Pharmacokinetic-Pharmacodynamic Basis of Optimal Antibiotic Therapy

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

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Pharmacokinetic-Pharmacodynamic Basis of Optimal Antibiotic Therapy Michael N. Neely and Michael D. Reed

As clinicians continuously strive to practice evidence-based medicine, the use of antibiotics can be frustratingly empiric. Ethical concerns, multiple confounding variables, and unclear end points hamper clinical infectious disease research. This empiricism is clearly evident in most recommendations for antibiotic dosing and duration of therapy, especially in children, because only a fraction of published pharmacokinetic (PK) and pharmacodynamic (PD) data is collected from this group of patients. Although pediatric data are more plentiful and better defined for antibiotics than for other drug classes used in pediatric patients, much more work needs to be done. The lack of specific and sound dosing and safety data for drugs used in children continues to hamper the ability to determine optimal dose regimens rapidly. “Off-label” use of medications in children unfortunately, and necessarily, remains common practice.1–3 Moreover, suboptimal antibiotic dose regimens most certainly contribute to the continued emergence of the virulent, multidrug resistant bacteria we encounter at the bedside today.4 In response to this lack of pediatric data, the US Food and Drug Administration (FDA) was granted additional authority through the Best Pharmaceuticals for Children Act (BPCA, 2002, 2007, 2012) and the Pediatric Research Equity Act (PREA, 2003, 2007, 2012). The BPCA extends patent exclusivity for 6 months for subsequent research focused toward a pediatric indication for on-patent drugs and prioritizes and supports pediatric labeling studies with off-patent drugs. The PREA mandates that any drug with potential use in children must also be studied in children unless it is granted a specific waiver by the FDA. This act is enforced automatically with any new drug application, including new indications for existing drugs. Failure to comply with PREA requirements can result in revocation of marketing approval for a drug. Both the BPCA and the PREA were made permanent in 2012 as part of the FDA Safety and Innovation Act (FDASIA). With a growing awareness of the important physiologic differences across the age spectrum in children and their many important influences on drug dosing, knowledge of an antibiotic’s PK and PD properties is necessary to determine optimal dosing. The increasing incidence of serious infections caused by multidrug-resistant pathogens combined with the ever-increasing emergence of virulent pathogen resistance underscores the importance of applying integrated antibiotic PK-PD–defined dosing in daily practice.5,6

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This chapter reviews basic PK principles and provides a framework for the clinician to apply these principles at the bedside.

BASIC CONCEPTS IN CLINICAL PHARMACOKINETICS Pharmacokinetics (PK) describes the time course of drug movement in the body; an understanding of a drug’s PK profile is essential to the design of an optimal dosage regimen. However, focusing on a drug’s PK profile alone provides the clinician with limited information about optimal drug dosing or, more importantly, clinical efficacy. PK principles are of clinical relevance only when they are integrated with the drug’s pharmacodynamic (PD) properties (i.e., the effects of the drug in the patient). With the exception of intravenous (IV) drug administration, a drug must be absorbed into the systemic circulation from its site of administration. Some drugs can be administered as a prodrug requiring in vivo metabolism to liberate the active moiety. Once absorbed, the drug is distributed within the body to accessible sites that are specific to the individual drug or drug class based on inherent physicochemical characteristics (e.g., lipid solubility, molecular weight, protein binding). Factors such as age, body habitus, and disease can influence this distribution. Simultaneous with the processes of absorption and distribution, many drugs undergo metabolism before excretion from the body. A drug’s PK and disposition profile can be artificially separated into semidiscrete periods of drug absorption, distribution, metabolism, and excretion (Fig. 291.1), to permit visualization and more accurate quantification. Knowledge of this information allows the clinician to predict drug concentrations and systemic exposures for the active drug that can be achieved at any time over a specified dosing interval after any dose of a given drug. With this information, an optimal drug dose and dose interval can be determined for any patient with a regimen that accounts for underlying pathophysiologic features and major organ function. The PK property bioavailability estimates the amount of a drug dose administered extravascularly (e.g., orally, intramuscularly) that is absorbed into the systemic circulation. Bioavailability is calculated as the area under the plasma drug concentration–time curve (AUC) achieved after extravascular drug administration divided by the AUC achieved after IV administration (e.g., AUCoral / AUCIV). Thus, to achieve the same

Pharmacokinetic-Pharmacodynamic Basis of Optimal Antibiotic Therapy

Drug concentration

Distribution

Absorption

Metabolism and elimination

Lag

Time

FIGURE 291.1  Overall biologic fluid (e.g., serum) drug concentration–time curve after extravascular drug administration. Each important process of drug disposition is indicated. Although these processes are compartmentalized graphically in the figure, in reality they occur simultaneously (see text for details).

systemic exposure with a drug administered orally as achieved with IV dosing, one simply divides the IV dose by the drug’s bioavailability (obtained from published sources) to determine the equivalent oral dose. Lower bioavailability is not necessarily a negative attribute unless the dose required is so large that the patient tolerates it poorly. However, for orally administered antibiotics, poor bioavailability can be a major limitation because unabsorbed drug remaining in the intestinal tract can adversely affect indigenous flora and often can lead to intestinal complaints and diarrhea (e.g., ampicillin vs. amoxicillin). Conversely, this property is sometimes therapeutically advantageous, as is the case for orally administered vancomycin to treat Clostridium difficile–associated colitis or nystatin for mucosal candidiasis. Bioavailability depends on the molecular weight, solubility, and permeability of the drug. Highly soluble and permeable drugs have excellent bioavailability, whereas the converse results in poor bioavailability. Drugs with opposing solubility and permeability have unpredictable and variable bioavailability, even within the same patient from dose to dose, because of variations in gastrointestinal pH, motility, and food content. Drugs can exhibit complex absorption patterns with delayed or multiple peaks in their blood (plasma or serum) concentrations arising from timed-release formulations, enterohepatic recycling, site-specific absorption within the gastrointestinal tract, or variations in gastric emptying and intestinal transit times. A drug’s peak plasma concentration is the characteristic most greatly affected by changes in the rate and extent of absorption, and reduced peaks theoretically can compromise the efficacy of concentration-dependent antibiotics, as discussed in the later section on pharmacodynamic correlates for antibacterial agents. Once absorbed into the systemic circulation, the distribution of a drug depends on specific characteristics inherent to the drug molecule. Small, non–protein-bound, nonionized lipid-soluble molecules are usually widely distributed (e.g., azithromycin), whereas larger, less lipid-soluble (i.e., polar) or highly protein-bound drugs traverse cell membranes poorly, thus restricting movement (e.g., aminoglycosides, vancomycin, echinocandins). The PK measurement that attempts to describe this process is the volume of distribution (Vd). Vd is a proportionality constant that relates the amount of drug in the body to its plasma concentration. Vd can be roughly conceptualized for an IV drug by the following simplified formula: Vd = dose / Cp, where Cp is the peak plasma drug concentration. Vd does not correspond to any true anatomic distribution or compartment, although the magnitude of Vd provides clues about a drug’s physiologic distribution. For example, for a drug with a very small Vd (i.e., 0.2 L/kg), a larger proportion of the drug is confined to extracellular fluid (composed of intravascular and interstitial fluid), whereas the distribution of a drug with a large Vd can involve extensive tissue binding, intracellular distribution, or both. Knowing a drug’s Vd (expressed in liters per kilogram of body weight) allows the clinician to estimate the dose necessary to achieve any desired plasma drug concentration. For example, the loading dose for a drug can be calculated from the following

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formula: loading dose = desired plasma drug concentration (mg/L) × Vd (L/kg) × patient body weight (kg). The age-specific Vd for the drug to be prescribed can be obtained from published sources or calculated for the individual patient, as outlined earlier. As inferred from the loading dose calculation, the first (or loading) dose of any drug is independent of a patient’s organ function or extent of underlying disease (e.g., renal failure). A patient’s first drug dose is dependent only on the Vd of the specific drug; all subsequent doses depend on the patient’s ability to clear (eliminate or metabolize) the drug. The PK property clearance (CL) estimates the volume of solvent (e.g., plasma, serum, or blood) from which all drug is removed per unit time. CL is therefore expressed in units of volume per time. Body CL is a composite estimate reflecting all mechanisms of drug CL, including renal, hepatic, and other forms of CL (e.g., lung), and it is calculated using the following formulas: CL = 0.693 × Vd / t1/2, where t1/2 is the drug’s elimination half-life; or CL = drug dose × F / AUC, where F is bioavailability. Knowledge of a drug’s CL is necessary to determine accurately the need for and proper timing of subsequent doses to maintain any desired drug concentration or degree of systemic exposure. Changes in organ function responsible for drug removal from the body are reflected by changes in a drug’s overall CL rate. Although clinically the t1/2 often is used at the bedside as a measure of drug CL and to determine subsequent drug dosing, this value merely reflects the time required for a given drug concentration in any biologic fluid to decrease by 50%, although this is not necessarily elimination from the body, as exemplified by all forms of amphotericin. If Vd is fairly constant in a patient in stable condition, t1/2 mirrors body CL, thereby permitting bedside application. The t1/2 can be estimated simply from the measured fall in plasma drug concentration after an individual dose (e.g., from the peak and trough plasma drug concentrations); to estimate the t1/2 in practice, usually one must obtain 2 measured drug concentrations and calculate t1/2 as ln(2) × −t / ln(C2/ C1), where ln(2) is the natural logarithm of 2 (~0.693) and t is the time between the 2 measured concentrations C1 and C2. Although the t1/2 is an extremely useful bedside application of PK, the accuracy of the t1/2 as a reflection of drug CL diminishes in situations of changing Vd, renal or liver function. For example, a drug’s Vd can be altered during extracorporeal membrane oxygenation (ECMO), septic shock, or severe liver disease with marked ascites. The PK principles just outlined for Vd, CL, and t1/2 assume that the drug follows first-order or linear PK characteristics. First order means that a constant fraction of drug is cleared per unit time (i.e., regardless of the initial concentration, the time to clear x% is the same). However, for certain drugs, such as voriconazole7,8 and phenytoin,9 the CL mechanisms can be saturated at clinically relevant concentrations, and thus their disposition is best described by using zero-order methodology or a combination of first-order elimination at lower concentrations and a gradual transition to zero-order elimination at higher concentrations (i.e. Michaelis-Menten kinetics). Zero order means that a constant amount of drug is cleared per unit time (i.e., the higher the initial concentration, the longer it will take to clear x%). Fortunately, most drugs used clinically follow first-order PK, which is simpler to apply clinically. The recognition that a drug’s disposition characteristics are first order allows the clinician to use simple proportions with relative accuracy to define patient-specific drug doses. For example, if a patient’s steady-state plasma drug concentration is half that desired (at any time point) and the drug follows first-order PK, the dose can simply be doubled to achieve the desired concentration. In contrast, for a drug with zero-order characteristics, doubling the dose can result in a much higher increase in the plasma concentration. Following repeated drug dosing, a steady-state condition is achieved (i.e., when the amount of drug administered to the patient equals the amount of drug eliminated [cleared] from the body). Simply put, “in = out.” The importance of steady-state conditions cannot be overemphasized because the drug concentrations in blood (plasma or serum) or tissue reported to be associated with drug efficacy or toxicity most often are the steady-state drug concentration. For drugs that follow first-order “proportional” PK characteristics, the drug’s t1/2 can be used to estimate the time to reach steady state (i.e., 4−5 times the t1/2 to reach steady state). A drug’s t1/2 can be calculated for an individual patient as described earlier, or an age-appropriate t1/2 often can be obtained from published sources and modified if necessary based on the patient’s elimination organ function.

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

Unfortunately, the clinician encounters many patients who deviate from the proposed PK characteristics found in published sources, especially in pediatrics. A far more sophisticated, powerful, and nuanced approach to dosage individualization is the application of population PK modeling techniques coupled with bayesian feedback, by using specifically designed software tools.10,11 Although these methods have the disadvantage of requiring specialized software, training, and knowledge, they have numerous advantages, including more accurate and rapid attainment of target drug concentrations without the need for steadystate conditions (including patients with unstable PK behavior),12–15 improved clinical outcomes,16–20 and reduced costs.16,21–24 A complete review of this topic is beyond the scope of this chapter, but interested readers are urged to contact experts in the field and consider these approaches when desiring to optimize individual therapy. The next sections discuss the general PK alterations that can influence both the magnitude and the frequency of antibiotic doses in neonates, patients with organ failure who are undergoing dialysis or ECMO, children with cystic fibrosis (CF), and patients with burns or septic shock. However, considerable variability exists within these generalizations, and any specific patient is likely to be best served by careful dose optimization in partnership with an expert in clinical pharmacology.

