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Long: Principles and Practice of Pediatric Infectious Diseases, 3rd ed.


Copyright 2008 Churchill Livingstone, An Imprint of Elsevier

Section B Anti-Infective Therapy

CHAPTER 289 Principles of Anti-Infective Therapy


John S. Bradley, Sarah S. Long When a child develops signs and symptoms consistent with a bacterial infection, the clinician must first decide if the child's illness is caused by an infection or other inflammatory process, and subsequently, whether an infection is likely to be caused by a microorganism that is susceptible to antibiotic therapy. Furthermore, for the child who may benefit from antimicrobial therapy, the clinician must select an agent that is the safest and most effective at curing the child's infection. Inappropriate antibiotic therapy given to a child with a viral infection exposes the child needlessly to the toxicities inherent in the antibiotic, adds to the selective pressure driving antibiotic resistance in bacteria, creates unnecessary costs to the medical system and may divert the focus of attention from the most appropriate evaluation and therapy for the child's actual infection. The selection of optimal antibiotic therapy for presumed bacterial infection is based on deduction of balance, benefits, and risks of specific therapy for each child.

SELECTING OPTIMAL ANTIMICROBIAL THERAPY


A number of questions must be addressed sequentially in order to choose optimal empiric and definitive antimicrobial therapy. They 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 below. BOX 289-1 Questions Pertinent to Choosing Antimicrobial Therapy Appropriately 1. 2. What is the clinical syndrome/site of infection? Pathogens are predictable by site Does the child have normal defense mechanisms (in which case causative agents are predictable) or are they impaired by underlying conditions, trauma, surgery, or a medical device (in which case causative agents are less reliably predictable)? What is the child's age? Pathogens are predictable by age What clinical specimen(s) should be obtained to guide empirical/definitive therapy? 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? What special pharmacokinetic and pharmacodynamic properties of a therapeutic agent are important regarding the site of the infection host? For any given infection site, what percent of children require effective antimicrobial therapy with agents first selected for treatment? Bacterial meningitis requires 100%, whereas 75% may

3. 4. 5.

6. 7.

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be acceptable for impetigo 8. What empiric therapy and what definitive therapy would be optimal? Agents with a broad spectrum of activity may be appropriate for empiric therapy, whereas those with a narrow spectrum of activity are preferred for definitive therapy What special considerations exist regarding drug allergy, drug interaction, route of administration, cost, alteration of flora, or selective pressure in an environment?

9.

Step 1: Predict the Infecting Organism


The first step in predicting the pathogen is to define the patient's site(s) of infection or the organ systems involved. Bacteria are tropic for tissues locally following invasion; certain species have a proclivity for causing certain infections. Examples are 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. On the other hand, certain pathogens can almost be dismissed in some circumstances when the site of infection is identified. Examples are S. aureus and Streptococcus pyogenes for meningitis and S. pneumoniae and Staphylococcus aureus for urinary tract infection.

Step 2: Consider Host Defense Mechanisms


The second question is whether the host is healthy, with intact immunity and normal integumental barriers to infection. If so, the causative pathogens are predictable. If the child has an underlying condition such as a defect in granulocyte number or function, or a B- or T-lymphocyte immunologic defect, whether congenital or acquired, nonpathogenic bacteria from both the host and the environment can cause infection. For an immune-competent child with trauma to skin or mucous membranes, a recent surgical procedure, or an indwelling medical device, a variety of relatively nonpathogenic commensals can also be causative pathogens, mandating therapy with an antibiotic or antibiotics that provide activity against a much broader range of organisms.

Step 3: Consider the Age of the Child


Infectious agents causing specific organ infections in immunocompetent hosts are predictable in many circumstances based on the age of the child and age-specific exposures. Examples are limitation of meningitis due to group B streptococci, Escherichia coli, and Listeria to the first 90 days of life. Developmental maturity of the immune system provides improved recognition of polysaccharideencapsulated pathogens such as Streptococcus pneumoniae or H. influenzae type b as infants approach the third year of life. Group childcare exposures in young infants are linked to the carriage of, and infection by, antibiotic-resistant strains of S. pneumoniae, requiring the practitioner to increase the antibiotic spectrum of selected agents in order to achieve the same level of treatment success as that achieved for a child not in group childcare. School-related exposure to S. pyogenes is associated with increased age-specific attack rates of infection, which is low in young infants. Likewise, adolescent exposure to sexually transmitted disease pathogens increases the potential causes of pyogenic arthritis such as Neisseria gonorrhoeae.

Step 4: Perform Diagnostic Tests


Every effort should be made to prove the etiology of the infection and obtain an isolate for susceptibility testing. The Gram stain is perhaps the simplest, least expensive, and most useful of the rapid tests because it provides 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 Gram stain result of a tissue sample may 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. In meningitis, the finding of gram-negative diplococci visualized on Gram stain of cerebrospinal fluid (CSF), suggesting N. meningitidis, should not exclude the possibility of H. influenzae

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type b, or of S. pneumoniae. An error in processing or interpreting the Gram stain must not lead to ineffective therapy of bacterial meningitis. Similarly, a Gram stain that demonstrates gram-positive cocci in clusters from endotracheal secretions in a neutropenic child with pneumonia should lead to the addition of agents active against staphylococci, not the elimination of agents active against Pseudomonas aeruginosa. Molecular techniques are emerging from research applications and are being used more frequently in clinical laboratories for the diagnosis of bacterial infections. Polymerase chain reaction is used to identify bacteria, viruses, and other microorganisms in a variety of specimens, and probes are used to identify organisms recovered in culture (see Chapter 286 , Laboratory Diagnosis of Infection Due to Bacteria, Fungi, Parasites, and Rickettsiae, and Chapter 287 , Laboratory Diagnosis of Infection due to Viruses, Chlamydia, and Mycoplasma). Advantages are obvious, but standardization and lack of an isolate for susceptibility testing are problems. [1]

