the US Food and Drug Administration (FDA) for treatment of invasive aspergillosis and mucormycosis in adults, but clinical data in the pediatric population are still very limited. The introduction of second-generation triazoles (voriconazole, posaconazole, and isavuconazole) has expanded the target organisms and use of azoles. In general, the azole family has activity against Candida albicans, the dimorphic fungi (eg, H capsulatum, B dermatitidis, C immitis, and C neoformans), and the dermatophytes. Itraconazole, voriconazole, posaconazole, and isavuconazole have activity against Aspergillus species. Voriconazole, posaconazole, and isavuconazole have even extended activities, being active against other hyaline and dematiaceous molds and against some of the fluconazole-resistant Candida species. Importantly, voriconazole lacks activity against zygomycetes, whereas posaconazole and isavuconazole have some activity depending on the isolate. All azole agents inhibit human cytochrome P450 enzymes to varying degrees. Therefore, possible drug-drug interactions should be carefully considered. Investigation of the pharmacokinetics of the newer azoles in neonates, children, and adolescents is ongoing. As new information emerges, recommended dosing regimens are likely to change. The recommended dosages indicated below should be verified prior to prescribing. Therapeutic drug monitoring for systemic azoles except for fluconazole or isavuconazole is recommended because of the wide inter- and intraindividual variability of serum drug levels.

Fluconazole (Diflucan) is effective for the treatment of esophageal, laryngeal, and vaginal candidiasis. It should also be considered in cases of oropharyngeal candidiasis unresponsive to topical therapy. Fluconazole can also be used for serious candidal infections in hemodynamically stable patients unless the infection is suspected to be caused by a fluconazole-resistant strain such as Candida krusei, Candida guillermondii, or Candida glabrata (see Table 242-1). The drug has also been used for antifungal prophylaxis in adult and pediatric recipients of hematopoietic stem cell transplants or solid organ transplants and in premature infants. Fluconazole can be used as initial therapy for mild cases of cryptococcal meningitis in adults with acquired immunodeficiency syndrome (AIDS) and for long-term suppression of cryptococcal infection. Its usefulness in treating patients with non-AIDS–associated cryptococcal meningitis has not been defined. Fluconazole is also effective in coccidioidal meningitis and other types of coccidioidomycosis.

Fluconazole is available as an oral suspension, a tablet, and an intravenous solution. It is well absorbed from the gastrointestinal tract, and the recommended oral and intravenous dosages are identical. For patients with moderate to severe oropharyngeal candidiasis, a dose of 100 to 200 mg daily for 7 to 14 days for adults, or a loading dose of 6 mg/kg followed by 3 mg/kg daily for 2 weeks for children is recommended. The recommended daily dosage for patients with systemic fungal infection is 400 to 800 mg for adults and approximately 6 to 12 mg/kg for children. Dosing recommendations for premature infants are based on both the gestational age and the postnatal age of the infant at drug initiation. Fluconazole has excellent penetration into the CSF and vitreous humor. Unlike the other azoles that are metabolized in the liver, fluconazole is concentrated and excreted unchanged in the urine (favorable for treating cystitis); thus, the dosage must be adjusted for patients with renal impairment. The most common side effects are gastrointestinal complaints; less frequently, hepatic enzyme activity may be elevated. Development of resistance to fluconazole, especially among Candida species, is reported with increasing frequency. Failure of fluconazole treatment may be attributable to resistance, especially in patients who have received chronic suppressive therapy, and to the drug’s fungistatic, rather than fungicidal, effects. Similar to the other azoles, fluconazole has many potential drug interactions to consider.

