Principles of Anti-Infective Therapy

PART IV  Laboratory Diagnosis and Therapy for Infectious Diseases SECTION B  Anti-Infective Therapy

SECTION B: Anti-Infective Therapy

289 Principles of Anti-Infective Therapy John S. Bradley and Sarah S. Long

The selection of optimal antibiotic therapy for presumed bacterial infection is based on the balance of benefits and risks of specific therapy for each child. Prescribing the right antibiotic or antibiotics early in the course of serious infection can save a life or avoid substantial morbidity. Inappropriate antibiotic therapy given to a child with a viral infection exposes the child needlessly to antibiotic toxicities, adds to the selective pressure driving antibiotic resistance in bacteria, creates unnecessary costs to the medical system, and can divert attention from evaluation and management of the child’s condition.

SELECTING OPTIMAL ANTIMICROBIAL THERAPY Several questions must be addressed to choose optimal empiric and definitive antimicrobial therapy. These questions revolve around identifying potential or presumed pathogens and considering the relative merits of antimicrobial agents for specific pathogens and circumstances (Box 289.1). The clinician should follow the steps outlined in the following paragraphs.

BOX 289.1  Questions Pertinent to Choosing Antimicrobial Therapy Appropriately 1. What is the clinical syndrome or site of infection? Pathogens are predictable by site. 2. Does the child have normal defense mechanisms (in which case causative agents are predictable), or are these mechanisms impaired by underlying conditions, trauma, surgical procedures, or a medical device (in which case additional potential pathogens should be considered)? 3. What is the child’s age? Pathogens are predictable by age. 4. What clinical specimens should be obtained to guide empiric definitive therapy? 5. Which antimicrobial agents have activity against the pathogens considered, and what is the current range of susceptibilities for each antibiotic against these pathogens in the practitioner’s hospital or clinic? 6. What special pharmacokinetic and pharmacodynamic properties of a therapeutic agent are important regarding the site of the infection and the host? 7. For any given infection site, what percentage of children requires effective antimicrobial therapy with agents first selected for empiric treatment? Bacterial meningitis requires ~100%, whereas ~75% may be acceptable for impetigo. 8. In contrast to empiric therapy, what definitive therapy would be optimal? Agents with a broad spectrum of activity may be appropriate for empiric therapy, but those with a narrow spectrum of activity are preferred for definitive therapy. 9. What special considerations exist regarding drug allergy, drug interaction, route of administration, cost, alteration of flora, or selective pressure in an environment?

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Step 1: Predict the Infecting Organism Defining the patient’s site or sites of infection or the organ system or systems involved can predict the pathogen or pathogens. Bacteria often are tropic for certain tissues; certain species have a proclivity for causing certain infections. Examples include the following: Neisseria meningitidis, group B Streptococcus, and Streptococcus pneumoniae for meningitis; S. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis for acute otitis media; and Staphylococcus aureus and Streptococcus pyogenes for cellulitis, osteomyelitis, and pyogenic arthritis.

Step 2: Consider Host Defense Mechanisms Is the host healthy, with intact immunity and normal integumentary barriers to infection? If so, the causative pathogens often are predictable. If the child has an underlying condition such as a defect in granulocyte number or function, nonpathogenic bacteria from both the host and the environment can cause infection. For an immunocompetent child with trauma to skin or mucous membranes, a recent surgical procedure, or an indwelling medical device, a variety of relatively nonpathogenic commensals also can cause infection, thus mandating empiric therapy that provides activity against a much broader range of organisms.

Step 3: Consider the Age of the Child Infectious agents causing specific target organ infections in immunocompetent hosts often are predictable based on the child’s age and exposures to pathogens specific to each age group. For example, group B streptococci and Escherichia coli are causes of meningitis almost exclusively during the first 90 days of life. Developmental maturation of the immune system as children approach the third year of life provides improved recognition for polysaccharide-encapsulated pathogens such as S. pneumoniae or H. influenzae type b. Group childcare exposes young children to Kingella kingae and infection with antibiotic-resistant strains of S. pneumoniae. School-related exposure to S. pyogenes is associated with increased middle-school age-specific attack rates of streptococcal pharyngitis. Adolescents’ exposure to sexually transmitted pathogens such as Neisseria gonorrhoeae increases the potential causes of pyogenic arthritis in that age group.

Step 4: Perform Diagnostic Tests Every effort should be made to prove the origin of the infection and to obtain an isolate for susceptibility testing. The Gram stain is a useful, rapid test to provide clues to the pathogen (e.g., swab in neonatal conjunctivitis), pathogenesis (e.g., aspirate in polymicrobial lung abscess), or interpretation of culture results (e.g., tracheal secretions in pneumonia). Although a Gram stain result of a tissue sample can lead to the inclusion of additional empiric therapy, it should not necessarily lead to exclusion of antibiotics customarily used in the empiric treatment of that infection. An error in processing or interpreting the Gram stain must not lead to ineffective empiric therapy. Nucleic acid detection is used increasingly for the diagnosis of bacterial, mycobacterial, viral, fungal, and parasitic infections. These techniques do not require isolation of viable organisms, and they can be applied to a variety of tissue specimens. Advantages of improved sensitivity are obvious, but causation cannot always be inferred, and current

Principles of Anti-Infective Therapy

methods often lack the ability to provide data on antimicrobial susceptibility.

Step 5: Consider Antibiotic Susceptibilities of Suspected Pathogens Bacteria can have multiple different mechanisms of resistance against a single antibiotic or against multiple types of antibiotics. The most common resistance mechanisms include cell wall permeability changes to prevent entry of the antibiotic into the pathogen, efflux pumps to eject antibiotics that enter the cell, bacterial enzymes that specifically inactivate antibiotics, and mutations that lead to alteration of the antibiotic’s target binding site (see Chapter 290). Bacteria can express resistance continuously (constitutively) or only on exposure to an antibiotic (inducible resistance). With such vast biologic variability in resistance mechanisms, efficient transmission of resistance genes among organisms, and variations in antibiotic use that create selective pressure, it is understandable that a single species such as E. coli can manifest different patterns of antibiotic resistance in different populations within the same local region, among regions of a country, and among countries of the world. Each healthcare association or hospital has a widely available antibiogram tool that is updated annually and allows the clinician to assess the current local resistance rates of pathogens. The probability that the antibiotic selected for empiric therapy will be effective against the presumed pathogen is directly related to the proportion of susceptible pathogens infecting patients in that location.

