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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.
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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]
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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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Pharmacodynamics [b]
Ribosome
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
Oxazolidinones
Rifamycins
Yes
Quinolones
Yes
Streptogramins
Yes
Nucleic acid
Metronidazole
Yes
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.
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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]
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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.
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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]
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Infection
Duration of Therapy
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
Uncomplicated pneumonia 10 days Complicated pneumonia (necrotizing or with lung abscess, empyema) Purulent pericarditis 1421 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
Nafcillin or vancomycin, 46 weeks plus Optional gentamicin, 35 days [a] Vancomycin, 46 weeks Additional therapy with aminoglycoside or rifampin also is given frequently
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
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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
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
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.
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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.
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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.
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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).
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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
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