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Clinical Pharmacology of Antiinfective Drugs
Effective antimicrobial treatment typically begins with empirical therapy at a dose that is most likely to cure the infection with the minimal risk of toxic effects. To select the correct dosage, clinicians need to understand and apply the principles of pharmacokinetics (PK) and pharmacodynamics (PD). This chapter will focus on basic pharmacology and the application of PK and PD principles to the most commonly used antiinfective drugs, to guide optimal therapy of common infections in the newborn and young infant.
Since the seventh edition of this book, progress has been made in understanding the PK and PD of many antimicrobial drugs in preterm and term neonates. We have added relevant new information for several drugs and added metronidazole to the list of drugs reviewed. To focus the reader’s attention on the most relevant and available literature we have trimmed the reference list. Information on antimicrobial drugs that are no longer used or rarely used have been omitted to make room for new information.
The clinical pharmacology, indication, dosing, and toxicity of licensed drugs from well-controlled studies submitted to and approved by the U.S. Food and Drug Administration (FDA) are included in the product label and available at www.daily.med.nlm.nih.gov or on the FDA general website at www.accessdata.fda.gov . However, the use of many drugs remains off-label in term and premature neonates because of inadequate PK, safety, and efficacy studies. We have organized drugs into the following five categories: (1) gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA); (2) gram-negative infections; (3) polymicrobial or complicated serious infections; (4) viral infections; and (5) fungal infections. The pharmacology of drugs in neonates is unique and should not be extrapolated from data derived from studies in older patients, whenever possible. Few drugs have been adequately studied in the extremely preterm infant, so many of the dosing guidelines in this high-risk patient group remain empirical. In such cases, we will review the mechanism of action and dosing relative to known PK-PD properties and safety. The National Institute of Child Health and Development (NICHD)-sponsored Pediatric Trials Network ( www.pediatrictrialsnetwork.org ) is conducting several antimicrobial trials in neonates with the goal of improved dosing and label guidance.
A few antimicrobial drugs have been associated with serious toxicity ( Table 37-1 ), and therefore their use in neonates is discouraged in developed countries. The most notable on this list is chloramphenicol. Chloramphenicol has been associated with circulatory collapse, otherwise known as “gray baby syndrome,” and death in infants resulting from drug accumulation after excessive dosages. This complication can be traced to immaturity of the glucuronyl transferase activity in the fetus and young newborn infants, coupled with diminished renal function. Chloramphenicol toxicity appears to be related to impaired mitochondrial protein synthesis, as well as to direct inhibition of myocardial contractile activity. Because this toxicity results from free-drug accumulation, multiple exchange transfusions or charcoal hemoperfusion may reverse the clinical syndrome by removing the free drug from the blood. Anemia resulting from dose-related marrow suppression is the most common untoward reaction to chloramphenicol; however, severe idiosyncratic bone marrow aplasia occurs in approximately 1 in 40,000 patients of all ages receiving the antibiotic.
Table 37-1
Drugs Not Routinely Used in Neonates ∗
| Drug | Potential Adverse Effect |
|---|---|
| Tetracycline | Depressed bone growth and teeth abnormalities |
| Chloramphenicol | Circulatory collapse, impaired mitochondrial protein synthesis, bone marrow aplasia; gray baby syndrome |
| Sulfonamide | Bilirubin displacement with rare but possible kernicterus; increased risk of hemolysis in G6PD-deficient infants |
| Trimethoprim-sulfamethoxazole | Bilirubin displacement with rare but possible kernicteru; increased risk of hemolysis in G6PD-deficient infants. Possible bone marrow suppression |
| Ceftriaxone | Highly protein bound, potential to displace bilirubin; cannot be co-administered with calcium-containing fluids because of risk of precipitation of ceftriaxone-calcium salts and serious cardiovascular adverse events |
G6PD, Glucose-6-phosphate dehydrogenase.
Basic Principles of Clinical Pharmacology
The rapidly changing physiologic processes characteristic of fetal and neonatal development profoundly affect the PK properties of antibiotics. Maturation affects total body water, drug metabolism, and drug elimination. Gastric absorption is highly variable. These changes can result either in subtherapeutic drug concentrations, thereby delaying bacterial eradication, or in toxic drug concentrations that cause morbidity. Common PK terms and abbreviations are defined in Table 37-2 .