Step 6: Consider Pharmacokinetic and Pharmacodynamic Properties of Drugs The route of administration, the absorption, tissue distribution, and drug elimination characteristics are all critical pieces of information to guide the selection of both drug and drug dosage in antimicrobial therapy. Eradication of pathogens causing infection requires the appropriate antibiotic exposure at the infected tissue site. For many agents, published data describe the average concentrations and variability of concentrations achieved at specific tissue sites over time. Unfortunately, for many older antibiotics this important information often is unavailable. To understand how likely an antibiotic will be in achieving a microbiologic cure, with otitis media and amoxicillin treatment used as an example, information is required on the range of amoxicillin concentrations achievable in the middle ear fluid (MEF) following administration of a specific mg/kg dose of amoxicillin. These data provide a measure of exposure of bacteria to amoxicillin in the middle ear fluid. Based on current knowledge, treatment success is linked to an amoxicillin exposure (in middle ear fluid in this case) that delivers an amoxicillin concentration higher than the minimal inhibitory concentration (MIC) of amoxicillin against the pathogen causing the infection, for at least 30% to 40% of each dosing interval. With this information, we can calculate the proportion of children given that specific dose who will likely respond to treatment. For different classes of antibiotics, different types of drug exposure may be required for bacterial eradication (see Chapter 291).1 In the treatment of meningitis, adequate antibiotic concentrations in the cerebrospinal fluid (CSF) are critical for cure. The concentration of aminoglycoside antibiotics in the CSF following intravenous infusion is likely to be inadequate to treat meningitis caused by gram-negative pathogens, even though CSF concentrations are approximately 20% of those achievable in serum. In contrast, the high serum concentration of penicillin after a large dose leads to a bactericidal CSF concentration against susceptible pneumococci, even though the CSF concentration of penicillin is only approximately 5% of that achievable in serum. A range of predictable serum concentrations and tissue concentrations of antimicrobial agents exists within any group of children. This variability can be defined for all children receiving the same dose of drug, and it represents the basic concept of “population pharmacokinetics.” For example, antibiotic concentrations in the serum and middle ear space are usually therapeutic at a given mg/kg dose, but they can be inadequate in a small but predictable percentage of children. However, unlike with acute otitis media, the clinician cannot risk inadequate dosing for even 1 child with meningitis. Logically, a single mg/kg dose of an antibiotic

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may not be effective in all children even for the same pathogen that causes infection at different tissue sites because the tissue concentration of that antibiotic can differ substantially among sites (e.g., urine vs. lung vs. CSF). The absorption, distribution, metabolism, and elimination of drugs are variable in children as a function of age-related developmental changes.2,3 The volume of distribution of antibiotics varies profoundly during the first year of life, as the proportion of body weight contributed by extracellular water and fat changes. Drugs that distribute preferentially into the extracellular water (e.g., penicillins) require a dose and dosing interval that recognize greater diffusion into neonatal interstitial tissue than occurs in older infants and children. Drug elimination based on metabolism and organ function generally increases during the first several weeks of life, peaks in infancy, and approaches adult values during adolescence. Many antibiotics require different mg/kg dosages during a child’s life to achieve optimal antibiotic exposure to maximize efficacy and minimize toxicity. The pharmacodynamic properties of an antibiotic describe how exposure of the antibiotic to the pathogen leads to a bacteriostatic or bactericidal effect and are important in designing an antibiotic dosing regimen (Table 289.1). Aminoglycosides kill bacteria in a concentrationdependent fashion. Therefore, it is desirable to achieve the highest concentration possible at the site of infection to achieve the fastest killing of bacteria. The maximum safe tissue concentration is dictated by the serum aminoglycoside concentration above which renal toxicity occurs. For other antibiotic classes, such as the penicillins, achieving tissue concentration greater than the MIC for that pathogen for 30% to 40% of the dosing interval is associated with microbiologic and clinical cure. For the penicillins, a higher concentration of the antibiotic at the infected tissue site, higher than a certain critical concentration close to the MIC, is not associated with faster sterilization of tissues or a better clinical outcome. The postantibiotic effect also is considered in dosing and varies by antibiotic (see Table 289.1). For the aminoglycosides, the postantibiotic effect is profound (i.e., an extended period of time lapses after the antibiotic concentration drops to less than the MIC before regrowth occurs). Conversely, other antibiotics (e.g., most penicillins) inhibit growth only until the concentration drops to less than the MIC. Differences probably reflect molecular mechanisms of antibiotic activity at the target site, the avidity of antibiotic binding to the target site, the rate of elimination of the antibiotic from the target site, and whether the damage to the target site structure is reversible or irreversible. Although growth of a population of organisms generally can be inhibited at a certain antibiotic concentration (the MIC) as defined by standard laboratory techniques, antibiotic concentrations that lead to less frequent emergence of resistance often can be determined by using unique assay conditions with higher inocula than those used in standard clinical assays. For some bacteria, resistance begins with a spontaneous nucleic acid mutation leading to an amino acid change that results in less avid binding of the antibiotic to the target site (well described for fluoroquinolones and S. pneumoniae). This single-step mutation may lead only to a slightly higher MIC. The antibiotic concentration required to inhibit the single-step mutant, however, may not be achievable in infected tissues when a standard antibiotic dosage is used. Second-step mutations may then occur during ongoing exposure to an antibiotic, thereby leading to more profound changes in the MIC and rendering the organisms fully resistant even at the highest attainable tissue concentrations. Often it is possible to identify the concentration of antibiotic required to prevent the selection of viable single-step mutants, the mutant prevention concentration (MPC); the MPC often is two- or threefold higher than the MIC.4,5 If the higher dosage required for the MPC can be prescribed without undue toxicity, the risk of selecting antibiotic-resistant strains that can subsequently infect that child or his or her contacts may be reduced.

Step 7: Consider Target Attainment In treating any child, the practitioner must assess the seriousness of the infection and the risk of injury or death if the antibiotic is not effective. For infections that are not life-threatening and cause minimal morbidity (e.g., impetigo), achieving a cure rate of 70% to 80% with a safe and inexpensive antibiotic often is acceptable, especially if the use of an alternative agent to achieve a 98% success rate for that infection carries

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PART IV  Laboratory Diagnosis and Therapy for Infectious Diseases SECTION B  Anti-Infective Therapy

TABLE 289.1  Pharmacodynamic Antibacterial Effect of Antimicrobial Agents by Primary Bacterial Target and by Antibiotic Class Primary Targeta

Antibacterial Class

Pharmacodynamicsb

Intracellular Activityc

Cell wall

β-Lactams (penicillins, cephalosporins, monobactams, carbapenems) Glycopeptides (vancomycin,d telavancin, dalbavancin, oritavancin, teicoplanine)

Bactericidal Time-dependent inhibition Carbapenems PAE against gram-positive and gram-negative organisms PAE only against gram-positive organisms Bactericidal Concentration (AUC)–dependent inhibition

Generally not effective

Cell membrane

Lipopeptides (daptomycin) Polymyxins (polymyxin B, colistin)

Bactericidal Concentration-dependent inhibition Long PAE (daptomycin) PAE (polymyxins)

Not known

Ribosome

Macrolides, azalides, ketolides

Bacteriostatic primarily Time-dependent with long PAE Long PAE

Yes

Tetracyclines, glycylcyclines

Bacteriostatic Time-dependent with long PAE

Yes

Lincosamides (clindamycin)

Bactericidal or bacteriostatic Time-dependent with PAE

Yes

Aminoglycosides

Bactericidal Concentration-dependent PAE

Generally not effective

Oxazolidinones

Bacteriostatic (except against Streptococcus pneumoniae) Time-dependent with PAE

Generally not effective

Rifamycins

Bactericidal with long PAE

Yes

Fluoroquinolones

Bactericidal Concentration-dependent with long PAE

Yes

Streptogramins

Bactericidal (except against Enterococcus faecium) Time-dependent with PAE

Yes

Metronidazole

Bactericidal Concentration-dependent with PAE

Yes

Sulfamethoxazole-trimethoprim

Bactericidal Concentration-dependent

Yes

Nucleic acid

a

The primary antibiotic target within the bacterial pathogen. The type of pharmacodynamic relationship that best describes antibiotic-mediated inhibitory or bactericidal activity. c The ability to treat intracellular pathogens, based on the penetration of antibiotic into the host cell by passive diffusion or by active uptake. d Activity is best described by AUC concentration-dependent pharmacodynamics in animal models. e Not marketed in the United States. AUC, area under the curve; PAE, postantibiotic effect, or the observation of delay in regrowth of organisms following removal of antibiotic from the media. b

an excessive risk of toxicity or high cost. For other infections that cause a higher degree of suffering or risk of organ damage (e.g., pyelonephritis or acute otitis media), a cure rate of 80% to 90% often is desirable. For serious, life-threatening infections (e.g., bacterial meningitis or septicemia in a neutropenic child), an expected bacteriologic cure rate of close to 100% must be achieved.1 No formal list of “approved” cure rates or “target attainment” rates exists. Accepted target attainment rates can differ among infections and hosts as assessed by physicians, families, and societies. Consideration of target attainment rates can help clarify decision making regarding relative merits, risks, and costs of antimicrobial management.