Itraconazole (Sporanox) has activity similar to that of fluconazole but is also active against Aspergillus species and certain dematiaceous molds. It is indicated for the treatment of sporotrichosis, blastomycosis, histoplasmosis, aspergillosis, and onychomycosis. It is also effective in tinea capitis in adults and children. Itraconazole has also been used for the prophylaxis and empiric therapy of fungal infections in neutropenic cancer patients and hematopoietic stem cell transplant recipients. The oral solution of itraconazole is effective therapy for oropharyngeal and esophageal candidiasis. Currently, the agent is available as an oral solution and a capsule. The preparations are not interchangeable; the oral solution produces greater systemic drug exposure than the equivalent dose in capsule form. Bioavailability of the capsule form is affected by the acidity of the stomach, and the capsules should be taken with food. The oral solution is less affected by stomach pH and should be taken on an empty stomach. Itraconazole is highly protein bound, and very little penetrates into the CSF. It is metabolized by the liver and excreted as inactive metabolites in the feces and urine. Although neither formulation is approved by the FDA for use in children, multiple pediatric studies describe the administration of itraconazole at dosages as high as 10 mg/kg/d for severe infections and 2.5 to 5 mg/kg/d for tinea capitis and onychomycosis. Serum itraconazole concentration for the treatment of invasive fungal infections, such as histoplasmosis and blastomycosis, should be at least 1 μg/mL by high-performance liquid chromatography (HPLC) or 3 μg/mL by bioassay. The duration of therapy for onychomycosis is 3 to 4 months. However, because the drug accumulates in the nail tissues, “pulse therapy” (repeated courses of 1 week of therapy, 3–5 mg/kg/d, followed by 1–3 weeks without therapy) has been reported to be effective for onychomycosis. As with fluconazole, gastrointestinal side effects occur most frequently. Use of itraconazole with terfenadine, cisapride, or astemizole can cause a serious drug interaction that produces life-threatening cardiac arrhythmias. Itraconazole has been reported to potentiate vincristine toxicity in children undergoing concurrent chemotherapy for leukemia.

Voriconazole (Vfend), a second-generation triazole and synthetic derivative of fluconazole, is approved for use in the treatment of invasive aspergillosis, serious Candida infections in nonneutropenic patients (eg, candidemia, disseminated disease, and infections caused by fluconazole-resistant species), and serious infections due to Scedosporium apiospermum and Fusarium species in patients refractory to or intolerant of other therapy. Voriconazole is currently the recommended initial therapy for invasive aspergillosis as it was shown to be superior to AMBD. Published reports suggest voriconazole also demonstrates activity in a variety of less common or refractory fungal infections. However, voriconazole is not active against the zygomycetes, and clinical reports have noted emergence of these infections following prophylactic administration of voriconazole.

Voriconazole is available as an intravenous preparation, tablet, and oral suspension. The pharmacokinetics of voriconazole are nonlinear in adults but appear to be linear in children. Thus, children require higher doses of voriconazole than adults. The most recent recommendation for children age 2 to 11 years is to start with an intravenous loading dosage of 9 mg/kg every 12 hours for 2 doses followed by 8 mg/kg every 12 hours. Serum drug concentrations should be monitored because of the intrapersonal variability in metabolism of this drug (eg, CYP2C19 polymorphism). Studies show that trough levels less than 1 μg/mL were associated with poorer clinical response and trough levels above 5.5 μg/mL with higher risk for neurotoxicity; therefore, a therapeutic target for trough levels in the range of 1.5 to 4.5 μg/mL has been proposed. Voriconazole concentrations in tissue and CSF exceed those of the trough plasma level several-fold. Similar to the other azoles, voriconazole has many potential drug interactions to consider.

Visual disturbances, elevated liver transaminases, and dermatologic reactions are the most common adverse effects associated with voriconazole administration. Visual disturbances include blurred vision, photophobia, and altered or enhanced visual perception and occur in approximately 25% to 45% of recipients. These reactions typically occur within 30 minutes of drug administration and have a median duration of 30 minutes. Increased liver transaminases occur in approximately 10% to 20% of recipients. For patients with mild to moderate hepatic insufficiency (Child-Pugh class A and B, scores 5 to 9), the manufacturer recommends giving the normal loading dose but halving the maintenance dose. There are no data available on administration in patients with more severe hepatic dysfunction. Rash, including photosensitivity, occurs in less than 10%. Dose adjustments for patients with renal insufficiency are not necessary for the oral formulation. However, the intravenous formulation of voriconazole is not generally recommended for patients with moderate to severe renal impairment because of possible accumulation of the cyclodextrin vehicle used in the intravenous formulation that may lead to nephrotoxicity. Of note, unlike fluconazole, urine concentrations of voriconazole do not reach therapeutic levels; thus, this agent should not be relied on to treat urinary tract infections.