Step 5: Consider Antibiotic Susceptibilities of Suspected Pathogens


Bacteria have a wide range of antibiotic resistance patterns (see Chapter 290 , Mechanisms of Antibiotic Resistance). Organisms can have single or multiple different mechanisms of resistance against a single antibiotic. Resistance mechanisms include ways: to keep the antibiotic out of the organism (cell wall changes or efflux pumps); inactivation of antibiotics enzymatically; alterations of the target binding site of the antibiotic; of these mechanisms. Organisms can have resistance mechanisms against antibiotics of a single class or many different classes. They can express resistance constitutively, or only on exposure to an antibiotic (inducible resistance). Some pathogens can have genetic dysregulation leading to the constitutive hyperproduction of resistance factors such as beta-lactamases. With such vast biologic variability in resistance mechanisms and efficient transmission of resistance genes between organisms, it is understandable that a single organism such as E. coli can manifest different patterns of antibiotic resistance in different populations within the same region, between regions of a country, and between countries of the world. In a single community, the E. coli causing a urinary tract infection likely has a very different resistance pattern in the child who was previously healthy and unexposed to antibiotics versus the patient with relapsed leukemia who has had a prolonged hospitalization in an Oncology Unit in a tertiary care pediatric hospital versus the prematurely born infant in an intensive care unit. The resistance patterns of E. coli from cities in the United States differ from those in Buenos Aires and Hong Kong due to local differences in antibiotic pressure and the types of transmissible resistance factors present in each location. Regardless of which population is under study, however, a range of susceptibilities is always present: some organisms are relatively more susceptible and others more resistant to specific agents. The hospital antibiogram is a widely available tool that allows the clinician to assess the current local resistance pattern for each pathogen and each antibiotic. These antibiograms are updated annually, as the resistance patterns can change substantially within a 12-month period. 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/Pharmacodynamic Properties of Drugs


The route of administration, the absorption, the tissue distribution of antibiotic at the site of infection, and the drug elimination characteristics are all critical pieces of information to guide the selection of both drug and drug dosage in antimicrobial therapy (see Chapter 291 , PharmacokineticPharmacodynamic Basis of Optimal Antibiotic Dosing). Eradication of pathogens causing infection requires the appropriate antibiotic exposure in the infected tissues. [2] For many agents, particularly those that have been investigated recently, 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 is often unavailable. To understand best how effective an antibiotic will be in achieving a microbiologic cure using otitis media and amoxicillin treatment as an example, information is required on the average and range of concentrations achievable in the middle-ear fluid following administration of a specific Food and Drug Administration (FDA)-approved dosage of amoxicillin, as well as the characteristics of amoxicillin elimination from this particular body site over time. These data provide a measure of exposure of the amoxicillin to

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bacteria in the middle-ear fluid (MEF). Based on the amoxicillin exposure required to achieve a microbiologic cure (presence of amoxicillin in MEF for at least 30-40% of each dosing interval), the proportion of children given that specific dosage who would likely respond or fail treatment is predictable. For different classes of antibiotics, different types of drug exposure may be required for bacterial eradication. [3] In the treatment of meningitis, adequate antibiotic concentrations in the CSF are critical for cure. The concentration of aminoglycoside antibiotics in the CSF following intravenous infusion is likely inadequate as single antibiotic therapy to treat meningitis caused by gram-negative pathogens, despite the fact that CSF concentrations are roughly 20% of those achievable in serum (see Chapter 292 , Antimicrobial Agents). In contrast, although CSF concentration of penicillin is only 5% of that achievable in serum, the high serum concentration leads to adequate CSF concentration if the pathogen has exquisite susceptibility to penicillin. Within the range of predictable tissue penetration of antimicrobial agents there is considerable variability among children receiving the same dose of drug. For example, antibiotic concentrations in the middle-ear space can be inadequate in a low but predictable percentage of children given the same mg/kg oral dosage. However, unlike acute otitis media, the clinician (and thus, dosing recommendations) cannot risk inadequate dosing for even one child with meningitis. The inherent variability among children of serum and site-of-infection tissue concentrations of antibiotics are relevant to other infections, such as pyogenic arthritis, pyomyositis, cellulitis, pneumonia. Clearly, one single dosage of an antibiotic may not be appropriate and effective for all susceptible pathogens causing infection at all tissue sites. The absorption, distribution, and elimination of drugs are variable in children by age and developmental changes. [4] [5] The volume of distribution of antibiotics varies profoundly during the first few years of life, being greater in the neonate than in the infant. Drug elimination based on organ function generally increases during the first several weeks of life, peaks in infancy, and approaches adult values during adolescence. Many antibiotics require different dosages during these stages of life in order to achieve the most appropriate antibiotic exposure to maximize efficacy and minimize toxicity (see Chapter 292 , Antimicrobial Agents) ( Table 289-1 ). TABLE 289-1 -- Pharmacodynamic Antibacterial Effect of Antimicrobial Agents by Primary Bacterial Target and by Antibiotic Class Primary Target [a] Cell wall Antibacterial Class -Lactams Penicillins Cephalosporins Monobactams Carbapenems Glycopeptides Vancomycin Teicoplanin [d] Cell membrane Lipopeptides Daptomycin Polymyxins Bactericidal Concentration-dependent Long PAE (daptomycin) PAE (polymyxins) Not known Carbapenems PAE against gram-positive and gram-negative organisms Pharmacodynamics [b] Bactericidal Time-dependent PAE only against gram-positive organisms Intracellular activity [c] Not generally effective

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Primary Target [a]

Antibacterial Class Polymyxin B Colistin

Pharmacodynamics [b]

Intracellular activity [c]

Ribosome

Macrolides, azalides, ketolides Tetracyclines, glycylcyclines Lincosamides (clindamycin) Aminoglycosides

Bacteriostatic or -cidal (Ketalides) Time- and concentration-dependent Long PAE Bacteriostatic Time-dependent Long PAE Bactericidal or -static Time-dependent PAE Bactericidal Concentration-dependent PAE Bacteriostatic (except against Streptococcus pneumoniae) Concentration-dependent PAE Bactericidal Long PAE Bactericidal Concentration-dependent Long PAE Bactericidal (except against Enterococcus. faecium) Concentration-dependent PAE Bactericidal Concentration-dependent PAE Bactericidal Concentration-dependent

Yes Yes

Yes

Not effective generally Not effective generally

Oxazolidinones

Rifamycins

Yes

Quinolones

Yes

Streptogramins

Yes

Nucleic acid

Metronidazole

Yes

Sulfamethoxazoletrimethoprim References for Table 289-1 : 72-102.

Yes

PAE, postantibiotic effect, or the observation of delay in regrowth of organisms following removal of antibiotic from the media.

a The primary antibiotic target within the bacterial pathogen. b The type of pharmacodynamic relationship that best describes antibiotic-mediated inhibitory or bactericidal activity.

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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 Not marketed in the United States.