Step 8: Consider Empiric and Definitive Therapeutic Decisions Separately For suspected serious infections, antibiotics with appropriately broad antibacterial activity at the highest tolerated dosage are selected for empiric therapy. Adequate empiric therapy is associated with decreased mortality rates and shorter hospital stays compared with inadequate empiric therapy for seriously ill adults.6–9 For the seriously ill child, knowledge of local resistance patterns for suspected pathogens should lead to selection of antibiotics with a likely achievable bacteriologic cure rate of >95%.

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Combination empiric therapy frequently is given when high cure rates are desirable to ensure adequate antimicrobial activity against all potential pathogens. A combination of vancomycin and a third-generation cephalosporin is used for empiric treatment of community-acquired meningitis because the use of a third-generation cephalosporin alone may not provide optimal therapy for S. pneumoniae with resistance to β-lactam agents. Empiric therapy for meningitis in the first 2 months of life consists of ampicillin in combination with a third-generation cephalosporin because the possible pathogens include Listeria monocytogenes, group B Streptococcus, and E. coli. Long-established combination therapies can be used for febrile neutropenic patients to ensure activity against Pseudomonas aeruginosa, enteric gram-negative bacilli, and S. aureus.7 Once the pathogen is identified, a narrow-spectrum agent frequently can provide the same degree (or a higher degree) of bacterial eradication and clinical efficacy with decreased toxicity, decreased selective pressure, and decreased cost. For example, initial therapy with a carbapenem agent for a patient with ventilator-associated pneumonia can be narrowed to cefotaxime if the pathogen isolated is a susceptible Klebsiella species rather than P. aeruginosa. In a patient with a postoperative wound infection, treatment with vancomycin and cefotaxime can be narrowed to ampicillin if a susceptible E. coli, rather than methicillin-resistant S. (MRSA) or Klebsiella species, is isolated. For a patient with catheterassociated septicemia who is treated with vancomycin and gentamicin and from whom ampicillin-susceptible Enterococcus is isolated, ampicillin

Principles of Anti-Infective Therapy

has superior antibacterial activity (and less toxicity) than vancomycin. For an outpatient with a cutaneous abscess presumed to be caused by S. aureus, empiric clindamycin can be replaced with an oral first-generation cephalosporin or β-lactamase-stable penicillin if the organism is methicillin susceptible. Definitive, convalescent outpatient therapy of serious infections initially treated in the hospital is reasonable if the risks of complications of the infection are negligible and if the parents and child can adhere to well-defined management plans and can return to the hospital quickly for any infection- or therapy-related problem. In some situations, either convalescent oral therapy or convalescent parenteral therapy is preferred. High-dose oral β-lactam therapy for bone and joint infections is one of the best evaluated step-down therapies for invasive infection.10 Parenteral antibiotics, such as ceftriaxone, that can be administered once daily are advantageous for outpatient therapy even though agents with a narrower spectrum of activity (or more potent activity) may be available because the narrower-spectrum or more potent agents require more frequent doses that may not be realistically administered in a home environment.11

Step 9: Special Considerations Considerations of drug allergy affect antimicrobial selection. The degree and type of drug reaction should be ascertained. The history of a morbilliform rash in a child 4 days after commencing amoxicillin therapy does not carry the same risk of a serious drug reaction as does the history of hives and airway obstruction following the first dose of amoxicillin. Cost considerations have become a greater issue as health insurers and governmental agencies develop antibiotic formularies that contain “approved,” less costly antibiotics with a narrow spectrum of activity. Antibiotic resistance of the suspected pathogen provides guidance for the selection of a particular agent. As antibiotic resistance in a community increases and failures with older, less active agents increase, formularies must be reassessed. An acceptable risk of failure must be determined by the treating physicians as well as by medical advisors to government and private insurers who determine formularies, to allow families to achieve acceptable cure rates and continue to have confidence in their healthcare providers.

ANTIMICROBIAL SUSCEPTIBILITY TESTING AND INTERPRETATION The primary purposes of performing antimicrobial susceptibility testing on clinical isolates are to guide therapeutic decisions for individual children and to amass data on susceptibilities of pathogens to a wide range of antibiotics to inform future decisions when a pathogen is not isolated. Susceptibility testing is performed routinely for most clinical isolates to inform decisions for individual children, with a few notable exceptions, such as for S. pyogenes, for which susceptibility to penicillin (but not macrolides) is predictable. A comparison of the antibiograms from sequentially isolated organisms from a child can provide guidance for interpretation of the clinical relevance of 2 or more isolates (e.g., coagulase-negative staphylococci as a true pathogen vs. contaminant). Comparing antibiogram data from the same bacteria isolated from several children on a hospital unit can provide insight into possible healthcare-associated infections.

Interpretation of Susceptibility Test Results An assortment of routine susceptibility test methods can be performed, including the disk diffusion (Bauer-Kirby) test, an antibiotic strip gradient-diffusion method (E-test), agar dilution with a mechanized inoculator, broth macrodilution or microdilution, and a short-incubation automated instrument method12 (see Chapter 286). Results usually are provided as a measure of the inhibition of growth of a defined inoculum of organisms following incubation in the presence of defined concentrations of an antibiotic. The MIC value provides an operational definition of a strain’s intrinsic antibiotic susceptibility and generally reflects the additive effects of multiple mechanisms of resistance, if present. Standardizing these susceptibility techniques and interpretation largely has been the task of the Food and Drug Administration (FDA) with