DRUG DISPOSITION IN SPECIFIC PATIENT POPULATIONS Neonates: the Ontogenic Basis of Drug Disposition As children mature physically, they also mature physiologically. This principle has important and clinically relevant implications for both drug PK and PD characteristics.25,26 Factors that influence drug absorption from the gastrointestinal (GI) tract include the surface area available for absorption, pH, gastric emptying time, exocrine pancreatic function, size of the bile acid pool, and bacterial colonization (Table 291.1). All these functions are variably altered in neonates, particularly those born prematurely, and in young infants relative to older children and adults.27,28 Changes in the amount and distribution of body water in neonates, as well as differences in quantitative and qualitative protein-binding characteristics, also are present and affect drug distribution. These ontogenic

differences in body water composition (i.e., increased Vd for water-soluble drugs) are reflected by the increased individual doses, on a milligram of drug per kilogram of body weight basis, prescribed for young infants and children compared with older children and adults. Although far from fully characterized, both the oxidative and conjugative hepatic metabolic enzyme systems are immature at birth and reach adult levels of activity at various times throughout early childhood.29 Renal function and elimination also mature as a function of gestational and postnatal age, with glomerular filtration reaching adult levels in infants of 34 weeks of gestation by approximately 3 to 5 months of age.30 Tubular secretion matures more slowly and reaches adult levels by approximately 8 to 9 months of age (see Table 291.1). As a result of these physiologic differences (see Table 291.1), infants <44 weeks of postconceptional or postmenstrual age generally have larger Vd and decreased antibiotic CL, which translate clinically to lower peaks, lower overall plasma drug concentrations, and longer t1/2 than observed in older infants and children. Furthermore, these infants can be more susceptible to drug-drug interactions at all levels, interactions that are likely to be significant for other drugs as well as antibiotics alone (see the later section on the basis for drug-drug interactions). The physiologic differences of young infants influence not only drug PK but also PD characteristics, which necessarily incorporate the mechanism of drug action. Developmental changes in receptor function are not as relevant to antibiotics because the receptor targets are on the infecting organism.31 However, host receptors can be involved in therapeutic antibiotic mechanisms (e.g., human kinases that phosphorylate acyclovir) or adverse antibiotic mechanisms. Despite lower CL and prolonged t1/2 in neonates relative to older children and adults, aminoglycosides cause less nephrotoxicity in neonates.32 This tolerance is thought to arise from differences in renal disposition characteristics, although the exact mechanism is unknown. The clinician must be aware that neonates are physiologically distinct and manifest altered antibiotic PK characteristics. Dosing strategies should be evaluated critically to make prescribing decisions to optimize therapeutic success. In the absence of neonatal dosing recommendations, knowledge of the altered PK patterns will make empiric dosing more rational when it is extrapolated from dosing recommendations for older children or adults.

Patients With Organ Failure and Principles of Dialyzable Drugs TABLE 291.1  Physiologic Changes in Children That Affect the Pharmacokinetic Characteristics of Drugs Neonates

Approximate Age Approaching Adult Level

Gastric pH

↑

3 mo

Gastric emptying

↓

6–8 mo

Pancreatic function

↓

9 mo

Body water

↑a

~3 yr

Protein binding

↓

12 mo

Parameter ABSORPTION

DISTRIBUTION

METABOLISM Hepatic drug-metabolizing or hepatic drug metabolism

↓

2 yr to adolescence

↓

Glomerular filtration: 3–5 mo

ELIMINATION Renal function

Tubular secretion: 8–9 mo a

The distribution of body water depends on age: the total body water (TBW) of neonates is approximately 75% of body weight, with approximately 50% intracellular (IC) and 50% extracellular (EC). A gradual decrease in TBW and a shift to IC distribution occur until adult values of 50% to 60% TBW, 33% EC, and 66% IC are reached at puberty. Data from references 328 to 331.

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The major routes of drug elimination are by the kidneys into urine and by the liver into bile. For most drugs only minor amounts are eliminated into other body fluids. Alterations in drug disposition result from failure of either of these organs of elimination or failure of the cardiopulmonary system to support their proper function. Patients in cardiopulmonary failure can experience alterations both in Vd as a result of increased total body water and in CL as a result of hepatic or renal dysfunction. Knowledge of the PK properties of individual drugs is crucial to understanding the magnitude of such effects. Drugs with a small Vd are more greatly affected because they tend to be distributed to extracellular fluid. The route of metabolism and elimination determines the impact of hepatic or renal dysfunction.

Extracorporeal Membrane Oxygenation ECMO influences drug disposition in several ways. ECMO circuitry can add up to 500 mL of volume to the patient, in which case Vd is increased; children weighing <20 kg will most likely experience corresponding lower peak drug concentrations and a longer t1/2. Further, drugs can bind to the oxygenation membrane, thereby potentially increasing both Vd and CL.33 Binding is increased with increasingly lipophilic drugs. CL can be reduced as a consequence of altered perfusion of the liver and kidneys.34,35 Alterations in the PK characteristics of antibiotics during ECMO have been relatively well characterized for gentamicin and vancomycin.36,37 Although the Vd of aminoglycosides is variably increased, the t1/2 can be doubled. Neither drug significantly binds to the oxygenation membrane, as predicted by low lipophilicity. The implication for dosing is that aminoglycosides should be administered every 18 to 24 hours initially (or less frequently in patients with renal failure) to infants undergoing

Pharmacokinetic-Pharmacodynamic Basis of Optimal Antibiotic Therapy

ECMO (with monitoring of serum drug concentrations), although no efficacy studies are available to support this recommendation. For vancomycin, Vd and t1/2 are increased, and CL is decreased, resulting in a suggested initial dose of 20 mg/kg IV every 18 to 24 hours for infants with a serum creatinine value <1.5 mg/dL. For infants with a higher serum creatinine concentration, the dosing interval must be extended. In all cases, serum vancomycin concentrations should be monitored. Increased ECMO-associated cefotaxime Vd has been documented, but the percentage of the dosing interval that is greater than the organism’s minimal inhibitor concentration (MIC) after standard doses during ECMO is not significantly different from the same doses while the patient is not undergoing ECMO, thus leading to no required dosing changes.38 Some reports have noted lowered plasma voriconazole concentrations requiring higher doses in patients receiving ECMO, a finding consistent with its high lipophilicity, and therapeutic drug monitoring is recommended.39,40 Caspofungin, which is less lipophilic, had reportedly lowered41 and unaltered40 concentrations in 3 patients receiving ECMO, with the result that no clear recommendation was made. Oseltamivir PK does not appear to be changed significantly.42 Indeed, a case report of a 6-year-old boy receiving both ECMO and continuous veno-venous hemofiltration demonstrated that low plasma levels of oseltamivir were likely caused by poor oral absorption rather than by marked changes in Vd or CL.43 For other antimicrobial agents for which plasma drug concentrations are unavailable, the clinician can only estimate dosing modifications based on the expected changes described earlier.34,35 In general, Vd and t1/2 are the same or are increased. Lipophilic drugs are more greatly affected than are hydrophilic drugs. However, patients undergoing ECMO usually have multiorgan failure, with renal failure and the use of continuous veno-venous hemofiltration the most problematic for many antibiotic regimens.

Dialysis For patients in acute or chronic renal failure who require dialysis, several options can be used for extracorporeal therapy, including intermittent or continuous hemodialysis (HD), hemofiltration (HF), or peritoneal dialysis (PD). HD and HF therapies can be combined.44,45 HD removes an antibiotic by diffusion across the dialysis membrane into the dialysate according to the drug’s concentration gradient. The amount of blood flow past the dialysis membrane and the composition and flow of dialysate influence the amount of drug removed. HF (without HD) removes antibiotics in the ultrafiltrate, which is a hydrostatically generated flow of water containing the dissolved drug. No drug concentration gradient is present. PD, in general, removes most antibiotics minimally. The volume of PD fluid generally is small (0.05–0.2 L/kg) in comparison with the Vd of antibiotics (0.2–>100 L/kg), so only a very small percentage of the total drug in the body is distributed to the PD fluid unless the antibiotic has a similarly small Vd. Furthermore, the intraperitoneal concentration of antibiotics is proportional to the concentration of free, non–protein-bound drug. The protein content of typical dialysate fluid is 0, so highly protein-bound antibiotics are poorly distributed to the peritoneal fluid. Increasing the amount of PD dialysate or the frequency of exchange increases the amount of drug extracted, but a cumulative amount extracted of <25% during a dosing interval is usually insignificant. In contrast, antibiotics administered into the peritoneal dialysate can reach therapeutic plasma concentrations if they can cross the peritoneal membrane, passage through which is enhanced in the presence of inflammation. Because the potential extra-abdominal volume for an antibiotic to diffuse into is much larger than the intra-abdominal volume, with equal concentrations across the peritoneal membrane at equilibrium, the amount of drug in the body is greater than in the peritoneal dialysate. All these modalities partially restore the ability of the body to eliminate an antibiotic that normally would be cleared by the kidneys. Although several thorough reviews have described the use of antimicrobial agents in these patients, none of the guidelines have pediatric dosing, and all strongly convey the same message: antimicrobial concentrations highly depend on factors intrinsic to the mode of dialysis itself and the drug’s PK properties (Table 291.2). This variability could have significant clinical implications.46,47 Although the clinician can apply principles outlined here to an individual patient to generate a qualitative assessment of the

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TABLE 291.2  Factors That Increase the Likelihood of Antibiotic Removal by Dialysis Factors Intrinsic to the Antibiotic

Factors Intrinsic to the Mode of Dialysis

Smaller volume of distribution (<1 L/kg)

CVVHDFa > CVVHa > CVVHDa > IHD ≫ PD

Smaller molecular mass (<2 kd)

Frequent dialysis

Reduced protein binding (<80%)

High flow rate of blood or dialysate

Neutral charge

Filter capacity and selectivity

Normally eliminated by kidneys (>30%)

Dialysate composition

a The differences in drug clearance among the continuous modes of hemodialysis or hemofiltration are less significant for small molecules, which include most hydrophilic antibiotics that are likely to be cleared by these modes. Among these, the largest are teicoplanin (1.9 kd), colistimethate, also known as colistin (1.8 kd), and vancomycin (1.5 kd). CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration; IHD, intermittent hemodialysis; PD, peritoneal dialysis.

need for dose adjustment, confirmatory measurement of drug concentrations is crucial when possible. Drugs with a small Vd (<1.0 L/kg) that are primarily confined to the extracellular compartment are available for filtration across the dialysis membrane. The pore size of HD membranes is approximately 0.5 kd, whereas HF membranes are usually approximately 50 kd. Most antibiotics are <1 kd. Passage across a membrane is inversely proportional to the square root of the molecular mass. Drug-protein complexes are too large to pass through the pores of intact dialysis membranes, so highly proteinbound antibiotics (>80%) pass through the membrane poorly. Further, the membranes carry a net negative charge; highly polar molecules do not cross the membrane efficiently. Antibiotics that are mainly eliminated by a functioning kidney are more likely to be eliminated by dialysis, and a simplistic rule of thumb predicts some removal of drugs that are eliminated >30% unchanged in the urine in patients with normal renal function. However, the fraction of an antibiotic normally cleared by active tubular secretion is not compensated for by dialysis, and this factor should be considered in any patient manifesting unexplained signs or symptoms of drug toxicity. Antibiotic dose adjustment in the absence of measurable drug concentrations in blood, dialysate, or ultrafiltrate, is a crude estimate, at best. Unfortunately, most pharmacology references consulted to determine dose recommendations use complicated formulas that require information the clinician often does not possess. Therefore a more intuitive approach is typical, and the clinician should first consider the relevance of potential drug accumulation by monitoring the patient closely for desired and undesired drug effects. Fortunately, most antibiotics have a very high therapeutic index (i.e., the ratio of therapeutic to toxic doses). “Safe” drugs can generally be allowed to accumulate moderately without risk of serious or irreversible toxicity, or both. In contrast, more rigorous dose adjustments should be applied for antibiotics that can be associated with toxicity (e.g., the aminoglycosides) because in general patients in renal failure, especially if they are uremic, are more prone to adverse effects from all drugs. Regardless of the dosing scheme selected, the clinician must monitor patients closely for specific evidence of toxicity related to the drug in question as well as expected clinical responses (see Chapter 289). Conversely, unaccounted-for extracorporeal elimination has major importance when subtherapeutic drug concentrations lead to clinical failure, which can happen when a drug dose is based on a patient’s intrinsic renal function without accounting for dialysis-mediated drug CL. Therefore, for most antibiotics, it is more important to avoid underdosing. Appendix 291.1 lists suggested adjustments for selected antibiotics in response to renal failure with or without dialysis.