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 (see Chapter 291 , PharmacokineticPharmacodynamic Basis of Optimal Antibiotic Dosing). Aminoglycosides kill bacteria in a concentration-dependent fashion. Therefore, it is desirable to achieve the highest concentrations possible at the site of infection. Unfortunately, the maximum safe serum concentration is limited by risk of toxicity. For other antibiotic classes, such as the penicillins, achieving tissue concentration above the minimum inhibitory concentration (MIC) for that pathogen for 30-40% of the dosing interval is associated with microbiologic and clinical cure. For this class of antibiotic, a higher concentration of penicillin at the infected tissue site is not associated with more rapid sterilization of tissues or better clinical outcome, although higher serum concentrations would likely be safe. The postantibiotic effect is also considered in dosing of antibiotics (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 below the MIC before regrowth occurs of organisms that remain viable after initial antibiotic exposure. On the other hand, exposure to other antibiotics (e.g., most macrolides) inhibits growth only until the antibiotic concentration drops below the MIC. Differences probably reflect molecular mechanisms of antibiotic activity by target site (e.g., ribosome or cell wall), 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 can generally be inhibited at a certain antibiotic concentration (the MIC), as defined by standard laboratory techniques, antibiotic dosages that lead to less frequent emergence of resistance can be better defined using higher inocula than those employed in standard clinical assays. Mechanisms of resistance include spontaneous nucleic acid mutations leading to amino acid changes that result in less avid target site binding. These single-step mutations often may lead to a slightly higher MIC for the mutant. The antibiotic concentration required to inhibit the single-step mutation may or may not be achievable in infected tissues. Second-step mutations in viable organisms during continual exposure to an antibiotic can lead to more profound changes in the MIC, rendering the organisms fully resistant at the highest tissue concentrations attainable. It is often possible to identify the concentration of antibiotic required to prevent the selection of viable single-step mutants, the mutant prevention concentration (MPC), which is often two- or threefold higher than the standard MIC. [6] [7] If the higher dosage required for the MPC can be achieved in tissues without undue toxicity, the risk of selecting antibiotic-resistant strains that can subsequently affect that child or his/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 bothersome (e.g., impetigo), but not life-threatening, achieving a cure rate of 70% to 80% with a safe and inexpensive antibiotic is often acceptable, especially if use of an alternative agent to achieve a 98% success rate has excessive risk of toxicity or high cost. For other infections that cause a degree of suffering or risk of organ damage (e.g., pyelonephritis or acute otitis media), the cure rate of 80% to 90% is often desirable. For serious, life-threatening infections (e.g., bacterial meningitis or septicemia in a neutropenic child), a cure of 100% must be achieved. [3] No formal list of approved cure rates, also called target attainments, exists. Accepted target attainment may differ between diseases, physicians, families, and societies. Collaborative understanding of the range of targeted cure rate is applicable to each child with any infection, from the premature infant with urosepsis, to the child with congenital heart disease and endocarditis, to the child with scoliosis and a device-associated infection. Setting targets can help clarify decision-making regarding relative merits, risks, and costs of management.

Step 8: Separate Empiric and Definitive Therapeutic Decisions

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Empiric therapy is selected based on the presumed pathogens at the site of infection, the local resistance patterns of the presumed pathogens as outlined above, and the desired cure rates selected by the clinician. In general, the sicker child demands treatment dosages and antibacterial activity associated with a higher rate of cure. Therefore, antibiotics with appropriately broad antibacterial activity at the highest tolerated dosage are selected for empiric therapy. Data suggest that adequate empiric therapy compared with inadequate empiric therapy for seriously ill adults is associated with decreased mortality and shorter hospital stays. [8] [9] [10] For the seriously ill child, knowledge of the local resistance patterns for suspected pathogens should lead to selection of antibiotics with a likely achievable cure rate of greater than 95%. Less critically ill children may not require broad-spectrum agents as empiric therapy, particularly if culture results can provide information within 48 to 72 hours on the most appropriate narrow-spectrum antimicrobial therapy, and the risks of delayed appropriate therapy are acceptable to the clinician and the family. Combination therapy is frequently given to ensure the appropriate antimicrobial activity against potential pathogens. Combination of vancomycin plus a third-generation cephalosporin is used for empiric treatment of community-acquired meningitis, as Streptococcus pneumoniae with decreased susceptibility to -lactam agents is a concern. Empiric therapy for meningitis in the first 2 months of life consists of ampicillin plus an aminoglycoside or third-generation cephalosporin because the possible causative agents include Listeria monocytogenes, group B streptococcus, and Escherichia coli. Long-established combination therapies or broad-spectrum monotherapy is currently recommended for febrile neutropenic patients to ensure activity against Pseudomonas aeruginosa, enteric gram-negative bacilli, and Staphylococcus aureus. [11] Because particular organisms are indigenous to a center, because differences exist in underlying diseases, treatments and host factors in children, and because different nosocomial pathogens are prevalent in children's centers versus adults' centers, caution is urged against simple adoption of strategies reported to be efficacious in adults. Once the pathogen is identified, a narrow-spectrum agent can frequently provide the same 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 ventilator-associated pneumonia can be narrowed to cefotaxime if the pathogen isolated is a susceptible Klebsiella species rather than Pseudomonas aeruginosa. A postoperative wound infection treated with vancomycin and cefotaxime can be narrowed to ampicillin if a susceptible E. coli, rather than methicillin-resistant Staphylococcus aureus (MRSA) or Enterobacter species, is isolated. 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 beta-lactamase-stable penicillin if the organism is not MRSA. In this way, the lifespan of clindamycin as an antistaphylococcal agent may be prolonged by decreasing exposure. Definitive, convalescent outpatient therapy of serious infections initially treated in the hospital can be acceptable if the risks of complications of the infection are negligible, the parents and child can adhere to well defined management plans and can return to hospital quickly for any infection- or therapy-related problem. Situations exist in which either convalescent oral therapy or convalescent parenteral therapy is preferred. High-dose beta-lactam therapy orally for bone and joint infections is one of the best evaluated step-down therapies of invasive infection. [12] Outpatient parenteral convalescent therapy (intravenous or intramuscular) of serious bacterial infections is sometimes chosen when adherence to oral antibiotic therapy is a concern, or vomiting or diarrhea could affect absorption of drug given orally. Although antibiotics that can be administered once daily such as ceftriaxone are advantageous, specific susceptibility of the pathogen and non protein-bound antibiotic concentrations at the tissue site also must be considered. An agent with narrow or better targeted activity that requires multiple daily administrations, or multiple agents, has been administered successfully in outpatients. [13]

Step 9: Special Considerations


Considerations of drug allergy for a particular agent, agents of the same type, or agents in the same class impact selection. The degree and type of drug reaction should be obtained. 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 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