Posaconazole (Noxafil) is a second-generation triazole that is closely related to itraconazole. It has even broader coverage than voriconazole with activity against the zygomycetes. Currently, posaconazole is indicated for treatment of oropharyngeal candidiasis (including refractory cases) and for antifungal prophylaxis in patients older than 13 years undergoing hematopoietic stem cell transplant or with prolonged neutropenia. In addition, posaconazole has demonstrated efficacy as salvage therapy in a variety of fungal infections, including aspergillosis, fusariosis, and zygomycosis.

Posaconazole is available as an oral suspension, an extended-release tablet, and an intravenous solution. Bioavailability of the oral suspension is unpredictable, but its absorption is improved with divided daily dosing and high-fat meals. Delayed-release tablets demonstrate less variability in pharmacokinetic parameters related to food intake when compared with the oral suspension and thus are useful in patients who cannot eat full meals. Dosage recommendations are the same for the delayed-release tablets and the intravenous form; these dosing recommendations are not interchangeable with the oral suspension dosing recommendations. In general, the intravenous formulation of posaconazole should be restricted to patients ≥ 18 years of age who are unable to take the extended-release tablet or suspension for the treatment of invasive fungal disease and whose infections are unable to be adequately treated by other intravenous antifungal agents. The recommended dose of the delayed-release or intravenous formulation for adolescents and adults is 300 mg twice daily as a loading dose followed by 300 mg daily for prophylaxis and treatment. Using the oral suspension, the recommended dose for adults is 200 mg 3 times daily for prophylaxis or 800 mg daily (divided 2–4 times) for treatment of serious infections. The adult dose is recommended for adolescents because a small number of older children, age 8 to 17 years, have demonstrated similar serum concentrations as adults. There are limited pharmacokinetic data for posaconazole in younger children. For antifungal prophylaxis in infants and children ≥ 8 months to < 12 years, 4 mg/kg/dose of oral suspension administered thrice daily is recommended. For treatment purposes, we suggest an oral suspension dosage of 4.5 to 6 mg/kg/dose 4 times daily in children weighing less than 34 kg or the adult dosage if weight is 34 kg or more. Posaconazole is generally well tolerated; gastrointestinal symptoms, including vomiting, abdominal pain, and diarrhea, are the most commonly reported side effects. The drug is primarily eliminated in feces as an unchanged form and is not a choice for urinary tract infection. Therapeutic drug monitoring is recommended, and experts suggest a trough concentration of ≥ 0.7 μg/mL for prophylaxis and ≥ 1.0 μg/mL for treatment of severe infections.

Isavuconazole (Cresemba) was recently approved by the FDA for treatment of invasive aspergillosis and invasive mucormycosis in adults (18 years and older). It is formulated as the prodrug, isavuconazonium sulfate, and available as both intravenous (IV) and oral formulations (capsules). The oral capsule has excellent bioavailability and a longer half-life, and it is easier to achieve good serum levels compared with the other second-generation triazoles. Neither IV nor oral formulations contain cyclodextrin vehicle, a solubilizing agent used in voriconazole or posaconazole; thus, IV isavuconazole can be used in patients with renal dysfunction, another advantage of this new agent. Isavuconazole is generally safe and well tolerated but has drug-drug interactions like the other azole agents. A double-blind, randomized controlled trial has shown noninferiority of this agent compared with voriconazole as initial therapy for invasive aspergillosis. Furthermore, isavuconazole was associated with less frequent adverse events than voriconazole. A single-arm, open-label trial with a matched control from the FugiScope database suggested equivalent efficacy of isavuconazole for zygomycosis compared with amphotericin B. Clinical experience with isavuconazole in the pediatric population is still very limited.