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the assistance of the Clinical and Laboratory Standards Institute (CLSI) and the United States Committee on Antimicrobial Susceptibility Testing (USCAST), both nonprofit organizations composed of participants from the pharmaceutical industry, the FDA, and academic institutions. Interpretation of the clinical relevance and direct clinical applications of MIC values are required beyond simple reporting of an MIC value.13 The misunderstanding that absolute values of the MICs can be compared across antibiotics can lead to errors in antibiotic management. Examples of misinterpretation could be that ampicillin and gentamicin MICs of 4 µg/mL for E. coli denote equivalence, or that the vancomycin MIC of 1 µg/mL and the ampicillin MIC of 2 µg/mL for Enterococcus denote the superiority of vancomycin. The variables inherent in disk susceptibility testing were discussed in the landmark report by Ericsson and Sherris,14 which formed the basis for the categorical interpretations recommended by Bauer and colleagues15 and subsequently the FDA and professional organizations that interpret in vitro susceptibility test results.16 The interpretation of the susceptibility test results is provided by the laboratory report as “S” (susceptible), “I” (intermediate), or “R” (resistant). A report result of “S” suggests that treatment with standard FDAapproved dosages can be expected. A report result of “I” suggests that some clinical failures can be expected at standard dosages because of decreased susceptibility of the pathogen to that antibiotic. A report result of “R” suggests that a microbiologic cure is unlikely because the pathogen is not inhibited by the antibiotic at achievable tissue concentrations following administration of standard, FDA-approved doses, infusion times, and infusion intervals. Interpretation is most valid when the distribution of MIC values across several hundred clinical isolates indicates a widely spaced, distinctly bimodal distribution of susceptible and resistant strains, such as S. aureus for penicillin and E. coli for ampicillin. The MIC value at which an organism changes from susceptible to nonsusceptible is called the breakpoint.13 The uniformity of reporting a single interpretation (S, I, or R) of a breakpoint for all infections caused by a single pathogen frequently is too simplistic and can be misleading, such as demonstrated by selecting a breakpoint when assessing the continuum of MIC values of penicillin for S. pneumoniae or MIC values of aminoglycosides for P. aeruginosa. The interpretation by clinicians of the clinical significance of MICs should be based on (1) the susceptibility values in a large population of isolates (range and mode of distribution, e.g., unimodal, bimodal, skewed), (2) the clinical pharmacology and pharmacodynamics of the drug (protein binding, volume of distribution, tissue concentrations over the dosing interval), and (3) clinical and microbiologic efficacy derived from prospective animal models and human clinical investigations. At the time an antibiotic is first approved for use by the FDA, MIC interpretative breakpoints are assigned to the antibiotic for various pathogens (often for specific tissue sites). As organisms develop new mechanisms for resistance following widespread use, the interpretation of the susceptibility results (the breakpoints) for a particular organism and a particular antibiotic can change. When ceftriaxone was first approved for use in children, S. pneumoniae was considered susceptible if the MIC value was ≤8 µg/mL. Pneumococci then expressed a novel mechanism of resistance, alteration in the many different penicillin-binding sites on the various cell wall synthesizing transpeptidase enzymes. Beginning in 1990, microbiologic failures in the treatment of meningitis occurred in children infected by organisms with a ceftriaxone MIC of 2 µg/mL. The breakpoints subsequently were changed so that only organisms with MIC ≤0.5 µg/mL were considered susceptible. However, with the knowledge that ceftriaxone concentrations in tissues such as lung or soft tissue are higher than in CSF, prospective data were collected that documented clinical and microbiologic success of ceftriaxone for infections outside the central nervous system in which the MIC for S. pneumoniae was up to 2 µg/mL. Therefore, 2 breakpoints for ceftriaxone now are used: a lower breakpoint of ≤0.5 µg/mL, considered “S” for central nervous system infections, and a higher breakpoint of ≤1 µg/ mL, considered “S” for infections outside the central nervous system (see Table 123.2). To add to the confusion regarding multiple breakpoints assigned to a particular antimicrobial agent and pathogen pair while recognizing that intravenously administered penicillin achieves far higher concentrations in serum and tissues than does orally administered drug, 2 new breakpoints for penicillin for S. pneumoniae also have been accepted: a lower

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PART IV  Laboratory Diagnosis and Therapy for Infectious Diseases SECTION B  Anti-Infective Therapy

breakpoint of ≤0.06 µg/mL, considered “S” for oral drug administration; and a higher breakpoint of ≤2 µg/mL, considered “S” for intravenous drug administration.17 The process of regular review of breakpoints for important pathogens against commonly used older, generic antibiotics has been legislated and will become standard in the near future. When the MIC value leads to an “S” interpretation in the laboratory report, the clinician should not assume that an antibiotic will always be effective for all infections at all tissue sites. Furthermore, because “S” indicates bacterial inhibition in the test system, the clinician must know whether the antibiotic is bactericidal, which can be required for certain infections (meningitis) or for certain hosts (those with neutropenia).

SITE OF INFECTION As a rule, only free, non–protein-bound drug is active in eradicating bacteria. For β-lactam agents, successively higher concentrations of antibiotic above the MIC present at the site of infection are not more efficacious in bacterial eradication because this class of agents displays time-dependent killing. Conversely, higher concentrations at the site of infection may enhance killing for aminoglycosides and other concentration-dependent drugs. Additionally, subinhibitory concentrations are not always ineffective; morphology and microbial adherence properties can be altered after exposure to subinhibitory concentrations of some antibiotics, with phagocytosis and intracellular killing subsequently enhanced by neutrophils.

Extracellular Infections Many bacterial infections occur in interstitial tissue fluid.18 For such infections, serum concentrations of antibiotics generally predict responses adequately. Antibiotics leave the vascular compartment and enter the extracellular fluid through passive diffusion. When the ratio of the surface area of vascular tissue to the site or volume of infection is high (e.g., in cellulitis, pneumonia, or pyelonephritis), antibiotic concentrations at that site are predicted by principles of passive diffusion. This is not the case when the volume of infection exceeds the surface area of the vasculature (e.g., abscess, fibrin clot, or cardiac vegetation). Passive diffusion principles alone also cannot be used to predict the extracellular fluid concentration of certain antibiotics at sites with active transport (e.g., urine or bile) or with a barrier to capillary permeability (e.g., into the ocular aqueous humor and CSF). The ability of antibiotics to pass through membranes by nonionic diffusion is related to lipid solubility. Lipid-soluble agents such as rifampin, chloramphenicol, trimethoprim, and isoniazid penetrate membranes and cross the blood-brain barrier better than the more highly ionized aminoglycosides. For meningitis, relatively large dosages of thirdgeneration cephalosporins, penicillin G, ampicillin, or vancomycin are required to achieve adequate concentrations in the CSF. Additionally, active transport out of the extracellular fluid, including the CSF, also can result in reduced concentrations in CSF of certain antibiotics such as β-lactam agents. Table 289.1 delineates the distribution characteristics of the major classes of antibiotics. Clinical evidence has indicated the inferiority of certain antibiotics used for the treatment of infection at sequestered tissue sites where penetration is poor (e.g., brain, eye, bone), and logical preference exists for the use of antibiotics known to accumulate at the site of infection. The vegetations of endocarditis, devitalized tissue, and bones are areas in which the penetration of most agents can be poor; high-dose and prolonged parenteral therapy usually is required, and surgical debridement of necrotic, nonperfused tissue can be necessary. The pharmacology of the drug can offer particular advantages. Agents eliminated by glomerular filtration or renal tubular secretion accumulate in urine. Fluoroquinolones, a few β-lactam agents (e.g., ceftriaxone and cefoperazone), and doxycycline are actively transported into bile, whereas first-generation cephalosporins and aminoglycosides diffuse passively. Clindamycin and the fluoroquinolones achieve excellent concentration in bone, although for infected bone with vascular necrosis, penetration of any antibiotic can be compromised. Only free drug is considered capable of antibiotic activity.19 Although only free drug passes through capillary walls and fibrin clots, intercompartmental diffusion will ultimately achieve an equilibrium between