Cystic Fibrosis CF is the most common potentially lethal genetic disorder in whites and remains a therapeutic challenge for pediatric and adult practitioners. The

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

disease is characterized by an elevated sweat chloride concentration, pancreatic exocrine insufficiency, thick and tenacious mucus secretions, and chronic obstructive pulmonary disease.48–50 A hallmark of CF is chronic microbial colonization of the lung with resultant repeated acute pulmonary infections or exacerbations.48–51 CF morbidity and death result from the pulmonary component of this disease, and treatment (e.g., antibiotics, ibuprofen) focuses on decreasing the inflammation that is responsible for the progressive, irreversible deterioration in lung function52 (see Chapter 106). However, optimal antibiotic therapy in patients with CF is complicated by potential differences in the disposition of many drugs.53 Unfortunately, the lack of adequate control groups in many studies precludes definitive conclusions regarding CF-induced alterations in drug PK. Nevertheless, these data provide consensus findings that patients with CF often have a larger Vd and enhanced body CL for many antibiotics, including aminoglycoside and β-lactam agents, compared with patients who do not have CF,.53–55 The reasons for these differences are unknown. CF-induced differences in drug Vd may merely reflect the difference in body composition in patients with CF, specifically, their limited adipose tissue. When the Vd for various drugs is expressed as a function of lean body mass rather than body weight characterized by kilograms, differences in drug Vd diminish. When drug dosing is based on the patient’s body weight, the real differences in the body composition of patients with CF necessitate higher individual milligram-per-kilogram drug dosing to achieve systemic drug exposure similar to that of patients who do not have CF.56 Drug elimination also appears to be enhanced in patients with CF.53,57 Despite well-characterized CF-induced hepatic dysfunction, particularly in patients with CF who are older than 15 years of age, the CL of many drugs that undergo hepatic metabolism may be unchanged or increased in patients with CF. Emerging data are revealing that the function of phase I mixed-function oxidases is selectively affected; the functional capacity of cytochrome P450 (CYP450) system isoforms CYP1A2 and CYP2C8 appear to be enhanced, whereas CYP2C9 andCYP3A4 are unaffected. With phase II reactions, the activity of glucuronyl transferase, N-acetyltransferase, and sulfotransferase can be similar or increased.58 Moreover, the renal CL of many drugs is increased in patients with CF. The mechanism is unknown, but it does not appear to be related to any disease-associated effect on the activity of the primary renal efflux transporter, P glycoprotein.59 The clinician must increase the amount and possibly the frequency of individual doses to compensate for the larger Vd and CL, as tolerated by the patient. Regardless of the dosing strategy used, close clinical monitoring for antimicrobial efficacy and safety is necessary. Additionally, in patients with CF, the amount and composition of sputum, as well as bacterial density, have been shown to reduce the bioactivity of many antibiotics (i.e., inoculum effect).60–62 These pathophysiologic variables must be considered when devising antibiotic regimens, including increasing systemic doses and attempting topical application through aerosol antibiotic administration.63,64

Septic Shock or Burn Injury Children in septic shock or who are severely burned can suffer dramatic physiologic changes.65–67 One can assume that any child with hemodynamic changes requiring significant fluid resuscitation or pharmacologic pressor support will be neither physiologically nor pharmacokinetically normal. The timing of physiologic changes is somewhat more characteristic with burns than with septic shock because the burn insult is of defined duration. The first phase in the 48 hours after a severe burn is characterized by an acute decrease in glomerular filtration as a result of hypovolemia and shock, with a rapid shift of intravascular fluid to the interstitial spaces. After 48 hours, with adequate resuscitation, the second phase is characterized by increased cardiac output, increased glomerular filtration (although not tubular secretion), hypoalbuminemia with reduced drug protein binding, and edema. Unfortunately, burned patients frequently sustain hypovolemic renal injury, which can antagonize postburn increased glomerular filtration. Additionally, the function of hepatic CYP450 enzymes appears to be depressed in burned patients. These factors and others have an important impact on drug disposition and require dose adjustments. Similar changes can be observed in patients with septic shock, with early increases in the Vd of hydrophilic drugs associated with increased

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capillary leak and fluid resuscitation, as well as organ blood flow associated with hyperdynamic cardiac output. Subsequent infection- and immune-mediated tissue damage can then compromise organ function, including drug metabolism and elimination. The temporal variability of the pathophysiologic changes associated with septic shock and burns makes the PK of antibiotics unpredictable. Nonetheless, some studies have revealed class-dependent patterns that can make antibiotic dosing more rational. Table 291.3 indicates the PK changes observed for various commonly used antibiotics and provides suggested dosing strategies. Ongoing awareness of the patient’s physiologic status and further monitoring of serum antibiotic concentrations or secondary markers such as creatinine CL and albumin are required to ensure that the most effective dosing regimens are maintained.

BASIS FOR DRUG-DRUG INTERACTIONS Pharmacokinetic Interactions A drug-drug interaction can exist at any phase of the PK profile (see Fig. 291.1): absorption, distribution, metabolism, or elimination. Frequently, these interactions are predictable qualitatively, if not always quantitatively. For example, knowing that clarithromycin inhibits the same hepatic enzyme responsible for metabolizing cyclosporine leads one to predict that clarithromycin is likely to raise the cyclosporine serum concentration and that a lower dose of cyclosporine may be required. However, actual quantitative adjustment of the cyclosporine dose must be based on measurement of the serum concentration or close monitoring of the patient (or both) for defined end points of efficacy and side effects. The first step consists of awareness of the possibility of a drug-drug interaction and knowledge of the PK properties of the respective drugs. The second step is assessment of the clinical relevance of a potential interaction. Clinical importance occurs when the amount of free (active) drug in the body is significantly altered such that therapeutic efficacy is compromised or toxicity is increased. An assessment of possible specific influences on each aspect of a drug’s disposition profile is outlined in the following sections.

Absorption The absorption of orally administered drugs can be altered by numerous factors: 1. Alterations in GI motility by pharmacologic or nonpharmacologic means. Intestinal motility can be influenced by the administration of gastrokinetic medications (e.g., metoclopramide, erythromycin) or decreased by drugs with anticholinergic or opiate properties. 2. The presence of food in the GI tract. Food can affect the absorption of many antibiotics. For example, itraconazole tablets and posaconazole liquid are better absorbed in the presence of fatty food, whereas itraconazole solution is better absorbed in the fasting state. 3. Alterations in gastric pH. Drugs that are highly charged cross membranes poorly, including the GI mucosal surface. In the normally acidic environment of the stomach, drugs that are weak acids are nonpolar; weak bases are charged. As the pH increases with the use of antacids, histamine (H2)-blocking agents, and proton pump inhibitors, weak acids become more polar and are thus absorbed less, whereas weak bases become less polar and are absorbed more readily. For example, increased gastric and proximal duodenal pH reduces the absorption of cefpodoxime,68 itraconazole capsules but not solution,69 oral ampicillin (product insert), and the antiretroviral drugs atazanavir and indinavir.70 In contrast, absorption of the antiretroviral drug raltegravir is enhanced by concomitant omeprazole, which raises pH.71 These examples notwithstanding, because most drug absorption occurs in the small intestine, which is buffered, gastric pH generally plays a minor role in the overall bioavailability of orally administered drugs. 4. Binding substances. Fluoroquinolones and tetracyclines are poorly absorbed in the presence of cationic ions such as the bismuth, calcium, aluminum, and magnesium ions found in vitamin supplements and antacids; concomitant use of these medications should be avoided. Such interactions can be avoided by separating administration by a minimum of 2 to 4 hours.

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TABLE 291.3  Pharmacokinetic Alterations of Specific Antibiotics With Suggested Dosing Strategies in Patients With Septic Shock or Extensive Burns Antibiotic

Pharmacokinetic Change

Suggested Dosing Strategy

Aminoglycosides

Generally increased clearance and Vd

1. Administer twice the standard multiple daily dosea 2. Measure drug concentration at end of infusion and 4 hr after end of infusion 3. If 4-hour concentration is <2 µg/mL (gentamicin, tobramycin) or <5 µg/mL (amikacin), administer another dose; otherwise, estimate Vd and t1/2, and administer second dose when trough concentration expected to be at target 4. Continue dose and schedule from step 3 5. Confirm therapeutic trough and peak 3 doses later

Glycopeptides (vancomycin, teicoplanin)

Generally increased clearance; fair correlation with CLCr; Vd is not affected

1. Measure CLCr as soon as possible (after initial 48 hr after burn) 2. Administer highest end of standard dose based on shortest dosing interval 3. Measure peak concentration at end of dosing interval 4. Time the measurement of trough level on CLCr, if availableb; if unavailable, measure trough before next dose is due after a standard short interval 5. Adjust dose and interval based on serum peaks and troughsc

β-Lactams (cefepime,332 ceftazidime, ticarcillinclavulanate, piperacillintazobactam333,334)

Vd is substantially increased; total clearance generally is correlated with CLCr; t1/2 is variably increased, but initial serum concentrations are less than normal

1. Measure CLCr as soon as possible (after initial 48 hr after burn) 2. Consider 50% increase over highest usual dose 3. Dosing interval depends on CLCr. If higher than normal, choose moderately short interval; if lower than normal, choose long interval

Carbapenems and monopenems (imipenem, meropenem, aztreonam)

Clearance correlates well with CLCr; Vd unchanged to somewhat increased

1. Measure CLCr as soon as possible (after initial 48 hr after burn) 2. Use high end of standard dose 3. Dosing interval depends on CLCr; If higher than normal, choose short interval; if lower than normal, choose long interval

a Once-daily dosing of aminoglycosides has been shown to result in extended periods of subtherapeutic plasma concentrations in excess of those seen in nonburned patients, thus potentially compromising efficacy, and standard multiple daily dosing carries a significant risk of subtherapeutic peaks. Therefore, higher dose multiple daily dosing is preferred initially.338 b The standard dose of vancomycin in children with the shortest interval is 15 mg/kg every 6 hours. If CLCr is 100% of normal for age, weight, and sex, measure trough 5 hours after the end of infusion (1 × normal dosing interval). If CLCr is 50% of normal, measure trough 11 hours after the end of infusion (2 × normal dosing interval). If CLCr is 200% of normal, measure trough 2 hours after the end of infusion (0.5 × normal dosing interval). c Based on the pharmacokinetic and pharmacodynamic characteristics of vancomycin, continuous infusion can be an alternative for patients with rapid clearance to avoid excessively large or frequent doses. Clinical data are limited, and the best-targeted serum concentration is not clear, but it is likely at least 8 × MIC, with the understanding that particular caution or alternate therapies should be considered if sustained vancomycin concentrations >30 mg/L are considered necessary.339–341 CLCr, creatine clearance; t1/2, drug’s elimination half-life; Vd, volume of distribution. Data from references 335 to 337, except where noted.

Distribution Drug interactions influencing distribution can result from interactions with drug displacement from plasma proteins, most notably serum albumin, and with drug transporters. Drug-drug protein displacement interactions represent drug interactions of common clinical concern but of rare clinical significance, specifically, displacement of one drug or substance (e.g., bilirubin) by another drug or substance from its binding site or sites (e.g., albumin) and leading to an increased concentration of free drug. The resultant increased free drug concentration undergoes distribution and CL and also is available for enhanced PD effect. However, all the following criteria must be fulfilled before such an interaction becomes problematic: 1. The antibiotic must be highly protein bound (> 80%). 2. It must have a small Vd (<1 L/kg). A larger Vd means that the bulk of the drug is extravascular and is not affected by changes in serum protein binding. 3. The drug must have a long t1/2. As drug is displaced from serum protein, it not only becomes biologically active but also becomes available for distribution to extravascular sites, metabolism, and excretion. For drugs with a short t1/2, any displaced excess free drug is quickly redistributed, inactivated, or eliminated from the body, thus promptly reaching a new equilibrium (within 3–5 half-lives). A lower amount of total drug (and thus a larger apparent Vd) characterizes this new equilibrium, and although the free fraction is higher, the absolute concentration of free active drug is the same as before. This disposition occurs with all displaced drugs, but the t1/2 of the displaced

free drug is the most significant factor because it determines the time for the displaced free drug to re-equilibrate. The longer the free drug t1/2, the greater is the amount of time that elevated active drug concentrations are available to augment the therapeutic or toxic effects (or both). The implication of a decreased total serum concentration but the same free concentration is that highly protein-bound drugs with therapeutic levels based on the total serum concentrations (e.g., voriconazole72,73) can appear falsely subtherapeutic because the active free drug concentration is not being measured. These arguments also apply when patients are profoundly hypoalbuminemic, which has the same effect on free and total drug kinetics as displacement from albumin. The reason is that both displacement and hypoalbuminemia result in reduction of available binding capacity. 4. The antibiotic must have a low therapeutic index (i.e., significant toxicity occurs at a serum concentration only slightly higher than therapeutic concentrations). Although several antibiotics meet some of the criteria outlined, none meets all of them. Therefore, concern about toxicity caused by the displacement of antibiotics from serum proteins appears to be unwarranted. The converse question is whether highly protein-bound antibiotics can displace potentially harmful substances that are bound to serum proteins. The area of greatest concern in pediatrics is displacement of albumin-bound bilirubin and subsequent kernicterus in a neonate. The most commonly implicated drugs are the sulfonamide antibiotics and ceftriaxone. The pathophysiology of kernicterus is incompletely understood but is more complex than simple displacement of albumin-bound

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TABLE 291.4  Antibiotics Classified According to Their Possible Ability to Displace Bilirubin From Albumin in Cord Blood Serum in Vitro Higha

Intermediate

Low

No Datab

Cefoperazone

Ampicillin

Aminoglycosides

Acyclovir

Ceftriaxone

Cefonicid

Amoxicillin

Amantadine

Dicloxacillin

Cefoxitin

Aztreonam

Amphotericin Bc

Sulfamethoxazole

Cephalexin

Cefamandole

Cidofovir

Sulfisoxazole

Erythromycin

Cefazolin

Clindamycin

Imipenem

Cefotaxime

Fluconazole

Nafcillin

Ceftazidime

Ganciclovir

Vancomycin

Cefuroxime

Meropenem

Ciprofloxacin

Metronidazole

Penicillin G

Neuraminidase inhibitors

Piperacillin

Protease inhibitorsc

Ticarcillin

Reverse transcriptase inhibitors

a

Avoid in neonates unless no alternative is available. b Although specific data regarding the ability of these antimicrobials to displace bilirubin are lacking, these drugs appear to be safe in this regard based on clinical experience and a low degree of protein binding. c Infants receiving amphotericin B or the protease inhibitor atazanavir can have elevated total serum bilirubin, but not because of displacement from albumin.

bilirubin. The only antibiotic that has actually been associated with kernicterus is IV sulfisoxazole,74 and this may have been a result of the sulfisoxazole diluent in the drug preparation administered. Supporting this inference is the lack of any reported case of kernicterus associated with use of the combination drug trimethoprim-sulfamethoxazole in neonates.75 Nonetheless, because the development of kernicterus involves the transfer of bilirubin from serum and tissue albumin to brain parenchyma in neonates,76 especially premature infants, it seems prudent to avoid the use of antibiotics that do or could potentially displace bilirubin unless no other choice is available. Commonly used antimicrobial agents and their ability to displace bilirubin are listed in Table 291.4.77–79

Metabolism Many drug-drug interactions occur at the level of drug CL, particularly for drugs that undergo metabolism. The CYP450 enzyme system is responsible for the metabolism of many drugs, including antibiotics. These enzymes can be inhibited, induced, or saturated by substrate. For antibiotics that are primarily metabolized by one CYP450 isoform, the potential exists for significant changes in serum concentration, given that CL is either increased or decreased because of changes in enzyme activity. The highest concentration of these enzymes is in the liver, but the intestinal mucosa also contains CYP450 enzymes and is the site of numerous drug-drug interactions that affect bioavailability. To predict a clinically significant drug-drug interaction, therefore, similar questions are asked regarding whether the antibiotic is primarily metabolized by 1 CYP450 isoform or has alternative or parallel metabolic pathways and whether a change in serum concentration would have significance. Specifically, if the serum concentration is lowered, could the antibiotic concentration−time course ratio fall short of the optimal PK-PD–predicted concentration−time course ratio? If the serum concentration is raised, could toxicity occur? Table 291.5 lists antimicrobial agents that modulate specific CYP450 isoforms that predispose a patient to potential drug-drug interactions when these drugs are coadministered with drugs metabolized by similar pathways. Knowledge of which isoform is primarily responsible for a drug’s metabolism provides the clinician with the insight at least to question the possibility of a metabolically based drug-drug interaction. For specific drug-drug interactions, refer to individual agents in Chapter 292.