Echinocandins

The echinocandins act by inhibiting the synthesis of 1,3-β-d-glucan, a major component of the fungal cell wall. Because there is no counterpart in the mammalian cell, the echinocandins are predictably much better tolerated compared to other antifungal agents. Currently, 3 echinocandins are commercially available. They are available only as IV formulations and have the same general spectrum of activity. They have long half-lives and can be dosed once daily. Echinocandins are fungicidal against Candida species, including azole-resistant species, and fungistatic against Aspergillus species. Echinocandins are not active against most of the noncandidal yeasts (eg, Cryptococcus species) or the majority of molds other than Aspergillus species.

Caspofungin (Cancidas) is approved for treatment of esophageal candidiasis, candidemia, and other candidal infections; as treatment of aspergillosis in patients who are refractory to or intolerant of other therapies; and as empiric therapy for presumed fungal infections in febrile, neutropenic patients. The agent is highly protein bound and penetrates into all major organs including the brain. However, the concentration in uninfected CSF is low, and there is a lack of clinical data to support its use in central nervous system infections. The recommended dosage for children is a loading dose of 70 mg/m² followed by daily administration of 50 mg/m² (maximum loading and daily maintenance dose of 70 mg). If concomitant inducers of hepatic cytochrome P450 enzymes are also given, the daily dose in pediatric patients should be 70 mg/m² (still with a daily maximum of 70 mg). No dose adjustment is indicated for patients who are on dialysis or have renal or mild hepatic insufficiency. Reduction in the daily dose from 50 to 35 mg is recommended for adults with moderate hepatic insufficiency (Child-Pugh class B, or score 7 to 9). There is no information on administration in patients with severe hepatic dysfunction. The most common adverse events reported with the use of caspofungin are mild increases in hepatic transaminases, gastrointestinal upset, and headache.

Micafungin (Mycamine) is similar to caspofungin and is indicated for the treatment of esophageal candidiasis and as prophylaxis in patients undergoing stem cell transplant. In addition, there are clinical studies demonstrating efficacy in disseminated candidiasis and in invasive aspergillosis in patients refractory to or intolerant of other antifungal therapy. Micafungin is highly protein bound and achieves highest tissue concentrations in the lung. Low levels can be detected in the brain, and levels are undetectable in CSF. Micafungin has been studied in children and neonates. The drug was well tolerated without dose-related toxicities. Recommended pediatric dosing for adolescents, children, or infants ≥ 4 months of age is 1 mg/kg/d (maximum dose of 50 mg daily) for prophylaxis and 2 to 3 mg/kg/d (maximum dose of 150 mg daily) for treatment. In salvage treatment studies of aspergillosis, children received doses up to 8.6 mg/kg/d safely. Premature infants less than 1000 g have a shorter half-life and more rapid clearance, and a dose of 10 mg/kg/dose once daily is recommended. For neonates > 1000 g, 7 to 10 mg/kg/dose once daily is recommended. Patients with renal insufficiency and mild or moderate hepatic dysfunction do not require dose adjustments of micafungin.

Anidulafungin (Eraxis) has a similar spectrum of activity and safety profile compared to other echinocandins. Animal data indicate a large volume of distribution, suggesting extensive tissue distribution. Tissue concentrations are highest in the lung and liver. Measurable concentrations were detected in the brain. The half-life is even longer than that of the other echinocandins, greater than 24 hours in adults. Anidulafungin is indicated for the treatment of esophageal candidiasis and candidemia and other forms of Candida infections (intra-abdominal abscess and peritonitis) in nonneutropenic patients. The recommended dosing for adults is a loading dose of 200 mg followed by a 100 mg daily dose for systemic Candida infections and a 100-mg loading dose followed by 50 mg daily for esophageal candidiasis. The pediatric equivalent is approximately 1.5 mg/kg/d and 0.75 mg/kg/d, respectively. Dose adjustment is not needed for renal insufficiency and mild, moderate, or severe hepatic insufficiency. As with the other echinocandins, anidulafungin is well tolerated, with gastrointestinal symptoms and mild increases in hepatic transaminases as the most commonly attributed events.