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antibiotic formularies that contain approved, less costly antibiotics with a narrow spectrum of activity. The antibiotic resistance pattern of the suspected pathogen provides guidance for the likelihood of cure using a particular agent. As antibiotic resistance in a community increases and failures with older, less active agents increase proportionately, formularies must be reassessed. An acceptable risk of failure needs to be determined by the treating physicians and medical advisors to the health plan 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 purpose of performing antimicrobial susceptibility testing on clinical isolates is to guide individual therapeutic decisions and amass collective data to apply when a pathogen is predicted but not proved. A detailed discussion of susceptibility testing is presented in Chapter 286 , Laboratory Diagnosis of Infection Due to Bacteria, Fungi, Parasites, and Rickettsiae. Susceptibility testing is routinely unnecessary for only a few bacteria, which might include organisms that are predictably susceptible to penicillins, for example, Streptococcus pyogenes and other -hemolytic streptococci, anaerobic streptococci, clostridia, Eikenella corrodens, and Pasteurella multocida. Testing is important for the vast majority of clinical isolates as they can display one or more mechanisms of antibiotic resistance or different susceptibility patterns in different regions of the world or in different patient populations. A comparison of the antibiograms from cultured pathogens can provide guidance for interpretation of the clinical relevance of two or more isolates from an individual patient (e.g., coagulase-negative staphylococci as a true pathogen vs. contaiminant) or in preliminary assessment of a nosocomial outbreak (e.g., gram-negative bacilli) prior to the use of more sophisticated molecular techniques to differentiate pathogens within a species.

Interpretation of Susceptibility Test Results


An assortment of routine susceptibility tests can be performed, including the disk diffusion (BauerKirby) test, an antibiotic strip gradient-diffusion method (E-test), agar dilution with a mechanized inoculator, broth macrodilution or microdilution (with or without the use of an instrument or a growth indicator), and the shortincubation automated instrument method. [14] [15] Results are usually 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 two most common methods employed to assess susceptibility are the minimum concentration of antibiotic required for inhibition of growth in micrograms/mL (MIC), and the measured diameter in millimeters of inhibition of growth around an antibiotic-containing disk in the BauerKirby disk diffusion technique. The MIC value provides an operational definition of a strain's intrinsic antibiotic susceptibility, generally incorporating the additive effects of multiple mechanisms of resistance, if present. Standardizing these susceptibility techniques and interpretation has largely been the task of the Clinical and Laboratory Standards Institute (CLSI, formerly National Committee on Clinical Laboratory Standards, or NCCLS). This nonprofit organization is comprised of participants from the pharmaceutical industry, the testing device manufacturers, the CDC, the FDA, and academic institutions. Interpretation and clinical application of MIC values are required. [16] Misunderstanding of the absolute values of the MICs can lead to errors in antibiotic management. Examples of misinterpretation could be that ampicillin and gentamicin MICs of 4 g/mL for E. coli denote equivalence, or that the vancomycin MIC of 1 g/mL and the ampicillin MIC of 2 g/mL for Enterococcus denote the superiority of vancomycin. The variables of the former were discussed in the landmark report by Ericsson & Sherris, [17] which formed the basis for the categoric interpretations recommended by Bauer and colleagues [18] and the CLSI. [19] The interpretation of the susceptitibility test results is provided by the laboratory report as S (sensitive), I (intermediate), or R (resistant). A report of S suggests that treatment with standard FDA-approved dosages could be expected to lead to clinical success if tissue concentration of drug at the infected site mimics the serum concentration. A report of I suggests that some clinical failures can be expected at standard dosages due to decreased susceptibility of the pathogen to that antibiotic. A report of R suggests that a microbiologic cure is unlikely as the pathogen is not inhibited by the antibiotic at achievable tissue concentrations. Susceptibility testing predicts failure better than success. Categorization is most valid when MIC values indicate a widely spaced, distinctly bimodal distribution of susceptible and resistant strains, such as Staphylococcus aureus for penicillin and Escherichia coli for ampicillin. The MIC values at which an organism is considered S, I, or R are called the breakpoints. [16] The uniformity imposed

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by arbitrary breakpoints for interpretation is frequently not microbiologically sound, such as in the continuum of MIC values of penicillin for Streptococcus pneumoniae or MIC values of aminoglycosides for P. aeruginosa. [20] The interpretion of the clinical relevance of MICs is based on: (1) the susceptibility of isolates in a large population (range and mode of distribution, such as unimodal, bimodal, skewed); (2) the clinical pharmacology of the drug (protein binding, volume of distribution, tissue concentations); and (3) clinical and microbiologic efficacy derived from prospective animal models and 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 (sometimes at specific tissue sites). As organisms develop new mechanisms for resistance, the interpretation of the susceptibility test results (the breakpoints) for a particular organism and a particular antibiotic can change. For example, when ceftriaxone was first approved for use in children, S. pneumoniae was considered susceptible if the MIC value was 8 g/mL. Pneumococci then developed a novel mechanism of resistance, alterations in the penicillin-binding site on the cell-wall-synthesizing transpeptidase enzymes. Beginning in 1990, microbiologic failures in the treatment of meningitis occurred in children infected by organisms with ceftriaxone MIC of 2 g/mL. The breakpoints were subsequently changed so that only organisms with MIC 0.5 g/mL were considered susceptible. However, with the knowledge that ceftriaxone concentrations in tissues other than the CSF are higher, prospective data were collected that documented clinical and microbiologic success of ceftriaxone for noncentral nervous system infections in which the MIC for Streptococcus pneumoniae was 2.0 g/mL. Subsequently, two breakpoints for ceftriaxone were proposed: a lower breakpoint of 0.5 g/mL for central nervous system infection, and a higher breakpoint of 1.0 g/mL for noncentral nervous system infections. The process of regular review of breakpoints for important pathogens against commonly used antibiotics is not well standardized. The clinician can never assume that an antibiotic will be effective in all clinical situations when the MIC leads to an S interpretation in the laboratory report. Furthermore, since S only indicates likely inhibition, the need for a bactericidal agent under certain conditions must be considered.

SITE OF INFECTION
As a rule, only free, nonprotein-bound drug is active in eradicating pathogens. For -lactam agents, excessive concentrations of antibiotic present at the site of infection are not more efficacious in bacterial eradication, as this class of agents displays time-dependent killing. Higher concentrations at the site of infection may enhance killing for aminoglycosides and other concentration-dependent drugs. [21] Subinhibitory concentrations are not always ineffective; however, morphology and adherence properties can be altered after exposure to subinhibitory concentrations of some antibiotics, with phagocytosis and intracellular killing enhanced by neutrophils.