Elimination The primary mechanisms of antibiotic elimination from the body involve elimination via bile, feces, urine, or combinations of these mechanisms. Drugs that are eliminated in the bile are subject to enterohepatic

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recirculation, which means that they can be reabsorbed into the circulation from drug-containing bile secreted into the intestines, resulting in complex absorption profiles characterized by multiple concentration peaks over the dosing interval. Amoxicillin can lower the effectiveness of oral contraceptives by altering the GI flora, reducing enterohepatic recirculation of the contraceptive, and enhancing elimination. Agents eliminated in urine can be filtered at the glomerular level and secreted at the tubular level. Fortunately, few drugs cause unwanted alterations at these sites. However, any agent that can reduce glomerular filtration (e.g., amphotericin B, cisplatin) can decrease the CL of the concurrently administered and filtered antibiotic, potentially necessitating dose adjustment. A notable example that has been used therapeutically is probenecid, a drug that inhibits the tubular secretion of organic acids by antagonizing the efflux effects of select organic anion transporters (OATs; see the later section on transporters). Probenecid can be coadministered with penicillin to reduce the extent of the antibiotic’s tubular secretion and promote its accumulation in the body. This drug is also administered with systemic cidofovir to mitigate toxicity of the drug by reducing intraluminal concentrations. Nevertheless, the lack of adequate guidelines for pediatric dosing of probenecid, the unpredictability of the drug-drug interaction, and the exact amount of drug accumulation and the potential that probenecid can also interfere with in vivo antibiotic distribution (antagonism by probenecid of the organic acid transport used by selected β-lactams into target tissue) preclude the common use of probenecid for this use in children or adults.

Transporters Transporters important to cellular homeostasis influence the bioavailability, distribution, and elimination of many drugs.80 Examples of such transporters are P glycoprotein (P-GP), the organic anion transport polypeptides (OATP), and the organic cation transporters (OCTs), which often are associated with drug efflux out of the cell or facilitation of intracellular drug uptake. Transporters are found in many organs and tissues including the intestinal tract, placenta, bloodbrain barrier, liver, and kidney and also are subject to induction and inhibition.81 Drugs can serve as substrates, inhibitors, inducers, or any combination of the 3, thereby resulting in complex interactions that can be difficult to predict quantitatively. Thus changes in the balance of cellular efflux or uptake in the intestine may decrease or increase bioavailability, whereas changes in tissues may affect Vd and drug CL. Antimicrobial agents that are substrates for the P-GP efflux transporter include select protease inhibitors, erythromycin, and the antifungal drugs ketoconazole and itraconazole. Substrates for OATs include the penicillins and select cephalosporins. Probenecid inhibition of OATP activity is still used as a part of the amoxicillin-probenecid drug

Pharmacokinetic-Pharmacodynamic Basis of Optimal Antibiotic Therapy

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TABLE 291.5  Antibiotic–Cytochrome P450 Interactionsa Isoenzyme

Substrate

Inhibitor

Inducer

1A1

Chloroquine, erythromycin, nitrofurantoin, raltegravir

Atazanavir, ketoconazole, norfloxacin, quinidine

Albendazole, fluconazole, itraconazole, mebendazole, primaquine, rifampin

1A2

Albendazole, erythromycin, griseofulvin, pyrazinamide, rifabutin, rifampin, terbinafine

Albendazole, artemesinin, clarithromycin, efavirenz, erythromycin, fluconazole, fluoroquinolones (especially ciprofloxacin), isoniazid, ketoconazole, lopinavir, nevirapine, ritonavir, tenofovir

Albendazole, griseofulvin, rifampin, ritonavir

1B1

Erythromycin

Doxycycline, ketoconazole

2A6

Artemisinin, artesunate, rifampin, zidovudine

2B6

Artemisinin, efavirenz, nevirapine, rifampin, ritonavir

Amprenavir, efavirenz, ketoconazole, nelfinavir, ritonavir, nevirapine

Artemisinin, efavirenz, nevirapine, rifampin, ritonavir

2C8

Amodiaquine, amprenavir, chloroquine, dapsone, fosamprenavir, quinidine, sulfadiazine, trimethoprim, zidovudine

Chloramphenicol, efavirenz, fluconazole, indinavir, isoniazid, ketoconazole, metronidazole, rifampin, ritonavir, saquinavir, sulfamethoxazole, trimethoprim

Griseofulvin, rifampin, ritonavir

2C9

Amprenavir, dapsone, fluconazole, fosamprenavir, metronidazole, quinidine, rifampin, sulfamethoxazole, trimethoprim, terbinafine, voriconazole

Adefovir, atovaquone, chloramphenicol, efavirenz, fluconazole, indinavir, isoniazid, ketoconazole, lopinavir, metronidazole, nelfinavir, pyrimethamine, sulfamethoxazole, tenofovir, trimethoprim, voriconazole

Dapsone, nelfinavir, rifapentine, rifampin, ritonavir

2C19

Amoxicillin, artemether, chloramphenicol, clarithromycin, dapsone, etravirine, nelfinavir, praziquantel, proguanil, rifampin, terbinafine, voriconazole, zidovudine

Amprenavir, chloramphenicol, clarithromycin, efavirenz, fluconazole, fosamprenavir, indinavir, isoniazid, ketoconazole, lopinavir, probenecid

Artemisinin, rifampin, ritonavir

2D6

Chloroquine, rifampin

Chloroquine, efavirenz, fluconazole, isoniazid, lopinavir, mefloquine, nelfinavir, nevirapine, praziquantel, proguanil, quinidine, ritonavir

Rifampin, rifapentine

2E1

Dapsone, isoniazid, proguanil, rifampin, sulfadiazine

Isoniazid, itraconazole, ketoconazole, tenofovir

Ciprofloxacin, isoniazid, rifampin

3A4, 3A5, 3A7

Albendazole, azoles, artemether, artemesinin, chloroquine, clindamycin, dapsone, erythromycin, HIV protease inhibitors and nonnucleoside reverse transcriptase inhibitors, ivermectin, macrolides and azalides, mefloquine, primaquine, quinidine, rifampin, terbinafine, tetracyclines, trimethoprim, zidovudine

Azoles, caspofungin, clindamycin, efavirenz, fluoroquinolones, HIV protease inhibitors, isoniazid, macrolides, mefloquine, metronidazole, quinidine, quinupristin-dalfopristin, primaquine, sulfamethoxazole, tetracyclines

HIV protease inhibitors and nonnucleoside reverse transcriptase inhibitors, rifampin, rifapentine, terbinafine

Rifampin Rifampin

a Currently described interactions are listed in http://bioinformatics.charite.de/supercyp/. Interactions may not be clinically significant, but have been described in vitro. The most significant inhibitors and inducers are shown in bold.

combination for uncomplicated Neisseria gonorrhoeae (amoxicillinsusceptible) disease.

PHARMACODYNAMIC INTERACTIONS PD interactions can affect efficacy or toxicity, and drugs can interact to diminish or augment either effect. As discussed in Chapter 289, these interactions can be synergistic, additive, indifferent, or antagonistic. Because PD interactions arise from relationships with a drug’s mechanisms of action, the clinician must be aware of these mechanisms. The appropriate question is whether the mechanisms of action of a patient’s medications are likely to be related in any way. Table 291.6 outlines some frequent examples of each type of PD-based interaction.

INTEGRATION OF PHARMACOKINETIC AND PHARMACODYNAMIC PRINCIPLES FOR OPTIMAL ANTIBIOTIC DOSING REGIMENS Identification and definition of optimal doses and dosing intervals for antimicrobial agents have eluded clinicians and investigators for decades. This problem can be attributed to the difficulty and delay in measuring outcome, specifically, clinical improvement, microbiologic eradication,

or survival. This difficulty in quantifying the effect of antibiotics is in contrast to other classes of drugs used in clinical medicine (e.g., antihypertensive drugs). Substantial research to date has described the PK properties for most antimicrobial drugs used in pediatric practice. The challenge remains to determine objective PD markers or end points that reflect optimal dosing to achieve the desired therapeutic response.82

Pharmacodynamic Correlates for Antibacterial Agents Antibacterial agents influence the life cycle of organisms in various ways. To alter bacterial growth, antibiotics must bind to a cellular target82–84 (Fig. 291.2). Binding of the drug to its target results in alteration of the normal function of the bacterium and leads to either inhibition of growth or cell death. In addition to the ability of an antimicrobial agent to reach its target site of action (i.e., the receptor), the drug also must possess sufficient affinity for its receptor, and it must achieve a sufficient concentration to affect bacterial function. These pharmacologic characteristics are the primary determinants of antimicrobial activity. Unfortunately, investigators are unable directly to quantify these characteristics clinically. As such, surrogate markers have been developed

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in an attempt to reflect these crucial cellular interactions. For antibacterial agents, in vitro tests such as the MIC and the minimal bactericidal concentration (MBC) are used as indirect measures of in vivo activity.85–87 However, these markers do not provide sufficient information on the temporal pattern of exposure of an organism to antimicrobial agents or the antimicrobial concentration that must be achieved relative to the MIC and the MBC to ensure a sufficient therapeutic response. Consideration of the laboratory procedures used in determining MICs and MBCs raises caution for use as primary indicators of clinical antimicrobial activity. First, measurements of MIC and MBC are obtained in bacterial growth media that are devoid of protein (e.g., represent 100% free active drug), which can have implications for agents that are highly bound to plasma proteins (e.g., >70%). Similar concentrations of free drug at the anatomic site of infection may not be achievable clinically because of extensive protein binding, drug molecular weight, and degree of ionization at pathophysiologic pH. Second, measuring MICs and MBCs usually involves maintaining a constant concentration of free drug for a standard period (generally 18–24 hours). Such a constant

TABLE 291.6  Examples of Pharmacodynamic Interactions Efficacy

Toxicity

INCREASED

INCREASED

Numerous examples exist: synergistic activity of β-lactam plus aminoglycoside against enterococci; β-lactam plus β-lactamase inhibitor for extended gram-negative and anaerobic coverage; trimethoprim plus sulfamethoxazole; quinupristin plus dalfopristin

Two potentially nephrotoxic antibiotics such as vancomycin plus an aminoglycoside can increase the likelihood of renal injury DECREASED Probenecid mitigates the nephrotoxicity of cidofovir342

DECREASED The antiretroviral drugs zidovudine and stavudine are antagonistic when coadministered, likely because of an interaction at the level of intracellular, molecular targets

Cell wall synthesis Cycloserine Vancomycin, teichoplanin Bacitracin Penicillins Cephalosporins Monobactams Carbapenems

concentration simulates a continuous infusion of antibiotic, whereas clinically, antibiotics are usually administered intermittently, which results in peaks and troughs rather than constant concentrations. Third, MICs or MBCs are measured on a standard inoculum of bacteria that may or may not reflect the actual density of bacteria present at the site of infection. Finally, the laboratory procedures used to determine the MIC and MBC do not account for the antimicrobial activity of various host defenses, including immunoglobulins and macrophages. In vitro susceptibility testing is especially valuable in identifying antimicrobial agents that will be ineffective in eradicating the pathogen. Conversely, a pathogen can appear susceptible to a particular agent from in vitro testing, yet information is lacking on the ability of the agent to achieve the necessary concentrations for a sufficient period at the site of infection to eradicate the pathogen. The immense importance of integrating such data with therapeutic outcome is exemplified by the PK-PD correlates in the successful treatment of bacterial meningitis.67,82,88 The time course of the drug must be integrated with the concentration at the receptor site to reflect the in vivo antibiotic-bacteria interaction adequately. As a result of the different mechanisms of inhibiting or killing bacteria and the position of safely achievable concentrations on the concentrationresponse curve, specific PK-PD properties can be correlated with efficacy (Table 291.7).89 The first pattern of activity is for drugs with concentrations near the upper, flat portion of the concentration-response curve and that have minimal postantibiotic effect (i.e., ongoing killing after serum concentrations have dropped to less than the MIC). The activity of these drugs depends on the duration of time that the antibiotic concentration exceeds the MIC (T >MIC).82 For these antibiotics, saturation of the bacterial killing rate is observed at certain multiples of the MIC, usually 2 to 4 times, and antibiotic concentrations exceeding this level generally do not achieve greater killing rates. Clearly, the duration that the antibiotic concentration exceeds the MIC of the pathogen is influenced by several factors, including the dosing interval, the pathogen, and the site of infection. Drugs that demonstrate this type of PK-PD relationship are referred to as time dependent. Some investigators refer to this class as concentration-independent antibiotics, but this term is not preferable because all antibiotics require a minimal concentration for efficacy. Examples of drugs that exhibit time-dependent killing include all the β-lactams (see Table 291.7). In contrast, a second pattern of bacterial killing has been characterized for drugs that have concentrations in the steeper portion of the concentration-response curve and that have some degree of

DNA gyrase Quinolones

DNA-directed RNA polymerase Rifampin Cell wall Protein synthesis (50S inhibitors) Erythromycin (macrolides) Chloramphenicol Clindamycin

DNA THFA

Folic acid metabolism

mRNA

Trimethoprim Sulfonamides

DHFA

Ribosomes 50 30

50 30

50 30

PABA Cell membrane Polymyxins

Chloramphenicol Transacetylase

Protein synthesis (30S inhibitors) Tetracycline Spectinomycin Streptomycin Gentamicin, tobramycin (aminoglycosides) Amikacin (tRNA) Mupirocin

FIGURE 291.2  Sites of action for major antibacterial drugs. DHFA, dihydrofolate; PABA, para-aminobenzoic acid; THFA, tetrahydrofolate. (Adapted from Neu HC. The crisis in antibiotic resistance. Science 1992;257:1064–1073.)