Other Systemic Antifungal Agents

Flucytosine (5-FC, Ancobon), a fluorinated pyrimidine related to fluorouracil, is indicated for treating serious infections caused by Candida species and C neoformans. It is converted to fluorouracil within fungal cells, where it interferes with ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) synthesis. Flucytosine is available in capsule form and is readily absorbed from the gastrointestinal tract. Because the drug is poorly protein bound and penetrates the blood-brain barrier, it is effective as adjunctive therapy for meningitis, in combination with amphotericin B. The recommended daily dosage is 50 to 150 mg/kg, divided into 4 equal doses. The dosage must be adjusted for patients with renal impairment, and caution should be used when flucytosine is administered to patients with underlying renal dysfunction. The target serum peak concentration of 5-FC for cryptococcal infection is between 30 and 80 μg/mL, and levels above 100 μg/mL should be avoided to avert bone marrow suppression, which is the most serious toxicity. Gastrointestinal complaints, hepatitis, and jaundice are frequent adverse effects. Flucytosine should be used in combination with other antifungal agents, such as amphotericin B, because pathogens rapidly acquire resistance to flucytosine when it is used alone.

Griseofulvin (Gris-peg and Grifulvin V) is indicated for treatment of superficial fungal infections of skin, hair, and nails that are caused by various species of dermatophytes, including Trichophyton, Microsporum, and Epidermophyton. The drug inhibits fungal cell mitosis by binding to fungal microtubules. The drug also binds to human keratin and renders keratin-rich tissue resistant to fungal infection. Absorption from the gastrointestinal tract is markedly variable but is thought to be increased by fatty meals and by the use of smaller griseofulvin crystals. Currently, formulations containing microsized and ultramicrosized griseofulvin crystals are commercially available. The daily dosage for children is approximately 10 mg/kg of ultramicrosized and 15 mg/kg of microsized griseofulvin, given as 1 dose or 2 divided doses. The duration of therapy depends on the location of the fungal infection; therapy must be continued until the infected tissue is replaced by normal tissue. Tinea corporis requires 2 to 4 weeks of therapy, tinea capitis 4 to 6 weeks of therapy, and infection of toenails at least 6 to 12 months of therapy. The safety of griseofulvin treatment is not established for children younger than 2 years of age. Griseofulvin is usually well tolerated; rash and urticaria are the most common adverse effects. Headache is also common. When given with warfarin, griseofulvin may result in decreased plasma warfarin concentration; it may also reduce the effectiveness of oral contraceptives. Phenobarbital may diminish the effectiveness of griseofulvin.

Terbinafine (Lamisil) is an allylamine that acts by inhibiting fungal synthesis of ergosterol, a component of the fungal cell membrane. It is available as a topical agent and also as an oral tablet for treatment of onychomycosis. The drug has not been tested in children and should be reserved for patients with refractory disease. The recommended adult regimen is 250 mg daily for 6 weeks for fingernail disease and 12 weeks for toenail disease. Children who weigh more than 40 kg should receive the adult dosage. The dosage should be 125 mg/d for children who weigh between 20 and 40 kg and 62.5 mg/d for children who weigh less than 20 kg. Gastrointestinal toxicity is observed most frequently.