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bound and free drug in tissues. Complex interactions at the tissue site probably account for the inconsistencies in prediction of clinical efficacy solely as a result of the degree of protein binding. In general, the plasma protein binding of aminoglycosides and fluoroquinolones is low, whereas binding for β-lactams can vary from low to very high for β-lactam agents. Multiple factors at the site of infection also can alter antimicrobial activity. Examples include the presence of purulent material, which results in a tissue environment with low pH. This situation leads to a decrease in the cationic aminoglycoside molecule charge that results in decreased binding and decreased antibacterial activity at the site of infection. Pathogens such as Bacteroides and Prevotella produce β-lactamase and can hydrolyze β-lactam agents.20 A wound hematoma can lower the ratio of the surface area of vascular tissue to the site or volume of infection; hemoglobin can bind penicillins and tetracyclines.21 Low oxygen tension in abscesses or ischemic tissue impairs active transport of aminoglycosides into bacterial cells. Although an acid pH in tissue or urine impairs the activity of aminoglycosides, nitrofurantoin, and methenamine, an alkaline pH enhances the activity of aminoglycosides and clindamycin. A high–bacterial-density infection such as streptococcal necrotizing fasciitis can be associated with slowed growth of bacteria with downregulation of cell wall transpeptidases that are the targets for β-lactam agents, thus making the organisms temporarily less susceptible to β-lactam antibacterial activity.22 The presence of a foreign body protects some organisms from host bactericidal action through biofilms and inhibition of neutrophil phagocytosis and, in addition, probably protects the pathogens by other, less well-defined mechanisms.

Intracellular Infections The unique properties of antimicrobial agents must be considered when the site of infection is intracellular because many antibiotics do not penetrate human cells (see Table 289.1). β-Lactam antibiotics, for example, are confined almost exclusively to plasma water and the interstitial fluid space. Such localization explains some discrepancies between apparent in vitro activity and therapeutic ineffectiveness. Intracellular pathogens include Listeria monocytogenes, Salmonella, Brucella, Legionella, Mycobacterium, Rickettsia, and Toxoplasma, as well as some pathogens that can cause persisting infections such as S. aureus and E. coli. Antibiotics that enter cells do so by a variety of mechanisms, including diffusion of relatively small lipid-soluble agents across a concentration gradient, pinocytosis of water-soluble agents, and carrier-mediated transport.23,24 Cellular accumulation of drug does not necessarily translate into efficacy against intracellular organisms; efficacy depends on whether the microbe and the drug are at the same intracellular site, how avidly the drug is bound to intracellular proteins and to the pathogen target site, and the molecular charge of the antibiotic at its intracellular location. Clindamycin, macrolides, and azalides are tropic for lysosomes, where they become protonated and concentrated.24,25 Fluoroquinolones have a large volume of distribution and a high tissue-to-serum ratio, as well as low-affinity intracellular binding; much of the fluoroquinolone body load thus is present intracellularly. For azithromycin, an even more dramatic intracellular location of antibiotic has been documented within phagocytic cells.24,25 The pharmacokinetic properties and intracellular accumulation of azithromycin are responsible for successful therapy of infection with intracellular pathogens and for shortened courses with respect to the number of days of antibiotic dosing required (including single-dose therapy).26 At the same time, azithromycin concentrations in serum, CSF, and the aqueous humor of the eye are negligible.27

DOSING, ROUTE, AND DURATION OF THERAPY Optimal dosing of an antimicrobial agent depends on relationships among the time course of concentration at the site of infection, the characteristics of antimicrobial activity, and adverse effects. In clinical practice, the route of administration of antibiotics often is based on additional practical considerations. Parenteral administration is required if an agent is absorbed poorly from the gastrointestinal tract, if a condition precludes administration or absorption of a usually well-absorbed drug, if an unusually high tissue concentration of drug

Principles of Anti-Infective Therapy

is required, or if adherence to an oral regimen for treatment of a significant infection cannot be ensured. Otherwise, substitution of oral for parental agents frequently is possible, even for serious diseases (e.g., pneumonia, osteomyelitis, pyogenic arthritis, orbital cellulitis) during convalescence. Oral therapy can replace parenteral therapy when highly absorbed and bioavailable agents are used to treat highly susceptible pathogens (e.g., trimethoprim-sulfamethoxazole for Pneumocystis pneumonia) and when the tissue concentrations of drugs at relevant sites are uniquely favorable (e.g., clindamycin or fluoroquinolone in bone). With a less favorable profile, parenteral therapy is given for the entire duration of therapy (at home or in the hospital). Abundant evidence for the effectiveness for different routes of administration is available when patient screening, selection of medical conditions, and follow-up are performed diligently.10,11,28 Advocacy for the best route of treatment of a child’s infection is a paramount consideration, with the risk of failure of therapy and the impact of the outcome taken into account. The appropriate duration of antibiotic therapy has been described more by experience and by “standard” treatment courses used for FDA antimicrobial drug approval than by prospective, well-controlled studies with duration of therapy as a separate variable as a specifically assessed outcome. Many factors are considered in the decision regarding the duration of therapy, including the intrinsic pathogenicity of the microbe, susceptibility to the agent used, the site of infection and penetration of the antibiotic, the use of synergistic combination therapy, the replication rate of the pathogen, the presence of a foreign body, and host factors that impair bactericidal capacity. In many situations, the severity of infection in all children is not uniform (e.g., pyelonephritis, soft tissue abscess), thus leading to differences in the time course of the child’s response to antibiotic therapy. In children with more severe pneumonia, treatment can be given parenterally until a clinical (and presumed microbiologic) response has occurred, and then oral convalescent “step-down” therapy can be provided for a defined time to achieve the desired total duration of therapy. With all infections, a recommendation for duration of therapy is based on the best available information for that child’s infection. Longer treatment courses can be more appropriate for more resistant organisms, for more severe infections associated with abscess formation especially if abscesses cannot be drained adequately, or for immunocompromised hosts. Delayed eradication of pathogens from the site of infection can occur in all these situations. The family should always be cautioned at the end of the treatment course to be alert for the signs and symptoms of relapse.

ANTIMICROBIAL COMBINATIONS Prevention of Emergence of Resistance Antibiotics can be used in combination in an attempt to (1) prevent or delay the emergence of drug-resistant subpopulations of the pathogen, (2) create synergy to improve outcomes, or (3) provide empiric therapy that will ensure that at least 1 antibiotic in the combination will be active against the infecting pathogen or pathogens. In most circumstances, published clinical data have been analyzed retrospectively with various antibiotic combinations for multiple infection entities, with conflicting conclusions.29–31 For certain populations of children, particularly those critically ill and with immunocompromise, combination therapy will likely improve outcomes, as suggested by retrospective subset analyses.30,31 Current data document improved outcomes with early, appropriate combination antibiotic therapy in sepsis. Mycobacterium tuberculosis treatment provides the best clinically documented example of the prevention of emergence of resistant bacteria. With a spontaneous resistance mutation frequency of approximately 108, the initial use of 2 or more agents to which the organism is reported as susceptible substantially reduces the probability that resistant organisms will be selected out and emerge during therapy.32 Treatment of Pseudomonas infection with a β-lactam, a fluoroquinolone, or an aminoglycoside alone can be associated with the emergence of resistant strains; 2-drug combination therapies can reduce the incidence of resistance to either component antibiotic. However, each antibiotic must provide the necessary exposure to pathogens in the infected tissues to ensure eradication of susceptible organisms. Inadequate dosing or poor tissue penetration of 1 antibiotic in a combination can lead to the

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selection of organisms resistant to that agent, despite the use of dual therapy. Rifampin is an antibiotic that is never used alone for the treatment of infection because of the rapid, frequent development of resistance following antibiotic exposure. Combining rifampin with vancomycin for coagulase-negative staphylococcal prosthetic valve endocarditis or ventriculoperitoneal shunt infection, or with a semisynthetic penicillin for S. aureus infections, can reduce the emergence of resistance while taking advantage of the unique tissue penetration and target site activity of rifampin.