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Pharmacokinetic-Pharmacodynamic Basis of Optimal Antibiotic Therapy

TABLE 291.7  Classification of Selected Antibacterials Based on Their Pattern of Antimicrobial Activity Pattern

Drug

Peak/MIC Concentrationdependent killing, prolonged postantibiotic effects

Aminoglycosides

10

Daptomycin343

100 (Staphylococcus aureus) 36 (Streptococcus pneumoniae) 0.25 (Enterococcus faecium)

Fluoroquinolones

10

Metronidazole

?

Carbapenems, aztreonam

>20%-40%

Cephalosporins

>20%-40%

Penicillins

>40%-60%

Azithromycin

25344

Clindamycin

?

Time >MIC Time-dependent killing, minimal postantibiotic effects AUC/MIC Time-dependent killing, moderate to prolonged persistent antibiotic effects

Target

Telithromycin 346

3345

Dalbavancin

1,000 (S. aureus) 100 (Streptococcus species)

Linezolid

80 (or trough > MIC)347

Metronidazole

70348

Macrolides

30349,350

Quinupristin-dalfopristin

?

Telavancin

219351

Tetracyclines

10

Tigecycline

18 (gram-positive organisms)352 7 (gram-negative organisms)353

Vancomycin

400 (trough ~8 × MIC)341

AUC, area under the curve; MIC, minimal inhibitory concentration. Data are from references 85 and 354 unless otherwise noted.

postantibiotic effect.90,91 The bactericidal ability of agents in this group depends on the peak concentration to MIC (peak/MIC) within the dosing interval. In other words, the higher the antibiotic peak concentration, the greater is the bacterial kill. Agents that demonstrate this type of PK-PD interface are referred to as concentration-dependent or peak-dependent antibiotics and include aminoglycosides and fluoroquinolones. A third class of drugs also has a postantibiotic effect, although it is typically more modest than that of the peak-dependent antibiotics, and these drugs lie near the upper portion of the concentration-response curve. For these drugs it is simply the AUC/MIC ratio that best describes activity. These are also called time-dependent drugs, but the moderate postantibiotic effect makes the choice of dose interval less critical than for time-dependent drugs that have little to no postantibiotic effect. Examples of AUC/MIC drugs include vancomycin and azithromycin. Fig. 291.3 depicts the relationships between drug concentration and effect. The clinical challenge relative to the PK-PD properties of T >MIC and peak/MIC or AUC/MIC is determining the target range for each that correlates with bacteriologic response. These relationships and targets are summarized in Table 291.7.

Clinical Utility of Antibiotic PharmacokineticPharmacodynamic Correlates The superior ability to predict bacteriologic cure by using integrated PK-PD characteristics, rather than MIC or MBC information solely (see

291

Table 291.7), helps standardize antimicrobial dosing in clinical trials and assists in guiding antimicrobial therapy for individual patients.82,86,90,92 Furthermore, providing adequate amounts of antibiotic for sufficient periods by optimal dosing based on PK-PD properties also may decrease the rate and extent of bacterial resistance. An appreciation of the PK-PD characteristics of aminoglycosides, combined with a better understanding of their safety profiles, led to once-daily dosing of aminoglycosides that can take advantage of the concentrationdependent killing characteristics of this class of antibiotics (i.e. peak/MIC correlation).93 Moreover, in patients with a poor clinical response, an understanding of a particular drug’s PK-PD characteristics allows the clinician rationally to assess the potential contribution of suboptimal dosing and to develop an effective, alternative regimen. In their assessment of published data, Craig and Andes94 demonstrated that the T >MIC for β-lactam antibiotics predicted bacteriologic efficacy with accuracy similar to that of the ratio of middle ear fluid concentration to MIC. Moreover, when the T >MIC exceeded 40% to 50% of the dosing interval, bacteriologic and clinical cure was achieved in 80% to 85% of the patients studied. Although most of the Streptococcus pneumoniae isolates in these studies were susceptible to penicillin, the same principles apply to nonsusceptible organisms. For example, conventional amoxicillin dosing (13.3 mg/kg/dose 3 times daily) would be expected to exceed the target T >MIC for penicillinsusceptible S. pneumoniae, whereas higher doses (45–50 mg/kg/dose twice daily) often are required to achieve the target T >MIC for many nonsusceptible isolates. It is not the increased dose of amoxicillin per se that correlates with increased efficacy, but rather the longer T >MIC afforded by higher initial concentrations. As an extension of this work, much attention has been paid to modeling improved efficacy of prolonged infusion of β-lactams against resistant gram-negative organisms,95 and this approach has been prospectively validated in critically ill adults in a randomized study.89 An awareness of PK-PD characteristics also permits more sophisticated interpretation of the breakpoints for in vitro susceptibility.96 In general, guidelines for interpretation are derived from the likelihood of bacteriologic success relative to the MIC of the infecting organism and the projected achievable serum concentration of antibiotic. A major exception is the breakpoint reporting for S. pneumoniae, for which additional interpretation is based on projected achievable central nervous system concentrations. Thus, if the infection is in an anatomic location other than that for which the breakpoints were derived, the breakpoints can be less relevant.

PHARMACOKINETIC AND PHARMACODYNAMIC RELATIONSHIPS OF OTHER ANTIMICROBIAL AGENTS Maximizing desirable PD outcomes in combination with minimizing undesirable adverse effects necessarily requires the ability to quantify such end points. Furthermore, an objective index variable must be identified to which therapy can be linked to achieve the therapeutic goals. Although our knowledge of PK-PD relationships for other antimicrobial agents (e.g., antifungal, antiviral, antimycobacterial) is not yet as advanced as for antibacterial agents, progress is being made.97–99 Antifungal MICs are determined most reliably for yeasts (e.g., Candida and Cryptococcus). The value of MICs lies in the assignment of susceptibility breakpoints: drug concentrations higher than which the isolate is considered resistant and lower than which it is considered susceptible. The Clinical Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) have established breakpoints for azoles, echinocandins, and flucytosine against Candida spp. Although some reliability is similar to MIC breakpoints for bacterial infections,100 controversy still surrounds the exact thresholds for susceptibility.101,102 Breakpoints for filamentous fungi, such as Aspergillus, still do not exist and will be difficult to generate now that combination therapy is widely used for Aspergillus and other filamentous fungal infections.103 We are only in the early stages of understanding optimal PK-based dosing of antifungal drugs, and Table 291.8 shows the hypothesized relationships and dosing implications.104 PK-PD dosing for antiviral drugs, as shown in Table 291.9, has been most commonly applied to therapy for human immunodeficiency virus

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

MIC Change in organism

Concentration

Kill

MIC %Time AUC

Stasis PAE

Growth Time

A

MIC

MIC

Kill Change in organism

Change in organism

Kill

Stasis

Growth C

Free drug concentration

B

Stasis PAE

Growth Free drug concentration

D

Free drug concentration

FIGURE 291.3  Relationship between concentrations and effects for antimicrobials. (A) The 3 classical categories of antimicrobial compounds: peak/minimal inhibitory concentration (MIC), time > MIC, and area under the plasma drug concentration–time curve (AUC)/MIC. (B) The reason that a drug’s pharmacokinetic-pharmacodynamic linkage may be peak/MIC. As the free drug plasma concentration increases (moving to the right on the x-axis), effect increases in a sigmoidal fashion following the blue curve. As the free drug concentration falls (moving to the left on the x-axis), effect diminishes, following the gold curve. The effect, in change of organism numbers is shown on the y-axis. Net kill is shown as dashed line above the horizontal. Net growth is shown below it. At the horizontal line stasis occurs, which corresponds to a free drug concentration at the MIC. Note that as the drug concentration falls (along the red curve), to less than the MIC, a continued net kill of organism can occur. This is a prolonged antimicrobial effect (PAE), which typifies peak/MIC drugs. The split effect curve (gold and blue) is termed “negative hysteresis” and can result from delayed action of a drug relative to plasma concentrations, such as a drug’s inhibition of microbial protein synthesis. (C) No PAE or negative hysteresis is present, and as soon as drug concentrations fall to less than the MIC, the organism begins to regrow, as is typical of time >MIC agents. (D) Finally, a moderate PAE is present, and the daily dose could be given less frequently as a larger dose (as long as dosing is not so infrequent as to allow regrowth) or more frequently in smaller doses, typical of AUC/ MIC agents.

TABLE 291.8  Proposed Pharmacokinetic-Pharmacodynamic Relationships for Antifungal Drugs

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Drug

PK-PD Relationship

Notes

Amphotericin B

Peak/MIC?

Single, large daily doses are more effective than smaller, frequent doses; the dosage is limited by toxicity to a maximum of 1.5 mg/kg/day

Lipid amphotericin B (AmBisome, Abelcet, Amphotec)

Peak/MIC?

As above, but the PK properties of the 3 preparations are different, and more studies are required to determine whether PD differences also exist. Lower toxicity in general permits a higher dosing of 5 mg/kg/day, and tolerability up to 15 mg/kg/day (Ambisome355) and 10 mg/kg/day (Abelcet356) has been reported, but added efficacy at the higher doses has not been demonstrated and may result in increased nephrotoxicity357

Fluconazole

AUC/MIC

Optimal dosing is 6 mg/kg/day IV or PO for susceptible isolates and 12 mg/kg/day for dose-dependent isolates. A loading dose of 25 mg/kg on day 1 should be strongly considered in infants.358 Doses >12 mg/kg offer unproven additional benefit and increase the risk of toxicity. A dose-MIC ratio of >50 or an AUC/MIC ratio of >25 have been suggested as targets359

Itraconazole

AUC/MIC

Target trough concentrations of >0.5 mg/L are recommended360

Posaconazole

AUC/MIC

Concentrations demonstrate high interpatient variability; in 2 pivotal phase 3 studies analyzed by the FDA, a plasma concentration of >0.35 mg/L 3–5 hr after dosing on day 2 was predictive of a concentration of >0.70 mg/L at the same time on day 7, which was associated with prevention of invasive fungal infections.360 Another study reported best treatment outcomes with average concentrations of >1.25 mg/L.361 In practice such concentrations are difficult to achieve in children with the suspension362; however, the newer delayed-release tablet formulation (approved for ≥13 years of age) has greatly enhanced absorption, and such concentrations are easier to obtain

Pharmacokinetic-Pharmacodynamic Basis of Optimal Antibiotic Therapy

291

TABLE 291.8  Proposed Pharmacokinetic-Pharmacodynamic Relationships for Antifungal Drugs—cont’d Drug

PK-PD Relationship

Notes

Voriconazole

AUC/MIC

Target trough concentrations of >1.0 mg/L have been associated with survival benefit in children7

Flucytosine

T>MIC

In vitro data suggest that peak efficacy occurs at a serum concentration–MIC ratio of 4 : 1. No data exist on the most effective duration of serum concentration higher than the MIC. If toxicity is problematic (typically with peak >100 mg/L), smaller, more frequent doses or even continuous infusion may be more effective, but human data are lacking. Usual peaks are 30−100 mg/L363

Echinocandins (caspofungin, micafungin, anidulafungin)

AUC/MIC

Clinical data are lacking, but in vitro and animal models suggest that for Candida species, a free drug AUC/MIC ratio of 5−20 (high end for C. albicans, lower for C. parapsilosis) may be adequate,364 which is an AUC/MIC ratio of 3,000 in patients.365 For Aspergillus species, the target is a free Cmax/MEC ratio of approximately 10366

AUC, area under the curve; Cmax, maximal concentration; FDA, Food and Drug Administration; IV, intravenously; MEC, minimum effective concentration, which is the minimum amount of drug to cause transition to a compact rounded hyphal form; MIC, minimal inhibitory concentration; PD, pharmacodynamic; PK, pharmacokinetic; PO, orally.