Table 37-2
Common Pharmacokinetic and Neonatal Terminology
| Term | Abbreviation | Definition | Units |
|---|---|---|---|
| Pharmacokinetic Terms | |||
| Maximum concentrations | C max | Maximum drug concentration at end of infusion. Alternatively, for drugs that are rapidly distributed (α-phase), the peak concentrations may be evaluated 30 minutes after end of infusion to give the concentration after the initial rapid phase of distribution | μg/mL |
| Minimum concentrations | C min | Minimum drug concentration just before subsequent dose | μg/mL |
| Clearance | CL | The amount of blood from which all drug is removed per unit time through both renal and nonrenal mechanisms | mL/min/kg L/hr/kg |
| Volume of distribution | Vd | Hypothetical volume of fluid through which a drug is dispersed | L/kg |
| Elimination rate constant | k e k e = Vd/CL |
For drugs with first-order kinetics, the ratio of clearance to volume of distribution (CL/Vd) | L/hr |
| Half-life | t ½ of β-phase = (0.693)/k e |
Time it takes to clear half of the drug from plasma. It is directly proportional to the Vd and inversely proportional to CL | hours |
| Bioavailability | F | The fraction of the administered dose that reaches the systemic circulation. F = 1 for intravenous administration. After oral administration, F is reduced by incomplete absorption, first-pass metabolism, and distribution into other tissue | % |
| Area under the concentration-time curve | AUC | Measure of total drug exposure, typically over 24-hour period | mg ∗ hr/L |
| Neonatal Terms | |||
| Gestational age | GA | Gestational age at birth, typically rounded down to completed weeks | weeks |
| Postnatal age | PNA | Chronologic age of infant, i.e., day of life | days |
| Postmenstrual age | PMA | Corrected GA on day of study, GA + PNA | weeks |
The PK of a drug describes the relationship between drug dose and subsequent concentration in the blood over time. Four basic components explain the PK of a drug: absorption, distribution, metabolism, and excretion. Absorption of drugs administered at extravascular sites typically occurs by passive diffusion across biologic membranes. This process is affected by chemical properties of the drug, such as its molecular weight, ionization, and lipid solubility, as well as by physiologic factors, such as local pH and blood flow, which undergo developmental changes as the newborn matures. The severity of infections and the inconsistent absorption after extravascular administration warrant that most antimicrobial therapies be delivered by the intravenous (IV) route in developed countries.
Oral absorption of antimicrobial agents is difficult to predict and can only be determined by carefully executed experiments. Bioavailability describes the fraction of an administered dose of a drug that reaches the systemic circulation. By definition, IV medications have 100% bioavailability. However, oral medications have decreased bioavailability because of incomplete absorption and first-pass hepatic metabolism. Unique neonatal features that impact absorption change with gestational and chronologic age include the alkaline gastric pH, slow gastric emptying, high gastrointestinal-to-whole body surface area ratio, increased permeability of bowel mucosa, irregular peristalsis, prolonged intestinal transit time, differences in first-pass hepatic metabolism, and the deconjugational activity of the intestinal enzyme β-glucuronidase.
Intramuscular (IM) absorption of antimicrobial agents is generally comparable to IV administration; however, substantial differences can exist because IM antibiotic absorption is dependent upon regional blood flow. IM absorption can be profoundly reduced in infants with hypoxia, hypotension, or poor tissue perfusion.
After drug absorption into the bloodstream, the dose of a drug is distributed into all of the body compartments and tissues that the product is physically able to penetrate, including water compartments and adipose tissue. This distributive phase is typically rapid, and the drug is said to distribute into its volume of distribution, or Vd. This volume is considered hypothetical because it is based on sampling drug concentrations in serum or plasma after dosing. Interpretation of these samples requires the assumption that the drug is uniformly distributed throughout the body. However, drugs do not distribute in a uniform fashion. Drugs that are water soluble or highly bound to plasma proteins have a high plasma concentration and a low Vd because the drug tends to remain in the blood. Drugs that are lipid soluble or bind extensively to tissue are present in the plasma in low concentrations and therefore have large Vds. Vd in the neonate is usually larger than in children (and premature infants larger than term infants) because of the larger extracellular water compartment in neonates.
The extracellular fluid volume in newborns is considerably greater than that in children and adults. In the first 3 months of life, it decreases substantially and then remains nearly constant throughout infancy and early childhood. Extracellular fluid volume is also increased with prematurity so that peak serum concentrations are lower in preterm infants compared to term infants after similar dosages. Expanded extracellular volumes prolong drug elimination and lead to longer half-lives. The clinical application of these concepts is particularly relevant to aminoglycosides because the efficacy is associated with the peak concentration, whereas toxicity is associated with trough concentrations.