Extracellular Infections
Most bacterial infections occur in interstitial tissue fluid. For such infections, serum concentrations of antibiotics generally predict responses adequately. Antibiotics leave the vasculature and enter the extracellular fluid (ECF) via passive diffusion. When the ratio of the surface area of vascular tissue to the site or volume of infection (SAV/V) is high (e.g., in cellulitis, pneumonia, 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, cardiac vegetation, skin blister, or tissue cage animal model). Passive diffusion principles alone also cannot be used to predict the ECF 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 bloodbrain barrier better than do the more highly ionized aminoglycosides. For meningitis, relatively large dosages of third-generation cephalosporins, penicillin G, ampicillin, or vancomycin are required in order to achieve adequate concentrations in the CSF. Additionally, active transport out of the ECF, including the CSF, can also result in reduced concentrations of certain antibiotics such as -lactam agents. Table 292-1 delineates the distribution characteristics of the major classes of antibiotics. Clinical evidence

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has indicated the inferiority of 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 (e.g., urine, bile). The vegetations of endocarditis, devitalized tissue, and bones are areas in which the penetration of most agents may be poor; high-dose and prolonged parenteral therapy is usually required, and surgical debridement is sometimes adjunctive or necessary therapy. The pharmacology of the drug can offer particular advantages. Agents eliminated by glomerular filtration, renal tubular secretion, or both accumulate in urine. Quinolones, a few -lactam agents (such as ampicillin, ceftriaxone and especially 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. The primary effects of the protein binding of antibiotics are slowing of excretion by glomerular filtration and a reduction in the volume of distribution. Although only free drug passes through capillary walls and fibrin clots, intercompartmental and pathogen end-target dynamic changes in binding, reversibility, and complex interactions at the tissue site probably account for the complexities in interpretation of clinical efficacy as a result of the degree of protein binding. Only free drug is considered capable of antibiotic activity. [22] Most examples of the poor activity of highly protein-bound drugs involve staphylococci. Multiple biologic factors affect the extent of protein binding: antibiotic concentration, the nature and concentration of protein, pH, lipid solubility, competition with other drugs or biologic components (e.g., bilirubin or fatty acids), and disease states such as uremia. In general, the plasma protein binding of aminoglycosides and quinolones is low, whereas binding is low to very high for -lactam agents. A high degree of protein binding precludes the use of sulfa drugs, ceftriaxone, and nafcillin in jaundiced neonates because the potential competitive displacement of bilirubin from albumin facilitates the diffusion of bilirubin into the brain. Multiple factors at the site of infection can also alter antimicrobial activity. Examples include the presence of purulent material, which can bind and inactivate aminoglycosides; copathogens such as Bacteroides and Prevotella, which produce -lactamase and can hydrolyze -lactam agents [23] ; hematoma, which lowers the SAV/V and contains hemoglobin that binds penicillins and tetracyclines [24] ; low oxygen tension in abscesses or ischemic tissue, which impairs active transport of aminoglycosides into bacterial cells; acid pH in tissue or urine, which impairs the activity of aminoglycosides, nitrofurantoin, and methenamine; alkaline pH, which enhances the activity of aminoglycosides and clindamycin; high-density infection such as streptococcal necrotizing fasciitis, which slows the bacterial growth rate, thereby downregulating target transpeptidases for -lactam agents [25] ; and the presence of a foreign body, which protects the organism from host bactericidal 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 eukaryotic cells (see Table 289-1 ). -Lactam antibiotics, for example, are almost exclusively confined to plasma water and the interstitial fluid space. Such localization explains some discrepancies between apparent in vitro activity and therapeutic ineffectiveness; the performance of susceptibility tests in cocultivation with phagocytic cells may be more predictive. Intracellular pathogens include Listeria monocytogenes, Salmonella, Brucella, Legionella, Mycobacterium, Rickettsia, and Toxoplasma, as well as persisting infections with Staphylococcus aureus and E. coli. Antibiotics that enter cells do so by a variety of mechanisms, such as diffusion of relatively small lipid-soluble agents across a concentration gradient, pinocytosis of water-soluble agents, and carrier-mediated transport. [26] 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, and the molecular charge of the intracellular antibiotic. Aminoglycosides accumulate slowly in intracellular lysosomes and mitochondrial organelles, where they bind irreversibly and thus have no antibacterial effect. Clindamycin, macrolides, and azalides are tropic for lysosomes, where they become protonated and concentrated. [26] This change can enhance therapeutic efficacy, but in one study, neither agent was active against susceptible strains of S. aureus within neutrophils. [27] Quinolones have a large volume of distribution and a high tissue-to-serum ratio, and low-affinity intracellular binding; much of the quinolone body load is thus present intracellularly. For

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azithromycin, an even more dramatic intracellular location of antibiotic has been documented, particularly within phagocytic cells. The pharmacokinetic properties and intracellular accrual of azithromycin are responsible for unique applications and shortened courses of therapy [28] [29] ; at the same time, it is noteworthy that drug concentrations in serum, CSF, and the aqueous humor of the eye are almost negligible. [30]

DOSING, ROUTE, AND DURATION OF THERAPY


Optimal dosing of an antimicrobial agent depends on relationships between the concentration at the site of infection, the characteristics of antimicrobial activity, and the particulars of its elimination and adverse effects (see Chapter 291 , PharmacokineticPharmacodynamic Basis of Optimal Antibiotic Dosing). Unfortunately, the optimal route of administration of antibiotics is often exchanged for the optimal setting of administration. Parenteral administration is required if an agent is poorly absorbed from the gastrointestinal tract, if a condition precludes administration or absorption of a usually absorbed drug, if an unusually high tissue concentration of drug is required, or if adherence to an oral regimen for treatment of a significant disease cannot be ensured. Otherwise, substitution of oral for parental agents is frequently possible, even for serious diseases (e.g., pneumonia, osteomyelitis, pyogenic arthritis, orbital cellulitis) during convalescent therapy. Oral therapy can replace parenteral therapy when highly absorbed agents are used to treat highly susceptible pathogens (e.g., trimethoprim-sulfamethoxazole for Pneumocystis carinii), when the tissue concentrations of drugs at relevant sites are uniquely favorable (e.g., clindamycin or fluoroquinolone in bone), and when the patient adheres to the plan for use of oral agents (at home or in the hospital). 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 of many approaches is available when patient screening, selection of medical conditions, and follow-up are performed diligently. [13] [31] [32] Advocacy for the best treatment of a child's infection, with the risk of failure of therapy and the impact of the outcome taken into account, is the paramount consideration. The duration of antibiotic therapy is determined more by experience than by experiment for most infections. Endocarditis is a possible exception. [33] 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), leading to differences in the timecourse of the child's response to antibiotic therapy. In children with pneumonia, treatment may be given parenterally until a clinical (and presumed microbiologic) response has occurred, then oral convalescent 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 may be more appropriate for more resistant organisms, or for immune-compromised hosts, as delayed eradication of pathogens from the site of infection can occur in both of 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. Table 289-2 presents examples of the duration of treatment based on scientific information (when available), consensus, or experience. TABLE 289-2 -- Duration of Systemic Antibiotic Therapy for Certain Bacterial Infections Infection Cellulitis/impetigo Orbital cellulits Duration of Therapy 10 days 10 days or longer Comments/Duration within Range Few data Depending on the pathogen (Haemophilus influenzae, Streptococcus pneumoniae shorter) and predisposition

