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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.
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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.
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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.
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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.
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GENERAL PRINCIPALS OF ANTIBIOTIC THERAPY
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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.
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Age- and Risk-Specific Use of Antibiotics in Children
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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.
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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).
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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.
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Immunocompromised and Hospitalized Patients
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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.
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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.
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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.
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ROUTE OF ADMINISTRATION
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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).
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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.
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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.
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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.
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CLASSIFICATION OF ANTIBIOTICS
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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.
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ANTIBIOTIC RESISTANCE
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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.
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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.
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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.
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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.
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The penicillins are divided into 3 groups on the basis of their antibacterial spectrum as detailed in the following discussion.
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Narrow-Spectrum, β-Lactamase–Sensitive Penicillins
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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.
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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 (t1/2) 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.
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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.
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Broad-Spectrum, β-Lactamase–Sensitive Penicillins
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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.
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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, t1/2, and excretion characteristics of the aminopenicillins are similar to those of penicillin.
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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.
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β-Lactamase–Resistant Penicillins
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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.
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Toxicity of Penicillins
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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.
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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.
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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.”
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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.
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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.
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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.
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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.
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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.
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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.
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First-Generation Cephalosporins
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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 t1/2 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.
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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.
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Second-Generation Cephalosporins
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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.
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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.
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Third-Generation Cephalosporins
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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.
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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.
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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.
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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.
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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.
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Fourth-Generation Cephalosporins
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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).
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Fifth-Generation Cephalosporins
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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.
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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.
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Toxicity of Cephalosporins
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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.
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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.
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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.
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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.
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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 t1/2 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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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 t1/2 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.
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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.
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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.
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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.
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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.
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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.
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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.
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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 t1/2 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 t1/2 of unchanged metronidazole, and doses usually have to be adjusted. Renal insufficiency usually does not necessitate dose adjustment.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Early manifestations of nephrotoxicity may include hypokalemia, glycosuria, alkalosis, hypomagnesemia, and hypocalcemia. Renal damage is dose-related and generally reversible.
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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.
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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.
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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.
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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.
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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.
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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.
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Other adverse effects of tetracyclines that are not age-related include gastrointestinal disturbances, photosensitivity, hepatotoxicity, and neurotoxicity. Hypersensitivity reactions to the tetracyclines are rare.
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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.
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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.
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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 t1/2 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.
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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.
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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.
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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 t1/2 of clindamycin is 2 to 4 hours.
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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.
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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.
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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.
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Minor abnormalities of liver function tests are quite common during clindamycin therapy, and cardiovascular collapse has been observed after rapid intravenous administration.
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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.
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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.
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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).
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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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