Protein binding can also impact drug distribution and elimination. Quantitative and qualitative differences exist between the serum proteins of newborns and those of older infants. These differences affect the degree to which antimicrobial agents are protein bound. Variables that impact protein binding include concentrations of plasma proteins (such as albumin), concentration of drug, drug affinity for protein binding sites, presence of competing substances for protein binding sites (e.g., furosemide, bilirubin), and plasma pH. Protein-bound drug has negligible antibacterial activity and remains in the intravascular space with limited distribution into tissue and limited excretion. Because only free drug is active and available for elimination, changes in protein binding can dramatically affect exposure and efficacy. Protein binding for some antibiotics is lower in neonates than in adults, so extrapolation is not advised, and the PK of the free drug needs to be determined.
Some antibacterial agents are capable of displacing bilirubin from albumin-binding sites, including the sulfonamides and ceftriaxone. Theoretically, jaundiced neonates receiving these antibiotics are at increased risk of developing kernicterus. This complication, however, has been documented only for sulfonamides. Most antimicrobial drugs do not displace bilirubin because most have a much lower binding affinity for albumin than bilirubin, and thus the extent of protein binding by an antibiotic does not necessarily correlate with bilirubin displacement.
Drugs start to be eliminated from the body as soon as they are delivered. If doses are given at a rate that balances the drug clearance (CL) rate, then target steady-state drug concentrations can be maintained. Drug CL represents the volume of blood, serum, or plasma completely cleared of drug per unit of time and has the units of volume/time, for example, L/hr or mL/min, or L/hr/kg for weight normalized CL. Clearance is not only related to infant size (L/hr/kg) but also to clinical characteristics, such as renal disease, hepatic disease, and drug interactions. Clearance of water-soluble drugs usually occurs via excretion into the urine, whereas lipid-soluble drugs are often metabolized to water-soluble metabolites by the liver before they can be excreted.
Drug elimination occurs through hepatic metabolism, renal excretion, or both, and is affected by physiologic maturation. Hepatic metabolism involves chemical transformation of the drug into a form that is more fat soluble for elimination in the bile and feces or a form more water soluble for elimination by the kidneys. The ontogeny of the cytochrome P-450–metabolizing enzymes in newborn development has been evaluated and reviewed. Newborns are at risk for toxicity from drug accumulation because of deficiencies in hepatic glucuronyl transferase or hepatic esterases. Drugs can also induce P-450 enzyme production, leading to drug interaction. Phenobarbital stimulates hepatic enzyme production, thereby increasing the CL and lowering serum concentrations of some drugs, including anticoagulants, corticosteroids, phenytoin, metronidazole, and theophylline.
Renal elimination of active drug or metabolites occurs via glomerular filtration and/or tubular secretion. Some drugs are reabsorbed in renal tubules, thus further altering their elimination rate. Renal function varies with gestational age (GA), postnatal age (PNA), and postmenstrual age (PMA) (neonatal abbreviations are reviewed in Table 37-2 ). The constant state of renal function fluctuation has a profound impact on antibiotic PK. In newborns, the glomerular filtration rate is 30% to 60% of adult levels. A remarkable increase in renal function occurs over the first 2 weeks of life. As a result, sustained serum concentrations and prolonged half-life values of many drugs eliminated through the kidneys are observed in the first days of life. After birth, renal function improves more slowly in premature infants, leading to prolonged drug elimination over the first few weeks of life. Drug elimination is also reduced in sick infants because of decreased renal blood flow resulting from respiratory insufficiency, hypotension, or dehydration. For example, hypoxemic infants have a prolonged serum half-life (t ½ ) of aminoglycosides. Therapeutic hypothermia is associated with reduced hepatic CL of morphine. Because renal function is constantly changing in the first month of life and with advancing GA, a PK profile needs to be determined on multiple occasions during this period to define the proper dosage and frequency of administration of an antibiotic.
Most drugs are cleared through first-order elimination. This means that a constant proportion of drug is cleared per unit of time. Initially, there is a steep fall in concentration, after which the decline becomes shallower as the amount of drug remaining decreases. When the concentration-time profile is plotted on a log-linear scale, the decline is linear because the shape of the relationship between concentration and time is described by an exponential function. The elimination rate constant (k e ) is the ratio of CL to Vd and is usually expressed in units of L/hr.