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Infection

Duration of Therapy

Comments/Duration within Range (chronic sinusitis in adolescent longer)

Pharyngitis (streptococcal) [72] Acute otitis media [28] [73]

10 days 10 days 1-, 3-, and 5-day courses may be adequate in certain cases (older age, rapid response, otoscopic improvement) with certain antibiotics (azithromycin, and certain oral beta-lactams agents) At least 1 week after resolution of symptoms Generally at least 1 week afebrile Few data; generally at least 5 days afebrile Depending on the clinical response, drainage, pathogen (Staphylococcus aureus, Streptococcus pyogenes longer; Haemophilus influenzae, anaerobes shorter); generally at least 1 week afebrile after drainage ceases) Depending on the pathogen (Staphylococcus aureus, enteric bacilli longer; Neisseria meningitidis shorter); generally at least 710 days afebrile

Acute sinusitis [74] Acute mastoiditis

1421 days 14 days or longer

Uncomplicated pneumonia 10 days Complicated pneumonia (necrotizing or with lung abscess, empyema) Purulent pericarditis 1421 days or longer

1014 days or longer

Endocarditis (native valve) [46] Penicillin-susceptible viridans streptococcus or Streptococcus bovis Penicillin, 28 days; or Penicillin, 14 days plus Gentamicin, 14 days; [a] or Vancomycin, 28 days Pencillin, 28 days

Penicillin-nonsusceptible viridans

Penicillin streptococcus or plus Streptococcus bovis Gentamicin, 14 days [a] or Vancomycin, 28 days Penicillin, Enterococcus species (moderately susceptible to or ampicillin, 46 ampicillin) [b] weeks Vancomycin, Depending on the duration of symptoms (< 3 months shorter; > 3 months longer)

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Infection

Duration of Therapy plus Gentamicin, 46 weeks [a]

Comments/Duration within Range

Methicillin-susceptible Staphylococcus aureus [c]

Nafcillin or vancomycin, 46 weeks plus Optional gentamicin, 35 days [a] Vancomycin, 46 weeks Additional therapy with aminoglycoside or rifampin also is given frequently

Methicillin-resistant Staphylococcus aureus [c] HACEK microorganisms

Ceftriaxone, 28 days or Ampicillin plus gentamicin, 28 days [a]

Meningitis [75] Group B streptococcus 14 days or longer 14 days or longer 21 days or longer 1014 days Gentamicin is also given frequently for 72 hours and until CSF is proved sterile; if isolate is penicillin-tolerant, gentamicin is continued Gentamicin is also given usually for 72 hours and until CSF is proved sterile At least 21 days and 14 days after CSF is proved sterile, whichever is longer; longer depending on the presence of infarction, abscess A least 710 days after CSF is proved sterile; the duration of therapy for pneumococci that are penicillin-nonsusceptible is not known

Listeria monocytogenes Enteric gram-negative bacilli Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitidis Brain abscess

10 days 57 days 2128 days or longer 1014 days 710 days 1421 days or longer Depending on the course, prompt and adequate drainage, pathogen (Staphylococcus aureus longer), and site (hip or shoulder longer); generally at least 710 days afebrile and Depending on the pathogen (gram-negative bacilli longer), drainage (at least 1014 days after drainage), and diminution on imaging study

Pyelonephritis Cystitis Acute pyogenic arthritis

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Infection

Duration of Therapy

Comments/Duration within Range after last drainage; therapy for 35 days has been adequate for gonococcal arthritis in adults

Acute osteomyelitis

2142 days or longer

Depending on the course, drainage, and pathogen (Staphylococcus aureus, enteric bacilli longer); generally at least 1014 days afebrile and until the sedimentation rate is almost normal Depending on the underlying condition, persistence of positive blood culture, and pathogen (Staphylococcus aureus, enteric bacilli longer); at least 35 days afebrile

Bacteremia without tissue focus

5-7 days or longer

Data for Table 289-2 from references 3739. References for Table 289-2 : 3739, 69, 72-75. Abbreviations: CSF, cerebrospinal fluid; HACEK, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae.

a The gentamicin dose is 3 mg/kg ideal body weight per day. b Similar therapy is given for penicillin-resistant viridans streptococcus (minimal inhibitory concentration, > 0.5 Lig/mL), for nutritionally variant viridans streptococcus, and for prosthetic valve endocarditis caused by viridans streptococcus or Streptococcus bovis. c In the presence of a prosthetic valve or other material, nafcillin or vancomycin is given for 6 weeks.

ANTIMICROBIAL COMBINATIONS
Prevention of Emergence of Resistance
Antibiotics are sometimes used in combination in an attempt to create synergy, or to prevent or delay the emergence of drug-resistant subpopulations of the pathogen. In most circumstances, data are insufficient to prove these effects. [3] [4] Mycobacterium tuberculosis provides the best clinically documented example. With a spontaneous mutation frequency of approximately 10 -8 , the initial use of two or more agents to which the organism is susceptible reduces the probability that resistant organisms can emerge to a very low level. Treatment of Pseudomonas infection with a -lactam, quinolone, or aminoglycoside antibiotic alone is associated with the emergence of resistant strains; dual-combination therapies may reduce the incidence of resistance to either component. [35] 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 one antibiotic in a combination may lead to the selection of organisms resistant to that agent, despite the use of dual therapy. Rifampin is one antibiotic that is never used alone for the treatment of infection because of the rapid development of resistance. Combining rifampin with vancomycin for coagulase-negative staphylococcal prosthetic valve endocarditis or ventriculoperitoneal shunt infection, or with a semisynthetic penicillin for S. aureus infections, may reduce the emergence of resistance while taking advantage of the unique properties of rifampin.

Alteration of Pharmacokinetics
The coadministration of a drug such as the uricosuric agent probenecid, which has no intrinsic antimicrobial activity, can have a significant impact on efficacy by delaying the renal excretion of a penicillin, thus increasing the time above MIC at the site of infection. Similarly, cilastatin, an inhibitor of renal

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dehydropeptidase, has no intrinsic antimicrobial activity but, in fixed combination with imipenem, prevents the degradation of imipenem and increases the serum half-life.