TABLE 291.9  Pharmacokinetic-Pharmacodynamic Targets for Antiretroviral and Antiviral Drugs Based on Clinical Data Drug

Target Cmin (ng/mL)

Notes

NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Efavirenz

1,000

Etravirine

275 (81–2,980)

Nevirapine

3,000

No efficacy target established; value is median (range) from clinical studies

PROTEASE INHIBITORS Atazanavir

150

Darunavir

3,300 (1,255–7,368)

No efficacy target established; value is median (range) from clinical studies in adults given 600 mg twice daily

Fosamprenavir

400

Measured as amprenavir

Lopinavir

1,000

Nelfinavir

800

Parent drug plus M8 active metabolite

Tipranavir

20,500

Not suggested for PI-naïve patients

50

Not suggested for treatment-naïve patients

72 (29–118)

No efficacy target established; value is median (range) from clinical studies in adults given 600 mg twice daily

AUC 35–50 µg/mL/hr

For prevention of CMV infection

ENTRY INHIBITOR Maraviroc INTEGRASE STRAND INHIBITOR Raltegravir NONANTIRETROVIRAL Ganciclovir105

AUC, area under the curve; Cmin, minimal concentration; CMV, cytomegalovirus; PI, protease inhibitor. Data on antiretroviral agents from Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. AIDSinfo. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 2015. www.aidsinfo.nih.gov.

(HIV) infection. The concept of MIC determination translates as the inhibitory concentration, or ICxx, where xx is the percentage of viral strains within a particular species for which replication is inhibited in vitro at drug concentration IC. Numerous studies have demonstrated a dose-response relationship for both protease inhibitors and nonnucleoside reverse transcriptase inhibitors and have identified threshold trough serum concentrations, or AUC, greater than which efficacy is improved (as measured by the reduction in viral load and increased CD4+ T-lymphocyte count). Studies also have demonstrated the safety and feasibility of antiretroviral therapeutic regimens tailored to specific patients to maintain serum drug concentrations within a predetermined range, although efficacy studies are yet to come. For non-HIV viral infections, some data suggest that the acyclovir effect is time dependent and that if the serum drug concentration remains higher than the IC50 of herpes simplex virus or varicella-zoster virus for at least 12 hours per day, clinical efficacy is maximized. Ganciclovir has been reported to have near-maximal efficacy to prevent cytomegalovirus infection when a target AUC of 35 to 50 µg/mL per hour is reached, with

a concomitant 10% to 20%, and 30% to 50% probability of the patient’s developing neutropenia and leukopenia, respectively.105

FUTURE CONSIDERATIONS Increasingly, drug dosing will be based on achieving PK-PD targets in individual patients rather than the traditional population-based recommendations of dosing ranges. Therefore studies of new antimicrobial agents must include an assessment of PK-PD relationships. The ongoing challenge in pediatrics is to ensure that the determination of these important surrogate markers or end points incorporates the important changes that occur with increasing age. Box 291.1 synthesizes the information presented in this chapter into questions that a thorough clinician should consider for every patient to whom antibiotics are to be administered. Box 291.2 provides a listing of useful websites for additional information. All references are available online at www.expertconsult.com.

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

BOX 291.1  Important Pharmacokinetic-Pharmacodynamic Issues to Consider When Determining the Dose of Antibiotics What is the known or suspected target pathogen? What is the minimal inhibitory concentration of available antibiotics for the pathogen? Will adequate concentrations of the drug be distributed to all infected sites? Are there any characteristics of the patient that will alter the usual pharmacokinetic properties of the drug? What process best describes the antibiotic antibacterial activity: time dependent or concentration dependent? Based on the pharmacokinetic-pharmacodynamic correlate, how often should the antibiotic be administered? With a suboptimal clinical response, should the individual dose be increased, administered more frequently, or both? Should a different drug be used?

KEY REFERENCES 1. Magalhães J, Rodrigues AT, Roque F, et al. Use of off-label and unlicenced drugs in hospitalised paediatric patients: a systematic review. Eur J Clin Pharmacol 2015;71:1–13. 2. Neville KA, Frattarelli D, Galinkin JL, Green TP. Off-label use of drugs in children. Pediatrics 2014;133:563–567. 4. Hsu AJ, Tamma PD. Treatment of multidrug-resistant gram-negative infections in children. Clin Infect Dis 2014;58:1439–1448. 5. Downes KJ, Hahn A, Wiles J, et al. Dose optimisation of antibiotics in children: application of pharmacokinetics/pharmacodynamics in paediatrics. Int J Antimicrob Agents 2014;43:223–230. 6. Sime FB, Roberts MS, Roberts JA. Optimization of dosing regimens and dosing in special populations. Clin Microbiol Infect 2015;21:886–893. 10. Neely M, Kaplan EL, Blumer JL, et al. Serum penicillin G concentrations are below inhibitory concentrations by two weeks after benzathine penicillin G injection in the majority of young adults: a population pharmacokinetic modeling approach. Antimicrob Agents Chemother 2014;58:6735–6741.

BOX 291.2  Useful Websites URL

Notes

redbook.solutions.aap.org

American Academy of Pediatrics Red Book Report of the Committee on Infectious Diseases (paid subscription required) Regularly maintained searchable database of treatment guidelines involving therapeutic agents for human immunodeficiency virus infection Searchable databases with links for prescribers to reproductions of the package insert National Library of Medicine PubMed/MEDLINE database of medical journal articles, many of which are available as full text items

aidsinfo.nih.gov

www.dailymed.nlm.nih.gov, www.drugs.com, and www.rxlist.com www.ncbi.nlm.nih.gov/ pubmed

www.idsociety.org/ Index.aspx

Infectious Diseases Society of America, which includes numerous freely available treatment guidelines

26. Funk RS, Brown JT, Abdel-Rahman SM. Pediatric pharmacokinetics: human development and drug disposition. Pediatr Clin North Am 2012;59:1001–1016. 27. Mooij MG, de Koning BA, Huijsman ML, de Wildt SN. Ontogeny of oral drug absorption processes in children. Expert Opin Drug Metab Toxicol 2012;8:1293–1303. 66. Ortwine JK, Pogue JM, Faris J. Pharmacokinetics and pharmacodynamics of antibacterial and antifungal agents in adult patients with thermal injury: a review of current literature. J Burn Care Res 2015;36:e72–e84.

APPENDIX 291.1  Usual Dosing, Therapeutic Targets, and Suggestions for Maintenance Dosing of Selected Antimicrobial Agents in Patients With Impaired Renal Functiona Adjustment of Usual Dosing for Renal Failure

Usual Dosing: Maintenance (Daily Max)

>60–90

30–60

<30

Amikacin (IM, IV)108,112–117

5–7.5 mg/kg q8h

60%–90% q12h

30%–70% q12–18h

20%–30% q24–48h

Gentamicin (IM, IV)114,118–121,127–130

2.5 mg/kg q8h

Streptomycin (IM, IV)114,122–124

20–40 mg/kg q24h (2 g/day)

Drug (Route) AMINOGLYCOSIDES

GFR (mL/min/1.73 m2)b Adjustment for Dialysisc

d

H: 66% after H P: 15–20 mg/L IP C: As for CLCr 30–60

60%–90% q8h

30%–70% q12h

20%–30% q24–48h

H: 66% after H P: 3–4 mg/L IP C: As for CLCr 30–60

Usual dosing

100% q24–72h

100% q72–96h

H: 50% after H P: 20-40 mg/L IP C: As for CLCr 30–60 P: 3–4 mg/L IP C: As for CLCr 30–60

Tobramycin

2.5 mg/kg q8h

60%–90% q8h

30%–70% q12h

20%–30% q24–48h

H: 66% after H P: 3–4 mg/L IP C: As for CLCr 30–60

CEPHALOSPORINS Cefaclor (PO)125

e

10–20 mg/kg q12h (1.5 g/day)

Usual dosing

15 mg/kg q12h (2 g/day)

Usual dosing

Usual dosing

50% q8h

H: 50–75% q8h P: No significant clearance C: Usual dosing

Cefadroxil (PO)126

100% q24h

100% q48h

H: 100% q48h P: No significant clearance C: As for CLCr 30–60

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APPENDIX 291.1  Usual Dosing, Therapeutic Targets, and Suggestions for Maintenance Dosing of Selected Antimicrobial Agents in Patients With Impaired Renal Function—cont’d Usual Dosing: Maintenance (Daily Max)

Drug (Route) Cefazolin (IV)127–130

Adjustment of Usual Dosing for Renal Failure GFR (mL/min/1.73 m2)b >60–90

30–60

<30

20–35 mg/kg q8h (12 g/day)

Usual dosing

100% q12h

100% q24h

14 mg/kg q24h (600 mg/day)

Usual dosing

50 mg/kg q8–12h (6 g/day)

100% q12h

8 mg/kg q24h (400 mg/day)

Usual dosing

50–75 mg/kg q6–8h

Usual dosing

Adjustment for Dialysisc H: 100% q24h P: 15 mg/kg IP q24h C: As for CLCr 30–60

Cefdinir (PO)131,132

Usual dosing

50% q24h

H: 50% q48h P: No significant clearance C: As for CLCr 30–60

Cefepime (IV)127,133–135

100% q16–24h

100% q24–48h

H: 50% q24h P: 15 mg/kg IP q24h C: As for CLCr >60–90

Cefixime (PO)136

75% q24h

50% q24h

H: 75% q24h P: No significant clearance C: As for CLCr 30-60

Cefotaximef (IV)137,138

Usual dosing

50% q6–8h

H: 50% q6–8h P: 500 mg IP q24h

(12 g/day)

C: As for CLCr 30–60 Cefoxitin (IV)139,140

20–40 mg/kg q6h (12 g/day)

100% q8h

Cefpodoxime (PO)141–143

5 mg/kg q12h (800 mg/day)

Usual dosing

Cefprozil (PO)144

15 mg/kg q12h (1 g/day)

Usual dosing

100% q8–12h

100% q24–48h

H: 100% q24–48h P: No significant clearance C: As for CLCr 30–60

Usual dosing

50% q12h

H: 50% q12h P: No significant clearance C: As for CLCr 30–60

Usual dosing

100% q24h

H: 100% q24h P: Significant clearance unlikely C: Likely as for CLCr 30–60

g

145

Ceftaroline (IV)

>12y: 8 mg/kg q12h (1.2 g/day)

Usual dosing

50 mg/kg q8h (12 g/day)

Usual dosing

50%–75% q12h

50% q12h

H: 50% q12h P: No significant clearance C: As for CLCr 30–60

Ceftazidime (IV)130,146–150

100% q12h

100% q24h

H: 100% q24h P: 50% IV q24h OR 125 mg/L continuous IP OR 15–20 mg/kg q24h IP C: 50–75% q12h

Ceftriaxone (IV, IM)151–154

50–100 mg/kg/day divided q12–24h (4 g/day)

Usual dosing

Cefuroxime sodium (IV)147

35-50 mg/kg q8h (6 g/day)

Usual dosing

Cefuroxime axetil (PO)147,155

15 mg/kg q12h (3 g/day)

Usual dosing

Cephalexinh (PO)156

25 mg/kg q6h (4 g/day)

Usual dosing

Usual dosing

Usual dosing

H: Usual dosing P: 50 mg/kg IP q24h C: Usual dosing

100% q8–12h

100% q24h

H: 100% q24h P: 15 mg/kg IP q24h C: As for CLCr 30–60

100% q12h

100% q24h

H: 100% q24h P: No significant clearance C: As for CLCr 30–60

Usual dosing

50% q6h

H: 50% q6h P: No significant clearance C: Usual dosing

PENICILLINS Amoxicillin (PO)

Amoxicillin with or without clavulanic acid (PO) (doses in amoxicillin)

25–90 mg/kg/day divided q8–12h (4 g/day)

Usual dosing

20–45 mg/kg/day 90 mg/kg/day (ES-600 formulation) divided q8–12h (1.75 g/day amoxicillin)

Usual dosing

Usual dosing

100% q12–24h

H: 100% q24h P: Significant clearance unlikely C: Usual dosing

Usual dosing

100% q12–24h

H: 100% q24h P: Significant clearance unlikely C: Usual dosing

Continued

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

APPENDIX 291.1  Usual Dosing, Therapeutic Targets, and Suggestions for Maintenance Dosing of Selected Antimicrobial Agents in Patients With Impaired Renal Function—cont’d

Drug (Route)

Usual Dosing: Maintenance (Daily Max)

Adjustment of Usual Dosing for Renal Failure GFR (mL/min/1.73 m2)b >60–90

30–60

<30

Adjustment for Dialysisc

100% q8h

100% q12h

H: 100% q24h

Ampicillin with or without sulbactam (IV, IM)157,158 (doses in ampicillin)

25–50 mg/kg q6h (12 g/day ampicillin) (8 g/day ampicillinsulbactam)

Usual dosing

Dicloxacillin (PO)

6.25 mg/kg q6h (2 g/day)

Usual dosing

Nafcillin (IV)

25–50 mg/kg q6h (12 g/day)

Usual dosing

Usual dosing

Usual dosing

Oxacillinj (IV)

25–50 mg/kg q6h (12 g/day)

Usual dosing

Usual dosing

Usual dosing

Penicillin G (IV)

100–300 kU/kg/day divided q4–6h (24 MU/day)

Usual dosing

50% q4–5h

50% q8h

25–50 mg/kg/day divided q6–8h (2 g/day)

Usual dosing

Piperacillin and tazobactam (IV)160–164 (doses in piperacillin)