Inhibition of β-Lactamases With certain fixed-combination drugs containing a primary β-lactam agent, the site of action of the second drug in the combination is not a vital microbial target binding site but rather the pathogen’s antibioticdegrading enzyme, responsible for resistance to the primary antimicrobial agent. Antistaphylococcal penicillins such as methicillin and nafcillin are degraded by staphylococcal β-lactamases. β-Lactamase inhibiting agents such as clavulanic acid, sulbactam, tazobactam, and avibactam display a specific affinity for and a degree of irreversible binding to the various bacterial β-lactamase enzymes, thereby protecting the companion β-lactam antibiotic from hydrolysis and allowing access to the target penicillin-binding proteins.33 Amoxicillin-clavulanate is especially useful in children when the potential causative pathogens are susceptible to amoxicillin except for the presence of β-lactamases produced by the pathogen (M. catarrhalis, H. influenzae, S. aureus, and Bacteroides fragilis). Piperacillin-tazobactam is a useful agent that extends the spectrum of activity of piperacillin to include additional gram-negative bacilli and methicillin-susceptible staphylococci; it may not, however, add to the activity of piperacillin alone against Pseudomonas because tazobactam does not effectively inhibit many of the β-lactamases produced by P. aeruginosa.

Synergy Target Site Synergy Combinations of antimicrobial agents can have a variety of effects on the target sites of an organism in vitro. The combination can be categorized as follows: (1) synergistic, when the combined effect of the drugs is significantly greater than the independent effects when the drugs are tested separately; (2) antagonistic, when the combined effect is significantly less than the drugs’ independent effects when tested separately; (3) additive, when the combined effect is the sum of the separate effects of the drugs tested; or (4) indifferent, when the combined effect is simply the effect of the more active drug alone. The clinical applications of these definitions are controversial. Synergy test results depend on the intrinsic activities of each antibiotic on an organism, the test system used, and whether the binding sites are similar or dissimilar.34–37 Despite the paucity of prospective clinical validation of in vitro results, biologically plausible reasons exist to believe that for certain infections, synergy has clinical relevance. Although performing prospective clinical studies for all combinations is not practical, concepts on classes of drugs with differing intracellular sites of activity and encouraging supportive in vitro data have evolved (e.g., penicillins in combination with aminoglycosides) to guide therapeutic choices. In clinical practice, combination therapy is common for serious infections, as demonstrated in a retrospective study of severe MRSA infections in which 50% of children received 3 or 4 agents simultaneously.38 With the combination of multiple agents, antagonism also can occur, and outcomes can be worse than with the use of only 1 or 2 agents.

Simultaneous Inhibition of Multiple Interrelated Targets A classic example of synergy of targeted activity at consecutive metabolic steps is represented by the combination of a sulfonamide with a dihydrofolate reductase inhibitor such as trimethoprim. The resulting inhibition of consecutive steps in the folic acid pathway leads to a significantly reduced MIC and can also enhance the drug’s bactericidal capacity. Streptogramin antibiotics (quinupristin-dalfopristin) include 2 biochemically distinct bacteriostatic compounds produced by Streptomyces

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that produce bactericidal activity when the agents are used in combination.39 The binding of the type A streptogramin at the acyl-amino transfer RNA (tRNA) acceptor site on the ribosome both prevents the binding of tRNA and also causes a conformational change in the ribosome, which enhances the binding of the type B streptogramin and thus causes steric hindrance to the extrusion of newly formed polypeptide chains from within the ribosome.

Combination of Cell Wall–Active Agents With RibosomalActive Agents Some instances of antibiotic resistance (e.g., to aminoglycosides) can result from a permeability barrier that precludes the drug’s reaching the intracellular target site. Agents that act on the cell wall (e.g., β-lactam agents, vancomycin) should enhance intracellular entry of an aminoglycoside. Unless the drug is rendered ineffective by aminoglycosidemodifying enzymes or resistance occurs at the ribosomal level, a combination could be expected to be synergistic. Such bactericidal synergy is demonstrable for viridans streptococci, group B streptococci, enterococci, staphylococci, Listeria and Corynebacterium species, P. aeruginosa, and Enterobacteriaceae. Generally for Enterococcus, streptomycin, gentamicin, and tobramycin are predictably synergistic with cell wall– active agents if the enterococcal strain is susceptible to aminoglycosides at 2000 µg/mL; laboratories provide standardized testing at this single-drug concentration. For gram-negative bacilli, exposure to aminoglycosides can enhance the permeability of the outer cell envelope to β-lactam antibiotics because of aminoglycoside-mediated production of altered, nonfunctional proteins that are incorporated into the cell wall. The superior clinical efficacy of combination over single-drug therapy has been documented in only limited clinical settings. For the treatment of enterococcal endocarditis, penicillin alone, which provides only bacteriostatic activity against enterococci, results in an unacceptable relapse rate. The addition of an aminoglycoside such as streptomycin or gentamicin results in clinical cure rates comparable with the rates attained in the treatment of endocarditis caused by penicillin-susceptible streptococci.40 Although similar clinical benefit is demonstrable in the animal model of endocarditis caused by penicillin-tolerant or relatively penicillin-resistant viridans streptococci (MIC of 1 µg/mL), no advantage is shown against fully susceptible strains; nonetheless, combination therapy for 2 weeks in patients with susceptible strains results in success rates comparable with those achieved when penicillin is administered alone for 4 weeks.40 The combination of nafcillin and gentamicin is synergistic in vitro against methicillin-susceptible strains of S. aureus; both retrospective data and limited prospective, comparative trials of nafcillin and gentamicin versus nafcillin alone in adults with endocarditis, as reviewed by meta-analysis, failed to show any longterm outcome benefit of combination therapy.41 Similarly, tolerance to the bactericidal effect of β-lactam agents among streptococci and staphylococci can be overcome in vitro by drug combinations, but superior clinical efficacy in human infections has not been proven. Combinations of ticarcillin or piperacillin with gentamicin, tobramycin, or amikacin exhibit in vitro synergy against many strains of P. aeruginosa. One prospective, randomized clinical trial of bacteremic patients with cancer confirmed better survival with carbenicillin in combination with gentamicin versus carbenicillin alone.42 Another prospective, but uncontrolled study of 200 patients with Pseudomonas bacteremia documented increased survival in patients receiving combinations, regardless of whether synergy was demonstrable in vitro.43 Confirmatory clinical evidence of the superiority of combination therapy for bacteremia caused by other gram-negative bacilli has been limited to neutropenic patients; such evidence documents the critical importance of susceptibility to the β-lactam component.42,44,45 With the advent of more potent, highly bactericidal agents such as the third-generation cephalosporins and carbapenems, the benefit of addition of an aminoglycoside can be difficult to demonstrate except under the most challenging clinical conditions of sequestered pathogens and an absent host response at the site of infection. Prospective, controlled studies under these conditions are not likely to be performed. A retrospective analysis of more than 4500 bacteremic adults in intensive care units who were treated early with combination therapy documented decreased mortality rates and shorter hospital stays compared with patients who