Inhibition of -Lactamases
Sometimes the site of action of a drug is not the vital microbial target binding site but a product of the microbe rendering resistance to antimicrobial agents. Antistaphylococcal penicillins such as methicillin and nafcillin are degraded by staphylococcal -lactamases. -Lactamase-inhibiting agents such as clavulanic acid, sulbactam, and tazobactam each display a specific affinity for and a degree of irreversible binding to the various bacterial -lactamase enzymes, thereby protecting the companion -lactam antibiotic from hydrolysis and permitting its access to the penicillin-binding proteins. [36] [37] Amoxicillin-clavulanate is especially useful in children when the potential causative pathogens are susceptible to amoxicillin except for the presence of -lactamases produced by the pathogen (Moraxella catarrhalis, Haemophilus influenzae, Staphylococcus 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 methicillinsusceptible staphylococci; it does not, however, enhance the activity of piperacillin against Pseudomonas as tazobactam does not effectively inhibit many of the beta-lactamases produced by P. aeruginosa.

Synergy Target Site Synergy


Combinations of antimicrobial agents can have a variety of effects on the target sites of a given organism in vitro. The combination can be: (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 first two definitions are dependent on the last two definitions, which are controversial and in turn depend on the intrinsic activities of each antibiotic on an organism, the test system used, and whether the binding site is similar or dissimilar. [38] [39] [40] Despite the paucity of clinically validated in vitro results, [41] there is good reason to believe that synergy has clinical relevance. [42] The notion remains appealing because the outcomes of certain severe clinical infections that are dependent on rapid bacterial killing may be better compared with monotherapies, and enhanced eradication of pathogens may allow for a possible shortened course of therapy. Although it is not practical to perform studies in most clinical settings, concepts regarding classes of drugs and microbes have evolved to guide therapeutic choices. An exposition of the laboratory methods used to detect the effects of combinations of antibiotics is available elsewhere [39] ; summary points about commonly used tests are made here. The broth or agar dilution checkerboard technique evaluates the inhibitory effect at a single point in time after 18 to 24 hours of incubation. Synergy is present when at least a fourfold reduction in the MIC of each antibiotic occurs when the agents are combined as compared with the MIC of each antibiotic tested separately, whereas antagonism results in corresponding increases in the MICs when antibiotics are combined ( Figure 289-1 ). The time-kill curve method measures the bactericidal effect at predetermined intervals (4, 8, or 24 hours) during incubation and compares the rate of killing by combinations of drug and drugs tested separately ( Figure 289-2 ). These methods are time-consuming and lack the ability to detect an additive response or synergy if both drugs have potent activity; furthermore, drug concentrations are constant over the timed experiment, and there is not agreement whether relevant concentrations of agents should be above or below the MIC. An E-test synergy method is also available. [43]

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Figure 289-1 The results of three theoretical checkerboard microdilution tests showing additive (A), synergistic (B), and antagonistic (C) effects of drugs A and B. Visible turbidity exists in each darkened well due to bacterial growth. The minimum inhibitory concentration (MIC) of each antibiotic tested alone against this organism is 2.0 g/mL. Doubling antibiotic concentrations for drug A are present on the abscissa and for drug B on the ordinate.

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Figure 289-2 Quantitative bacterial killing curves illustrating the (A) indifferent, (B) synergistic, and (C) antagonistic effects of two theoretical antibiotics (A and B) at specific concentrations against a single organism.

The basic checkerboard antibiotic interaction method is standardized by the CLSI, and reproducible in assessing inhibition of growth. However, drug interactions providing bactericidal activity or antagonism are less well standardized, [44] and have not been well correlated with clinical outcomes. An example is testing of the combination of a -lactam agent plus an aminoglycoside against resistant strains of P. aeruginosa; checkerboard tests can show indifference while killing curves show synergy. [38] Another example is the combination of ampicillin or vancomycin with an aminoglycoside against enterococci, which shows synergistic killing without enhancement of inhibition.

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

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inhibition of consecutive steps in the folic acid pathway results in a significantly reduced MIC and can also enhance the drug's bactericidal capacity. Streptogramin antibiotics (quinupristin-dalfopristin) include two biochemically distinct bacteriostatic compounds produced by Streptomyces that produce bactericidal activity when used in combination. The binding of the type A streptogramin at the acyl-amino 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, which then causes steric hindrance to the extrusion of newly formed polypeptide chains from within the ribosome.

Combination of Cell Wall-Active Agents with Ribosomal-Active Agents


Some instances of antibiotic resistance (e.g., to aminoglycosides) can be due to a permeability barrier that precludes the drug reaching the intracellular target site. Agents that act on the cell wall (e.g., -lactam agents, vancomycin) could enhance the entry of an aminoglycoside; unless the drug is rendered ineffective by aminoglycoside-modifying enzymes or resistance occurs at the ribosomal level, a combination would 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. For gram-negative bacilli, exposure to aminoglycosides can enhance the permeability of the outer cell envelope to -lactam antibiotics due to aminoglycoside-mediated production of altered, nonfunctional proteins that are incorporated into the cell wall. 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 g/mL; laboratories provide standardized testing at this single-drug concentration. 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. [45] 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 g/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 to those achieved when penicillin is administered alone for 4 weeks. [46] The combination of nafcillin plus gentamicin is synergistic in vitro against methicillin-susceptible strains of Staphylococcus aureus; a retrospective, large controlled clinical trial of nafcillin plus gentamicin versus nafcillin alone in adults with endocarditis failed to show any advantage of combination therapy. [47] Similarly, although tolerance to the bactericidal effect of -lactam agents among streptococci and staphylococci can be overcome in vitro by drug combinations, superior clinical efficacy in human infections has not been proved. 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 cancer patients confirmed better survival with carbenicillin plus gentamicin versus carbenicillin alone [48] ; 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. [49] 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 -lactam component. [48] [50] [51] With the advent of more potent, highly bactericidal agents such as the third-generation cephalosporins and carbapenems. The benefit of the addition of an aminoglycoside may 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. In vitro synergy of clindamycin and gentamicin has been reported against some strains of viridans streptococci and antagonism against others. [52] Limited studies have shown synergy of trimethoprimsulfamethoxazole plus amikacin against Enterobacteriaceae (organisms that are susceptible to both

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alone) [53] and against Nocardia asteroides. [54] Ciprofloxacin with aminoglycosides or various -lactams is infrequently synergistic against Enterobacteriaceae, but it can be occasionally (with aminoglycosides) or frequently (with imipenem) synergistic against strains of P. aeruginosa [55] ; antagonism is rare. Rifampin has synergistic bactericidal activity with teicoplanin against methicillin-sensitive and methicillinresistant S. aureus, [56] with vancomycin against coagulase-negative staphylococci, [57] and with ampicillin against Listeria. [58] In a multicenter, prospective randomized trial of an antipseudomonal -lactam plus an aminoglycoside (with or without rifampin orally) in patients with P. aeruginosa bacteremia, rifampin use was associated with a higher bacteriologic cure rate (98% versus 86%), but no difference in survival. [59] Other unique properties of rifampin make it useful in post exposurre prophylaxis, in elimination of microbial carrier states, and in combination therapy for infections related to medical devices.