COMBINATION SYSTEMIC ANTIFUNGAL THERAPY

As multiple classes of systemic antifungal agents are now available, there is considerable interest in combining agents for the treatment of serious invasive fungal infections. The combination of AMBD plus 5-flucytosine in cryptococcal meningitis and AMBD plus fluconazole in candidemia remained the only combinations supported by evidence from randomized clinical trials until recently. A randomized controlled trial has recently shown that combination therapy with voriconazole plus anidulafungin for invasive aspergillosis had trends for better survival compared to voriconazole monotherapy. Outside these settings, however, there are limited clinical data to support the use of combination antifungal therapy as definitive antifungal therapy. Considering the increased toxicity associated with dual therapy and some animal data suggesting antagonistic effects (eg, amphotericin B vs azoles), combination antifungal therapy (other than those currently supported by clinical trials) should be used with caution.

TOPICAL ANTIFUNGAL AGENTS

Topical antifungal agents are available in many different preparations, including ointment, cream, solution, lotion, powder, oral and vaginal troches, and vaginal tablets. Topical agents are the treatment of choice for superficial fungal infections of the skin, mucosa, and cornea, such as dermatophytosis (tinea corporis, tinea cruris, tinea pedis), tinea versicolor, candidiasis, and fungal keratitis. Creams and lotions are generally preferable to ointments for treating diseases of the skin. Powders are used only in moist areas such as the feet, groin, or other intertriginous areas. Several of the agents used as systemic therapy are also available as topical preparations. In such cases, the mechanism of action is the same, but the efficacy of the topical agents depends on their direct interaction with the fungal organisms on the surface of the skin or mucous membranes. In selecting a topical antifungal agent, consideration should be given to the type of preparation needed and the cost. Several agents now available without prescription may be used as first-line therapy for tinea corporis, with more expensive preparations reserved for resistant infection.

Polyene Antifungals

Nystatin belongs to the polyene class with the mechanism of action similar to that of amphotericin B, but nystatin is active only against superficial candidiasis. The agent is available as a cream, ointment, powder, vaginal tablet, oral tablet, pastille, and suspension. Nystatin suspension is the treatment of choice for oral candidiasis and should be administered 4 times daily. Children who are able should be instructed to swish the suspension around the mouth and then swallow. Side effects include nausea and bad taste, but both are manageable. Topical nystatin is also frequently used for candidiasis in the diaper area and is available in combination with corticosteroids. Nystatin powder is effective for treating superficial candidiasis in skin folds, but care should be taken to prevent young infants from inhaling the powder when it is applied to their necks.

Azoles

Multiple azole antifungal agents are available as topical preparations. They are active against Candida species, Trichophyton species, Microsporum species, and, in some cases, Malassezia furfur. When used as directed, topical azoles cause few side effects. Some redness and irritation can occur.

Clotrimazole is available as an oral troche, vaginal tablet, vaginal cream, cream, and lotion. All but the oral troches are available over the counter. A clotrimazole and corticosteroid combination is also available, but it should be used with caution in children, who may absorb proportionally larger amounts of corticosteroid and thus be more susceptible to systemic toxicity. Miconazole is also available over the counter as a cream, spray, powder, lotion, and vaginal cream. These agents are readily available and inexpensive, and they should be the treatment of choice for tinea corporis (including tinea pedis and tinea cruris) and vaginal candidiasis. Topical ketoconazole, econazole, sulconazole, sertaconazole, and oxiconazole are also available. These agents should be considered second-line agents because of cost. Ketoconazole is available as a shampoo for treatment of tinea versicolor but is ineffective for tinea capitis. Terconazole, butoconazole, and tioconazole are available only as vaginal preparations.

Allylamines

Three topical allylamine agents—terbinafine, naftifine, and butenafine—are currently available. As a group, allylamines are active against the dermatophytes.

Other Topical Antifungal Agents

Tolnaftate is a synthetic thiocarbamate active against dermatophytes but ineffective for infections caused by Candida species and less effective than the azoles for tinea corporis. Many preparations of tolnaftate are available without prescription. Ciclopirox is a synthetic topical antifungal agent with broad-spectrum activity against the dermatophytes, including M furfur.

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