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were given monotherapy, for both gram-negative and gram-positive pathogens.31,46 Published data exist on the effect of in vitro combination testing for antimicrobial agents approved during the past few decades against common pathogens. Data on some older drugs also may exist, particularly for currently isolated pathogens that can be multidrug resistant. For example, clindamycin and gentamicin in vitro have been reported to show synergy against some strains of viridans streptococci and antagonism against other strains.47 Some studies have shown synergy of trimethoprim-sulfamethoxazole in combination with amikacin against Enterobacteriaceae for organisms that are susceptible to both drugs.48 Ciprofloxacin in combination with an aminoglycoside or various β-lactam agents is infrequently synergistic against Enterobacteriaceae, but it can be synergistic against strains of P. aeruginosa with aminoglycosides or carbapenems49; antagonism is rare. When daptomycin was tested in combination with rifampin or gentamicin against MRSA, additive or indifferent effects usually were observed, without synergy or antagonism. Daptomycin in combination with β-lactam agents showed unexpected synergy in vitro against MRSA. The clinical relevance of these findings requires human clinical investigation.50 Rifampin has synergistic bactericidal activity with vancomycin against coagulase-negative staphylococci51 and with ampicillin against Listeria.52 The unique tissue penetration properties of rifampin make it useful not only in postexposure prophylaxis to prevent or eliminate microbial colonization with meningococcus, but also in combination therapy for infections related to medical devices.

Antagonism Despite the paucity of documented reports of the clinical significance of antagonism among antimicrobial agents, multiple examples are demonstrable in vitro; thus caution is needed in their use, especially for infections in hosts with impaired defenses. Combinations of a bacteriostatic agent with a β-lactam antibiotic can antagonize the bactericidal activity of the β-lactam antibiotic, as documented with the combination of chloramphenicol and ampicillin against group B Streptococcus. Combinations of chloramphenicol or tetracycline and aminoglycosides also are also antagonistic for gram-negative bacilli. In addition, chloramphenicol antagonizes the bactericidal effect of ciprofloxacin against S. aureus, E. coli, and P. aeruginosa. In a combination of agents that bind to similar locations within the ribosome (e.g., clindamycin, erythromycin, spiramycin, chloramphenicol, streptogramins), the drugs can either complement each other and enhance activity or compete with each other and antagonize activity.53

JUDICIOUS USE OF ANTIBIOTICS (ANTIMICROBIAL STEWARDSHIP) Antimicrobial agents are the principal therapeutic tools for pediatric infectious disease specialists and are among the leading interventions in all of pediatrics. Overuse of this tool is increasingly threatening its effectiveness. In 2009, $10.7 billion was spent on antibiotic therapy in the United States. Differences were observed in antibiotic expenditures when these expenditures were analyzed by location of antibiotic sales, with the majority of sales in the outpatient setting, 87% in community pharmacies.54,55 The spread of antimicrobial resistance led to ongoing concern about such unnecessary drug use among physicians and increasingly among patients or parents and resulted in national guidelines for antimicrobial stewardship.56 Common pathogens such as S. pneumoniae and S. aureus typically remain treatable, but resistance in these organisms raises costs and increases the likelihood of treatment failure. Hospital-associated pathogens such as Enterobacter, Klebsiella, Acinetobacter, Pseudomonas, or Enterococcus may not be treatable with available agents.57 Microbial resistance is driven by antimicrobial exposure. Many studies have linked recent exposure to antimicrobial agents to an increased risk for carrying or being infected with resistant pneumococci.58,59 During a course of prophylactic antibiotics to prevent acute otitis media, the proportion of children carrying resistant strains of pneumococci, H. influenzae, and M. catarrhalis increased, with a return to baseline levels only after the selective pressure of the antimicrobial regimen was removed.60 Avoiding such selective pressure that drives resistance by

reducing antimicrobial exposure is the focus of a variety of public health strategies to control resistance. A set of principles from the Centers for Disease Control and Prevention (CDC) for judicious antimicrobial use in children with upper respiratory tract infections summarized scientific evidence for curtailing such use and was published as a guide to appropriate antibiotic use.61 The CDC’s current Get Smart: Know When Antibiotics Work program provides materials for healthcare professions in outpatient and inpatient settings, as well as for parents, that are designed to encourage appro­ priate prescribing practices (http://www.cdc.gov/getsmart/community/ index.html). Programs for judicious use have been studied in private practice, managed care organizations, emergency departments, and community clinics.62–67 Successful reductions in prescribing have been documented when groups in active intervention programs that include both physicians and patients have been compared with groups receiving no intervention other than information. Most importantly, decreased antibiotic use has not led to increased complications of “untreated infections”.62,67 Limited but convincing evidence indicates that the decrease in prescribing of antibiotics is leading to slowing of the spread of resistant bacteria.56,66–68 The Guidelines for Antibiotic Stewardship from the Infectious Diseases Society of America outline strategies to promote appropriate antibiotic selection and duration of therapy and evaluate the potential impact on the development of antibiotic resistance.54 Unfortunately, few

prospective, high-quality investigations specifically in children are available that document the impact of improved practices on a decrease in colonization or infection with resistant organisms.67,68 All references are available online at www.expertconsult.com.

KEY REFERENCES 7. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:e56–e93. 8. Zhang D, Micek ST, Kollef MH. Time to appropriate antibiotic therapy is an independent determinant of postinfection ICU and hospital lengths of stay in patients with sepsis. Crit Care Med 2015;43:2133–2140. 10. Keren R, Shah SS, Srivastava R, Pediatric Research in Inpatient Settings Network, et al. Comparative effectiveness of intravenous vs oral antibiotics for postdischarge treatment of acute osteomyelitis in children. JAMA Pediatr 2015;169:120–128. 33. Toussaint KA, Gallagher JC. β-lactam/β-lactamase inhibitor combinations: from then to now. Ann Pharmacother 2015;49:86–98. 54. Suda KJ, Hicks LA, Roberts RM, et al. A national evaluation of antibiotic expenditures by healthcare setting in the United States, 2009. J Antimicrob Chemother 2013;68:715–718. 57. Pogue JM, Kaye KS, Cohen DA, et al. Appropriate antimicrobial therapy in the era of multidrug-resistant human pathogens. Clin Microbiol Infect 2015;21:302–312. 65. Hersh AL, Jackson MA, Hicks LA, et al. Principles of judicious antibiotic prescribing for upper respiratory tract infections in pediatrics. Pediatrics 2013;132: 1146–1154.