Antagonism
Despite the paucity of documented reports of the clinical significance of antagonism between antimicrobial agents, multiple examples are demonstrable in vitro; thus, caution is needed in their use, especially in infections in hosts with impaired bactericidal defenses. Combinations of a bacteriostatic agents can antagonize the bactericidal activity of a -lactam antibiotic, especially by inhibiting the production of autolysin (e.g., tetracycline) or bacterial replication (e.g., chloramphenicol) by Streptococcus pneumoniae. Combinations of chloramphenicol or tetracycline plus aminoglycosides are also antagonistic for gram-negative bacilli. In addition, chloramphenicol antagonizes the bactericidal effect of ciprofloxacin against Staphylococcus aureus, Escherichia coli, and P. aeruginosa. A combination of agents that all bind to the similar locations within the ribosome (e.g., clindamycin, erythromycin, spiramycin, chloramphenicol, streptogramins) could compete for or alter target sites if used together. [39] Antagonism exists between some -lactam combinations against gram-negative bacilli, and they may have an individual and environmental clinical impact, especially if one agent stimulates the production of beta-lactamases that degrade the second agent. Finally, prolonged in vitro exposure of aminoglycosides to -lactam drugs can lead to inactivation of the aminoglycoside, an effect that is pertinent in patients who have both agents placed in the same intravenous administration chamber, and possibly when drugs are instilled into body cavities (e.g., peritoneal dialysates).

JUDICIOUS USE OF ANTIBIOTICS


Antimicrobial agents are the principal therapeutic tool for pediatric infectious disease specialists and are among the leading interventions in all of pediatrics. Overuse of this tool is increasingly threatening its effectiveness. Young children have the highest rate of consumption of the approximately 110 million courses of antibiotics prescribed each year in the United States. [60] In addition to the many appropriate indications for such drugs, 17 million courses were given to individuals with the common cold. [60] The spread of antimicrobial resistance has led to ongoing concern about such unnecessary use among physicians and increasingly among patients or parents. Common pathogens such as Streptococcus pneumoniae and Staphylococcus aureus typically remain treatable, but resistance in these organisms complicates therapy, raises cost, and increases the likelihood of treatment failure. Hospital-acquired pathogens such as Enterobacter, Klebsiella, Acinetobacter, or Enterococcus may not be treatable with available agents. 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. [61] During a course of prophylactic antibiotics to prevent acute otitis media, the proportion of children carrying resistant strains of pneumococci, Haemophilus influenzae, and Moraxella catarrhalis increased, with a return to baseline levels only after the selective pressure of the antimicrobial regimen was released. [62] Avoiding such selective pressure by reducing antimicrobial exposure is the focus of a variety of public health strategies to control resistance. A set of principles for judicious antimicrobial use in children with upper respiratory tract infections summarizing scientific evidence for curtailing such use has been published as a guide to appropriate antibiotic use. [63] Evidence is accumulating that promotion of the judicious use of antimicrobial agents has

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reduced excess prescribing. Programs for judicious use have been studied in private practice, managed care organizations, emergency departments, and community clinics. [64] 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. [64] [65] Nationwide trends toward decreased prescribing for upper respiratory tract conditions in the United States [66] [67] have been documented. More limited but convincing evidence exists that the decrease in prescribing is leading to slowing of the spread of resistant bacteria. [29] [68] [69] Guidelines for Antibiotic Stewardship from the Inffectious Diseases Society of America outlines strategies to promote appropriate antibiotic selection and duration of therapy and evaluate the potential impact on the development of antibiotic resistance. [70] Unfortunately, there are no prospective investigations of impact of improved practices on a decrease in documented infections caused by antibiotic resistant pathogens in children.

References
1. Fredricks DN, Relman DA: Application of polymerase chain reaction to the diagnosis of infectious diseases. Clin Infect Dis 1999; 29:475-486.quiz 487-478. 2. Levison ME: Pharmacodynamics of antimicrobial drugs. Infect Dis Clin North Am 2004; 18:451-465.vii 3. Bradley JS, Dudley MN, Drusano GL: Predicting efficacy of antiinfectives with pharmacodynamics and Monte Carlo simulation. Pediatr Infect Dis J 2003; 22:982-992. 4. Kearns GL, Abdel-Rahman SM, Alander SW, et al: Developmental pharmacology - drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349:1157-1167. 5. Bjorkman S: Prediction of cytochrome p450-mediated hepatic drug clearance in neonates, infants and children: how accurate are available scaling methods?. Clin Pharmacokinet 2006; 45:1-11. 6. Drlica K, Malik M: Fluoroquinolones: action and resistance. Curr Top Med Chem 2003; 3:249-282. 7. Hansen GT, Zhao X, Drlica K, et al: Mutant prevention concentration for ciprofloxacin and levofloxacin with Pseudomonas aeruginosa. Int J Antimicrob Agents 2006; 27:120-124. 8. Kollef MH: Gram-negative bacterial resistance: evolving patterns and treatment paradigms. Clin Infect Dis 2005; 40(Suppl. 2):S85-S88. 9. Micek ST, Lloyd AE, Ritchie DJ, et al: Pseudomonas aeruginosa bloodstream infection: importance of appropriate initial antimicrobial treatment. Antimicrob Agents Chemother 2005; 49:1306-1311. 10. Shorr AF, Kollef MH: Ventilator-associated pneumonia: insights from recent clinical trials. Chest 2005; 128:583S-591S. 11. Hughes WT, Armstrong D, Bodey GP, et al: Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002; 34:730-751. 12. Nelson JD: Skeletal infections in children. Adv Pediatr Infect Dis 1991; 6:59-78. 13. Tice AD, Rehm SJ, Dalovisio JR, et al: Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines. Clin Infect Dis 2004; 38:1651-1672. 14. Jorgensen JH: Laboratory issues in the detection and reporting of antibacterial resistance. Infect Dis Clin North Am 1997; 11:785-802. 15. Jorgensen JH, Ferraro MJ: Antimicrobial susceptibility testing: special needs for fastidious organisms and difficult-to-detect resistance mechanisms. Clin Infect Dis 2000; 30:799-808.

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