2–9 mo: 80 mg/kg q8h >9 mo: 100 mg/kg q8h >40 kg: 3 g q6h (16 g/day)

Usual dosing

Ticarcillin and clavulanate (IV)165,166

50 mg/kg q4–6h (18 g/day)

66% q4–6h

i

159

Penicillin VK (PO)

P: 100% q12h IP C: Usual dosing

Usual dosing

Usual dosing

H/P: No significant clearance C: Usual dosing H/P: No significant clearance C: Usual dosing H/P: No significant clearance C: Usual dosing H: 50% q8h P: No significant clearance C: 50% q4–5h

50% q4–5h

50% q8h

H: 50% q8h P: No significant clearance C: 50% q4–5h

66% q6–8h

66% q8h

H: 66% q12h + 20% after H P: No significant clearance and IP tazobactam not well absorbed C: As for CLCr 30–60

66% q8h

66% q8–12h

H: 66% q12h + 100% after H P: 100% q12h IV C: As for CLCr 30–60

MONOBACTAM Aztreonam (IV)167–169

30–40 mg/kg q8h (8 g/day)

Usual dosing

50%–75% q8h

25% q8h

H: 25% q8h + 12.5% after H P: 100% q8h IP or 25% q8h IV C: As for CLCr 30–60

CARBAPENEMS Doripenemk (IV)170

3 mo–2 yr: 20 mg/kg q8h (3 g/day)

Usual dosing

<13 yr: 15 mg/kg q12h ≥13 yr:1 g q24h (1 g/day)

Usual dosing

15–25 mg/kg q6h (4 g/day)

Usual dosing

50%–75% q8h

50%–75% q12h

H: Likely similar to other carbapenems P: Significant clearance unlikely C: As for CLCr 30–60

Ertapenem (IV)171–173

Usual dosing

50% q12h

H: 50% q12h + 15% after H if H <6h after last dose P: Significant clearance unlikely C: Likely as for CLCr 30–60

Imipeneml (IV)174–183

50% q8h

50% q12h

H: 50% q12h + 25% after H if H <6 hr after last dose P: No significant clearance C: As for CLCr 30–60

Meropenem (IV)184–193

20–40 mg/kg q8h (6 g/day)

Usual dosing

100% q12h

50% q12–24h

H: 50% q24h; Or 100% q48h P: No significant clearance C: As for CLCr 30–60

FLUOROQUINOLONES Ciprofloxacin (IV, PO)194–197

10–20 mg/kg q12h (1.5 g/day)

Usual dosing

Levofloxacin198–206 (IV, PO)

<5 yr: 10 mg/kg q12h ≥5 yr: 10 mg/kg q24h (750 mg/day)

Usual dosing

Moxifloxacinm (IV, PO)207,210,211

10 mg/kg q24h (400 mg/day)

Usual dosing

50% q12h

50% q18h

H: No significant clearance P: No significant clearance C: As for CLCr 30–60

50% q24h

50% q48h

H: No significant clearance P: No significant clearance C: As for CLCr 30–60

Usual dosing

Usual dosing

H: No significant clearance P: No significant clearance C: Significant clearance unlikely

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APPENDIX 291.1  Usual Dosing, Therapeutic Targets, and Suggestions for Maintenance Dosing of Selected Antimicrobial Agents in Patients With Impaired Renal Function—cont’d

Drug (Route)

Usual Dosing: Maintenance (Daily Max)

Adjustment of Usual Dosing for Renal Failure GFR (mL/min/1.73 m2)b >60–90

30–60

<30

Adjustment for Dialysisc

MACROLIDES AND LINCOSAMIDES Azithromycin (IV, PO)212

5–12 mg/kg q24h (0.5 g/day 2 g/single dose PO)

Usual dosing

Usual dosing

Usual dosing

H/P/C: Usual dosing

Clarithromycin (PO)

7.5 mg/kg q12h (1 g/day)

Usual dosing

Usual dosing

50% q12h

H/P/C: Significant clearance unlikely

Clindamycin (IM, IV)213

20–40 mg/kg divided q8h (4.8 g/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: Usual dosing

Clindamycin (PO)

10–40 mg/kg divided q6–8h (1.8 g/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: Usual dosing

Erythromycinn (PO)214

12.5 mg/kg q6h (4 g/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: Usual dosing

Telithromycin (PO)

No data

Usual dosing

Usual dosing

75% q24h

H: 75% q24, after dialysis on dialysis days

(800 mg/day)

P: Significant clearance unlikely C: Usual dosing TETRACYCLINES Doxycyclineo (IV, PO)215

1–2 mg/kg q12h (200 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Tigecyclinep (IV)

8–11 yr: 1.2 mg/kg q12h 12–17 yr: 50 mg q12h 100 mg/day

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

10 mg/kg q8h (1.2 g/day)

Usual dosing

Usual dosing

Usual dosing

H: Usual dosing

OXAZOLIDINONES Linezolid (IV, PO)216–220

P: Significant clearance unlikely C: Usual dosing

Tedizolid (IV, PO)

No data

Usual dosing

Usual dosing

Usual dosing

H: Usual dosing P: Significant clearance unlikely

(200 mg/day)

C: Usual dosing OTHER ANTIBACTERIAL AGENTS Chloramphenicol (IV)221,222

12.5–25 mg/kg q6h (4 g/day)

Usual dosing

Usual dosing

Usual dosing

Daptomycinq (IV)223,229–232

2–6 yr: 12 mg/kg q24h 7–17 yr: 7–9 mg/kg q24h (6 mg/kg/day)

Usual dosing

Usual dosing

100% q48h

Metronidazoler (IV, PO)233–235

7.5–15 mg/kg q8h (4 g/day)

Usual dosing

Nitrofurantoin (PO)

1–2 mg/kg q6h (400 mg/day)

Usual dosing

Avoid

Avoid

H/P/C: avoid

Quinupristindalfopristins (IV)236,237

7.5 mg/kg q8h (22.5 mg/kg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Trimethoprimsulfamethoxazole (IV, PO)238–240

4–6 mg/kg q12h

Usual dosing

Usual dosing

100% q12–24h

H: 100% q24h

Pneumocystis:

Usual dosing

100% q8h

100% q12–24h

P: No significant clearance

H: Usual dosing P/C: No significant clearance H: 100% q48h P:100% q48h; Or 7 mg/kg IP q24h C: 8 mg/kg IV q48h

Usual dosing

75% q6h

H: Usual dosing P: No significant clearance C: Usual dosing

5 mg/kg q6–8h

C: As for CLCr 30–60

(20 mg/kg/day) Vancomycint (IV)167,241–245

15 mg/kg q6h (2 g/day)

100% q12–24h

10 mg/kg q24–96h

10 mg/kg q4–10 days

H: 10 mg/kg after H P: 50–100% IP q24h C: As for CLCr 30–60

Continued

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

APPENDIX 291.1  Usual Dosing, Therapeutic Targets, and Suggestions for Maintenance Dosing of Selected Antimicrobial Agents in Patients With Impaired Renal Function—cont’d

Drug (Route)

Usual Dosing: Maintenance (Daily Max)

Adjustment of Usual Dosing for Renal Failure GFR (mL/min/1.73 m2)b >60–90

30–60

<30

Adjustment for Dialysisc

15–25 mg/kg q24h (2.5 g/day)

Usual dosing

Usual dosing

100% q48h

H: 100% q48h

15–20 mg/kg q24h (1 g/day)

Usual dosing

ANTITUBERCULOUS AGENTS Ethambutol (PO)246–248

P: No significant clearance C: Likely usual dosing

Ethionamide (PO)249

Usual dosing

50% q24h

H: 50% q24h P: No significant clearance C: Likely usual dosing

Isoniazid (IV, PO)247,250–252

10–20 mg/kg q24h (300 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: Usual dosing

Para-aminosalicylic acid (PO)122,249

100–150 mg/kg q12h (10 g/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: Usual dosing

Pyrazinamideu (PO)122,247,250,253,254

15–30 mg/kg q24h (2 g/day)

Usual dosing

Usual dosing

100% q48–72h

H: As for CLCr <10

Rifampin (IV, PO)122,247,250

10–20 mg/kg q12h (600 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Amphotericin B (IV)

0.5–1.5 mg/kg q24h (1.5 mg/kg/day)

Usual dosing

Usual dosing

100% q24–48h

H/P/C: No significant clearance

AmBisome (liposomal amphotericin B) (IV)

3–5 mg/kg q24h (7.5 mg/kg/day)

Usual dosing

Usual dosing

100% q24–48h

H/P/C: No significant clearance

Abelcet, Amphotec (lipid amphotericin B) (IV)

5 mg/kg q24h (5 mg/kg/day)

Usual dosing

Usual dosing

100% q24–48h

H/P/C: No significant clearance

Fluconazole (IV, PO)163,255–259

3–12 mg/kg q24h PO/IV (400 mg/day)

Usual dosing

50% q24h

50% q48h

H: 100% after H

Isavuconazolev (IV, PO)

No data (600 mg/day isavuconazole)

Usual dosing

Usual dosing

Usual dosing

H/P/C: Significant clearance unlikely

Itraconazolew (IV, PO)260,261

2.5 mg/kg q12h (200 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Posaconazolex (PO)262

>8–13 yr: 200 mg q6h or 400 mg q12h >13–17 yr: 200 mg q8h No data for IV or DR oral formulations (800 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Voriconazole (IV, PO)263–266

7–10 mg/kg q12h (800 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Anidulafunginy (IV)

1.5 mg/kg q24h (100 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Caspofungin (IV)

50 mg/m2 q24h (50 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Micafungin (IV)

1–4 mg/kg q24h (150 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

P: As for CLCr <10 C: No data

ANTIFUNGAL AGENTS Polyenes

Azoles P: As for CLCr <30 C: As for CLCr 30–60

Echinocandins

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291

APPENDIX 291.1  Usual Dosing, Therapeutic Targets, and Suggestions for Maintenance Dosing of Selected Antimicrobial Agents in Patients With Impaired Renal Function—cont’d Usual Dosing: Maintenance (Daily Max)

Drug (Route)

Adjustment of Usual Dosing for Renal Failure GFR (mL/min/1.73 m2)b >60–90

30–60

<30

Adjustment for Dialysisc

100% q18h

100% q24h

H: 100% after H

Other Antifungals Flucytosinez (IV, PO)269,270

12.5–37.5 mg/kg q6h (150 mg/kg/day)

100% q12h

Griseofulvin ultramicrosize (PO)

1.5 mg/kg q24h (750 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Terbinafineaa (PO)

<25 kg: 125 mg q24h 25–35 kg: 125 mg q24h >35 kg: 250 mg q24h (250 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: Significant clearance unlikely

10–20 mg/kg q8h (IV) (60 mg/kg/day IV)

100% q8h

100% q12h

50-100% q24h

H: 50% q24h

20 mg/kg q6h (PO) (4.8 g/day PO)

100% q6h

100% q6h

100% q8–12h

P: 50% q24h

No established pediatric dose or frequency

Usual dosing

Contraindicated, but consider 40%–60%

Contraindicated, but consider 10%–30%

P: No significant clearance C: As for CLCr 30–60

ANTIVIRAL AGENTS Antiherpes Acyclovirbb (IV, PO)273–278

Cidofovircc (IV)

Foscarnet (IV)284–286

C: 100% q24h

Induction: 40–90 mg/kg q12h

H: Consider 100% 2h before HD P: Consider 10% C: No data H: 50% after H

50%–75% q12h

50%–75% q24h

Avoid

P: 75% q48−72h C: No data

Maintenance: 90–120 mg/kg q24h

50%–75% q24h

50%–75% q48h

Avoid

50%–100% q12h

50% q24h

25% q24h

50%–100% q24h

25% q24h

12.5% q24h

Usual dose

Usual dose

50%–100% q24h

H/P/C: As for acyclovir

Usual dosing

Usual dosing

Usual dosing

H/P/C: No data, but likely as for ganciclovir

Usual dosing

Usual dosing

Usual dosing

(180 mg/kg/day) Ganciclovirdd (IV)287–291

Induction: 5 mg/kg q12h

H: 25% after H

Maintenance: 5 mg/kg q24h

P: No significant clearance C: 100% q48h

(10 mg/kg/day) Valacyclovir (PO)

292

Valganciclovir (PO)

20 mg/kg q8–12h (3 g/day) Induction: 7 mg × BSA × CrCL q12h Maintenance: 7 mg × BSA × CrCL q24h (1.8 g/day)

Anti-influenza Amantadineee (PO)293,294

2.2–4.4 mg/kg q12h (200 mg/day)

Usual dosing

100% q24h

100% q48h

H/P: 100% once weekly

Oseltamivir (PO)295–297

2 mg/kg q12h (150 mg/day)

Usual dosing

100% q24h

50% q24h

H: 0.5 mg/kg after H

C: No data P: 50% once weekly C: As for CLCr 30–60

Continued

1495

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

APPENDIX 291.1  Usual Dosing, Therapeutic Targets, and Suggestions for Maintenance Dosing of Selected Antimicrobial Agents in Patients With Impaired Renal Function—cont’d

Drug (Route) Peramivirff (IV)298

Rimantidinegg (PO)

Zanamivir (inhaled)

Usual Dosing: Maintenance (Daily Max) All doses are mg/kg q24h: 0–30 days: 6 31–90 days: 8 91–180 days: 10 181 days–5 yr: 12 6–17 yr: 10 (600 mg/day)