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Importance of appropriate empirical antibiotic therapy for methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother 2010;65:2658–2665. 7. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:e56–e93. 8. Zhang D, Micek ST, Kollef MH. Time to appropriate antibiotic therapy is an independent determinant of postinfection ICU and hospital lengths of stay in patients with sepsis. Crit Care Med 2015;43:2133–2140. 9. Micek ST, Welch EC, Khan J, et al. Resistance to empiric antimicrobial treatment predicts outcome in severe sepsis associated with gram-negative bacteremia. J Hosp Med 2003;6:405–410. 10. Keren R, Shah SS, Srivastava R, et al. Pediatric Research in Inpatient Settings Network. Comparative effectiveness of intravenous vs oral antibiotics for postdischarge treatment of acute osteomyelitis in children. JAMA Pediatr 2015;169:120–128. 11. Tice AD, Rehm SJ, Dalovisio JR, et al. Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines. Clin Infect Dis 2004;38:1651–1672. 12. Jorgensen JH, Ferraro MJ. Antimicrobial susceptibility testing: a review of general principles and contemporary practices. Clin Infect Dis 2009;49:1749–1755. 13. Jorgensen JH. Who defines resistance? The clinical and economic impact of antimicrobial susceptibility testing breakpoints. Semin Pediatr Infect Dis 2004;15: 105–108. 14. Ericsson HM, Sherris JC. Antibiotic sensitivity testing: report of an international collaborative study. Acta Pathol Microbiol Scand [B] Microbiol Immunol 1971;217(suppl 217):1+. 15. Bauer AW, Kirby WM, Sherris JC, et al. Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol 1966;45:493–496. 16. 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Briones E, Colino CI, Lanao JM. Delivery systems to increase the selectivity of antibiotics in phagocytic cells. J Control Release 2008;125:210–227. 24. Mandell GL. Uptake, transport, delivery, and intracellular activity of antimicrobial agents. Pharmacotherapy 2005;25:130S–133S. 25. Van Bambeke F, Barcia-Macay M, Lemaire S, et al. Cellular pharmacodynamics and pharmacokinetics of antibiotics: current views and perspectives. Curr Opin Drug Discov Devel 2006;9:218–230. 26. Gordon EM, Blumer JL. Rationale for single and high dose treatment regimens with azithromycin. Pediatr Infect Dis J 2004;23(suppl):S102–S107. 27. Jaruratanasirikul S, Hortiwakul R, Tantisarasart T, et al. Distribution of azithromycin into brain tissue, cerebrospinal fluid, and aqueous humor of the eye. Antimicrob Agents Chemother 1996;40:825–826. 28. Bradley JS, Ching DK, Hart CL. Invasive bacterial disease in childhood: efficacy of oral antibiotic therapy following short course parenteral therapy in non-central nervous system infections. Pediatr Infect Dis J 1987;6:821–825. 29. Lutsar I, Telling K, Metsvaht T. Treatment option for sepsis in children in the era of antibiotic resistance. Expert Rev Anti Infect Ther 2014;12:1237–1252. 30. Sick AC, Tschudin-Sutter S, Turnbull AE, et al. Empiric combination therapy for gram-negative bacteremia. Pediatrics 2014;133:e1148–e1155. 31. Vazquez-Grande G, Kumar A. Optimizing antimicrobial therapy of sepsis and septic shock: focus on antibiotic combination therapy. Semin Respir Crit Care Med 2015;36:154–166. 32. American Thoracic Society, Centers for Disease Control and Prevention, Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1–77. 33. Toussaint KA, Gallagher JC. β-lactam/β-lactamase inhibitor combinations: from then to now. Ann Pharmacother 2015;49:86–98.

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Overcoming bacterial resistance by dual target inhibition: the case of streptogramins. Curr Drug Targets Infect Disord 2001;1:215–225. 40. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005;111:e394–e434. 41. Falagas ME, Matthaiou DK, Bliziotis IA. The role of aminoglycosides in combination with a beta-lactam for the treatment of bacterial endocarditis: a meta-analysis of comparative trials. J Antimicrob Chemother 2006;57:639–647. 42. Klastersky J, Glauser MP, Schimpff SC, et al. Prospective randomized comparison of three antibiotic regimens for empirical therapy of suspected bacteremic infection in febrile granulocytopenic patients. Antimicrob Agents Chemother 1986;29:263–270. 43. Hilf M, Yu VL, Sharp J, et al. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients. Am J Med 1989;87:540–546. 44. Klibanov OM, Raasch RH, Rublein JC. Single versus combined antibiotic therapy for gram-negative infections. Ann Pharmacother 2004;38:332–337. 45. Paul M, Benuri-Silbiger I, Soares-Weiser K, et al. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ 2004;328:668. 46. Kumar A, Zarychanski R, Light B, et al. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensitymatched analysis. Crit Care Med 2010;38:1773–1785. 47. Duperval R, Bill NJ, Geraci JE, et al. Bactericidal activity of combinations of penicillin or clindamycin with gentamicin or streptomycin against species of viridans streptococci. Antimicrob Agents Chemother 1975;8:673–676. 48. Parsley TL, Provonchee RB, Glicksman C, et al. Synergistic activity of trimethoprim and amikacin against gram-negative bacilli. Antimicrob Agents Chemother 1977;12:349–352. 49. Giamarellou H, Petrikkos G. Ciprofloxacin interactions with imipenem and amikacin against multiresistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 1987;31:959–961. 50. Steenbergen JN, Mohr JF, Thorne GM. Effects of daptomycin in combination with other antimicrobial agents: a review of in vitro and animal model studies. J Antimicrob Chemother 2009;64:1130–1138. 51. Lowy FD, Chang DS, Lash PR. Synergy of combinations of vancomycin, gentamicin, and rifampin against methicillin- resistant, coagulase-negative staphylococci. Antimicrob Agents Chemother 1983;23:932–934. 52. Tuazon CU, Shamsuddin D, Miller H. Antibiotic susceptibility and synergy of clinical isolates of Listeria monocytogenes. Antimicrob Agents Chemother 1982;21:525–527. 53. Auerbach T, Mermershtain I, Davidovich C, et al. The structure of ribosomelankacidin complex reveals ribosomal sites for synergistic antibiotics. Proc Natl Acad Sci USA 2010;107:1983–1988. 54. Suda KJ, Hicks LA, Roberts RM, et al. A national evaluation of antibiotic expenditures by healthcare setting in the United States, 2009. J Antimicrob Chemother 2013;68:715–718. 55. Hicks LA, Bartoces MG, Roberts RM, et al. U.S. outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. Clin Infect Dis 2015;60:1308–1316. 56. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007;44:159–177. 57. Pogue JM, Kaye KS, Cohen DA, et al. Appropriate antimicrobial therapy in the era of multidrug-resistant human pathogens. Clin Microbiol Infect 2015;21:302–312. 58. Samore MH, Magill MK, Alder SC, et al. High rates of multiple antibiotic resistance in Streptococcus pneumoniae from healthy children living in isolated rural communities: association with cephalosporin use and intrafamilial transmission. Pediatrics 2001;108:856–865. 59. Hicks LA, Chien YW, Taylor TH Jr, et al. Active Bacterial Core Surveillance (ABCs) Team. Outpatient antibiotic prescribing and nonsusceptible Streptococcus pneumoniae in the United States, 1996−2003. Clin Infect Dis 2011;53:631–639. 60. Brook I, Gober AE. Prophylaxis with amoxicillin or sulfisoxazole for otitis media: effect on the recovery of penicillin-resistant bacteria from children. Clin Infect Dis 1996;22:143–145. 61. Dowell SF, Marcy SM, Phillips WR, et al. 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66. Low DE, Pichichero ME, Schaad UB. Optimizing antibacterial therapy for community-acquired respiratory tract infections in children in an era of bacterial resistance. Clin Pediatr (Phila) 2004;43:135–151. 67. Pichichero ME, Green JL, Francis AB, et al. Outcomes after judicious antibiotic use for respiratory tract infections seen in a private pediatric practice. Pediatrics 2000;105:753–759. 68. Patel SJ, Larson EL, Kubin CJ, et al. A review of antimicrobial control strategies in hospitalized and ambulatory pediatric populations. Pediatr Infect Dis J 2007;26:531–537.