Adjustment of Usual Dosing for Renal Failure GFR (mL/min/1.73 m2)b >60–90

30–60

<30

Adjustment for Dialysisc

Usual dosing

25% q24h

16% q24h

H: 2.5% q24h P/C: No data

1–9 yr: 5 mg/kg q24h (150 mg/day)

Usual dosing

Usual dosing

75% q24h

H: No significant clearance

≥10 yr: 100 mg q12h (200 mg/day)

Usual dosing

Usual dosing

75% q12h

10 mg q12h

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant systemic absorption from inhalation

H: No significant clearance

P/C: Significant clearance unlikely

Antiretrovirals Nucleoside Reverse Transcriptase Inhibitors Abacavir (PO)299

8 mg/kg q12h (600 mg/day)

Usual dosing

Usual dosing

Usual dosing

Didanosine (PO)300,301

>8 mo: 100 mg/m2 q12h (400 mg/day)

Usual dosing

100% q24h

50% q24h

P/C: Significant clearance unlikely H: 37.5% q24h P: 37.5% q24h

EC formulation:

C: No data

20–<25 kg: 200 mg q24h

Usual dosing

50% q24h

Avoid

25–<60 kg: 250 mg q24h

Usual dosing

50% q24h

Avoid

>60 kg: 400 mg q24h

Usual dosing

50% q24h

50% q24h

0–3 mo: 3 mg/kg q24h >3 mo: 6 mg/kg q24h (240 mg/day)

Usual dosing (capsule)

100% q48h (capsule)

100% q72h (capsule)

H: 100% q96h (capsule), 25% q24h (solution)

Usual dosing (solution)

50% q24h (solution)

33% q24h (solution)

P/C: No data, likely some clearance

4 mg/kg q12h (300 mg/day)

Usual dosing

100% q24h

16-66% q24h

H: No significant clearance

<30 kg: 1 mg/kg q12h 30–60 kg: 30 mg q12h > 60 kg: 40 mg q12h (80 mg/day)

Usual dosing

>35 kg: 300 mg q24h (300 mg/day)

Usual dosing

(400 mg/day) Emtricitabine (PO)

Lamivudine (PO)302–304

P: No significant clearance C: As for CLCr 30–60

Stavudine (PO)305

Tenofovir (PO)306

50% q12h

50% q24h

H: 50% q24h P: Likely as for CrCL <30 C: Likely as for CLCr 30–60

100% q48h

100% q72–96h

H: 100% once weekly P: Significant clearance unlikely C: No data

Zidovudine (IV, PO)307–311

Treatment:

Usual dosing

Usual dosing

Usual dosing

H: 50% q8h

240 mg/m2 q12h

P: 50% q8h

Prevention:

C: Likely usual dosing

2 mg/kg q6h (PO) 1.5 mg/kg q6h (IV) (600 mg/day) Nonnucleoside Reverse Transcriptase Inhibitors

1496

Efavirenz (PO)312–314

200 mg + 50 mg/5 kg over 15 kg q24h (600 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Etravirine (PO)315

100 mg + 25 mg/5 kg over 20 kg q12h (400 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Pharmacokinetic-Pharmacodynamic Basis of Optimal Antibiotic Therapy

291

APPENDIX 291.1  Usual Dosing, Therapeutic Targets, and Suggestions for Maintenance Dosing of Selected Antimicrobial Agents in Patients With Impaired Renal Function—cont’d Usual Dosing: Maintenance (Daily Max)

Drug (Route) Nevirapine (PO)316–318

Adjustment of Usual Dosing for Renal Failure GFR (mL/min/1.73 m2)b >60–90

30–60

<30

Adjustment for Dialysisc

150 mg/m2 q12h (400 mg/day)

Usual dosing

Usual dosing

Usual dosing

H: Usual dosing after H

No data

Usual dosing

Usual dosing

Usual dosing

H/P/C: Significant clearance is unlikely

P: Usual dosing C: Likely usual dosing

Rilpivirine (PO)

(25 mg/day) Protease Inhibitors Atazanavir (PO)319

100 + 50 mg/10 kg over 15 kg q24h (800 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Darunavir (PO)315

20–30 kg: 375 mg q12h ≥30–40 kg: 450 mg q12h ≥40 kg: 600 mg q12h (1.2 g/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Fosamprenavir (PO)

30 mg/kg q12h (2.8 g/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

OR 18 mg/kg + 3 mg/kg ritonavir q12h (1,400 mg/day) Indinavirhh (PO)

500 mg/m2 q8h (2.4 g/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Lopinavir (PO)313

230 mg/m2 q12h (800 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Nelfinavir (PO)318,327

45–55 mg/kg q12h (2.5 g/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Ritonavir (PO)317

400 mg/m2 q12h (600 mg/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

Saquinavir (PO)

No established pediatric dose

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

14 mg/kg q12h (1 g/day)

Usual dosing

Usual dosing

Usual dosing

H/P/C: No significant clearance

No established pediatric dose

Likely usual dosing

Likely usual dosing

Likely usual dosing

H/P/C: Significant clearance unlikely

No established pediatric dose (800 mg/day)

Likely usual dosing

Likely usual dosing

Likely usual dosing

H/P/C: Significant clearance unlikely

Adefovir (PO)

>12 yr: 10 mg q24h (10 mg/day)

Usual dosing

100% q48h

100% q72h

H: 100% weekly

Entecavir (PO)

>16 yr: 0.5–1 mg q24h (1 mg/day)

Usual dosing

100% q48h

100% q72h

H: 100% weekly

Ribavirin (PO)

7.5 mg/kg q12h (15 mg/kg/day)

Usual dosing

Avoid

Avoid

H/P/C: Avoid

(2 g/day) Tipranavir (PO) Other Antiretrovirals Maraviroc (PO)

(1.2 g/day) Raltegravir (PO)

315

Antihepatitis P/C: No data

a

Package inserts and several review articles106–110 on antibiotic dosing in renal failure and the various modes of dialysis were consulted for each drug. Recommendations are a synthesis of these sources and the pharmacokinetic characteristics of each drug; where available, supplemental references are included. Data are based primarily on studies in adults because very few pediatric studies are reported in any published source. Usual doses are for children with normal renal function beyond the neonatal period and for maintenance of systemic drug levels after an initial loading dose (which is typically standard in patients with impaired renal function). Doses herein can differ from those recommended by manufacturers (see package inserts) and in many cases are not approved for children.

Continued

1497

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

APPENDIX 291.1  Usual Dosing, Therapeutic Targets, and Suggestions for Maintenance Dosing of Selected Antimicrobial Agents in Patients With Impaired Renal Function—cont’d The preferred method for estimating GFR in children is the revised Schwartz formula: GFR (mL/min/1.73 m2) = 0.413 Height (cm) / Plasma creatinine (mg/dL).111 This formula is most accurate in the GFR range of 15 to 75 mL/min/1.73 m2, and values outside this range should be reported only as less than or below these limits. c These dose projections are only guidelines and are based on standard intermittent hemodialysis 3 times weekly, continuous peritoneal ambulatory dialysis with 3 to 4 daily exchanges, and continuous renal replacement with ultrafiltration rates of approximately 1 L/hr. The advent of high-flux or extended intermittent hemodialysis, earlier use of continuous renal replacement in critically ill patients who have residual renal function, and the myriad of settings possible for all forms of ultrafiltration and dialysis make the possibility of clinically significant underdosing or overdosing very real indeed. Measurement of serum drug concentrations must be used when feasible. “No significant clearance” means that the drug should be dosed according to the recommendation for a given degree of renal failure, without regard to dialysis schedule. For intermittent hemodialysis, unless “no significant clearance” is noted, dialysis should always be timed to give the scheduled dose at the end of the dialysis session. If this is not possible, clinicians must use their best judgment about administering a supplemental dose after dialysis, depending on when the next regular dose is due and the relative risks of drug toxicity versus subtherapeutic concentrations. Peritoneal dialysis, as discussed in the text, removes most drugs poorly from blood; therefore, unless indicated, oral or intravenous drugs should be administered according to the patient’s underlying renal function. However, many drugs can achieve therapeutic serum concentrations when administered intraperitoneally; hence recommendations for this route are included. d Serum drug concentrations should be monitored. Concurrent administration with penicillins can result in subtherapeutic gentamicin or tobramycin. Peritoneal absorption increases with inflammation. Doses for once-daily aminoglycoside regimens in patients with normal renal function generally should not be used in patients with compromised renal function; hence they are not reported here. e Peritoneal absorption of cephalosporins is generally good. f Active metabolite of cefotaxime also accumulates in ESRD. The dose should be further reduced for hepatic and renal failure. g Usual dose of ceftaroline is if the patient is >12 years of age; not approved for patients <18 years of age. h To treat urinary tract infection in ESRD with cephalexin, the usual dose should be administered. i Drugs with renal and hepatic excretion such as nafcillin require little change unless both mechanisms are impaired. j Drugs with renal and hepatic excretion such as nafcillin or oxacillin require little change unless both mechanisms are impaired. k Doripenem is not approved for patients <18 years of age. Doses in children appear to result in similar exposure as in adults receiving 1 g IV q8h. 170 l Imipenem neurotoxicity can occur, especially in ESRD. m Moxifloxacin is not approved for patients <18 years of age. Dose recommendation is based on a study,207 allometric scaling from adult dose, and a case report.208 In addition, a case report noted a dose of 13 mg/kg q24h used in an infant.209 The single study showed that 10 mg/kg resulted in slightly lower exposure than the adult dose of 400 mg,207 so the dosing remains uncertain. n Ototoxicity from erythromycin can occur with prolonged high doses in ESRD. o Doxycycline is the preferred member of the tetracycline class for use in patients with impaired renal function. p Tigecycline is not approved in children <12 years of age. q Daptomycin is not approved for use in children. The doses listed are planned for studies, although these studies are not currently enrolling.223 Some reports have noted dosing and pharmacokinetics in children at the same dose as for adults (4–6 mg/kg q24h), although the exposure can be lower in the pediatric patients relative to the adults.224–226 Investigators have even reported the use of intraventricular daptomycin in a toddler at a dose of 2.5 mg in 5 mL normal saline, administered every 24 hours through ventriculostomy that was locked for 30 minutes after administration and then reopened.227 One study found that daptomycin failure was independently associated with severe renal failure, thus raising the question whether the recommended dosing for these patients is suboptimal.228 r Dosage adjustment of metronidazole is necessary because the metabolite accumulates in ESRD, although this is cleared by hemodialysis and continuous renal replacement. s Microbiologically active metabolites of quinupristin-dalfopristin can accumulate in renal failure and can be cleared by dialysis. t Serum vancomycin concentrations should be monitored. u Serum pyrazinamide concentrations are the best guide. v Iavuconazole is dosed as the prodrug isovuconazonium sulfate; 372 mg of the prodrug is equivalent to 200 mg of active isavuconazole. w β-Cyclodextrin, the vehicle for the oral liquid and intravenous itraconazole and voriconazole preparations, is cleared by the kidneys and accumulates in patients with significant renal failure after intravenous administration; oral dosing is therefore preferred in patients with CrCL<50. Absorption of liquid itraconazole is superior to the capsules; thus liquid itraconazole is preferred for oral therapy. x Posaconazole dosing in children has not been established, but in children 8 to 13 years of age, 200 mg of suspension 4 times daily or 400 mg twice daily (800 mg/day) provided exposure similar to that observed in adult dosing. For patients 13 to 17 years of age, 200 mg 3 times daily (600 mg/day) provided similar exposure. The newer IV and DR oral tablets both achieve much better plasma concentrations in adults, but pharmacokinetic results and dosing recommendations are not yet available for children <13 years of age. For children >13 years of age, adult doses are used. y Anidulafungin is not approved in children, but 1.5 mg/kg/day in infants to adolescents results in exposures similar to those in to adults who receive 100 mg/day.267,268 z Serum flucytosine concentrations should be monitored; bone marrow suppression is more common in azotemic patients. aa Terbinafine is not approved in children. The usual dosing provided here has been shown to reproduce adult exposures from 250 mg/day.271,272 bb Acyclovir impairs urate secretion and can cause gout; uric acid levels should be monitored. cc No pediatric dose has been established for cidofovir. Dosing ranging from 5 mg/kg weekly (induction) followed by 3 to 5 mg/kg weekly to biweekly (maintenance), to 1 mg/kg thrice weekly, to 0.25 to 1 mg/kg every other week have been used for adenovirus, cytomegalovirus, and polyomavirus infections in children.279–282 Although the package insert states that the drug is contraindicated in renal failure, the reported dosing guidelines were developed with the intent to change the label.283 dd The maintenance ganciclovir dose is half the induction dose; bone marrow suppression is more common in azotemic patients. ee Amantadine neurotoxicity is more common in ESRD. ff Peramivir is not licensed for use in patients <18 years of age. gg These doses are for prophylaxis only. Rimantidine is not indicated for influenza treatment in patients <16 years of age. hh Indinavir is not approved in children. Doses shown to approximate adult exposures include 50 mg/kg, 500 mg/m2, and 600 mg/m2, all administered every 8 hours.320–326 BSA, body surface area; C, continuous renal replacement; CLCr, creatinine clearance (calculated or measured); DR, delayed-release; EC, enteric-coated; ESRD, end-stage renal disease; GFR, glomerular filtration rate; H, intermittent hemodialysis; HIV, human immunodeficiency virus; IM, intramuscular(ly); IP, intraperitoneal(ly); IV, intravenous(ly); kU, thousand units; MU, million units; P, continuous peritoneal dialysis; PO, oral(ly). b

1498

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