Each patient has their own unique elimination rate constant (k e ) that reflects the CL and Vd of the drug. The elimination rate constant can be converted into the clinically meaningful concept of drug half-life, the time it takes for the concentration of a drug to fall to half (see Table 37-2 ). Half-life estimates are patient specific. For drugs eliminated by first-order kinetics, the elimination rate constant represents the ratio of drug CL and Vd. For patients with renal insufficiency, delayed renal CL of gentamicin will result in a half-life that can be three times as long as patients with normal renal function. Patients with fluid overload have a large Vd and a longer half-life and therefore may need to receive a higher dose of medication less frequently.
Optimizing Antimicrobial Therapy Using PK-PD Principles
Optimizing antimicrobial therapy in neonates requires a thorough understanding of the relationship between dose and exposure (PK) and between exposure and optimal response to therapy (PD). Our goal is to provide an integrative approach using knowledge from microbiology (minimal inhibitory concentration [MIC], minimal bactericidal concentration [MBC]), PK, and PD such that we can have a high probability that a specific dose of an antibiotic can cure a particular infection in a defined population of infants. Carefully designed clinical trials can then be performed to confirm the results of such an integrative modeling and simulation approach.
Minimal Inhibitory Concentration
The in vitro drug susceptibilities of commonly encountered bacterial pathogens allow comparison of potencies for eradication. Ideally, both the MIC and the MBC should be determined. To account for the great variation in pathogens and susceptibilities in different nurseries and geographic regions, this knowledge can be generated for each specific newborn unit. The higher the MIC, the more difficult it is to eradicate a pathogen with that drug, even if the MIC falls within the established sensitivity range.
Pharmacokinetic Data
New analytic techniques and the computer algorithms for population PK model analysis have made PK evaluation of drugs in infants more feasible. PK explains the relationship between drug dose and the concentration of drug in the plasma or serum over time. PK studies are performed after a single dose and after multiple doses to determine concentrations at steady state. Drug levels can now be measured using mass spectroscopy in as little as 0.1 mL obtained by heel stick. For drugs that exhibit protein binding, it is important to measure the quantity of total and non–protein-bound drug. Subsequently, multiple serum samples are obtained to determine concentrations of the drug at a given time after the dose. The serum half-life (t ½ ) and Vd are calculated by plotting the serum concentration-time curves and calculating the CL, a measure of the disappearance of drug from serum. Population PK analysis allows investigators to study a medication in a diverse group of preterm and term infants of different ages so that changes in drug CL and Vd can be explained by maturational covariates (GA at birth, PNA, PMA reviewed in Table 37-2 ), weight, or renal function in a mathematical model. Monte Carlo simulation using these models of drug CL and Vd is used to predict and compare drug exposure from different dosing regimens to provide dose adjustments for maturational changes in an infant.
It is clinically important to determine the active drug concentrations in the cerebrospinal fluid (CSF). Central nervous system (CNS) penetration of drugs is usually expressed as the fraction of CSF drug concentrations divided by the plasma or serum concentrations because most studies link a single CSF sample with a simultaneous blood sample. In the 1980s, new antibiotics were tested in a rabbit model of meningitis before use in infants to determine the CSF penetration and bactericidal activity of the drug against commonly encountered meningeal pathogens. More data are needed to understand the CSF penetration of antimicrobial drugs in the presence or absence of meningitis in neonates. Some current antimicrobial trials are attempting to collect CSF from standard-of-care sampling to measure drug levels in CSF.
Although CSF concentrations represent the closest approximation of drug concentration in the CNS, they only represent one compartment and can underrepresent drug exposure in brain parenchymal tissue. Amphotericin and echinocandins have been used successfully to eradicate CNS fungal infections, yet they are detected at very low levels in the CSF. Drugs cross the blood-brain and blood-CSF barrier through diffusion and transport systems. Efflux channels can remove drugs from the CSF. CNS infection also tends to cause an increase in permeability of the blood-brain and blood-CSF barriers. In addition to CSF evaluation, it remains important to consider the physiochemical properties of the drug, including molecular size, lipophilicity, plasma protein binding, and active transport mechanisms. Higher serum exposures are often warranted when treating CNS infections to allow for drug entry into both the parenchymal tissue and the CSF. Intraventricular therapy is traditionally avoided if systemic therapy is available because studies of intraventricular aminoglycosides administration show an association with threefold increase in mortality compared with standard treatment with IV antibiotics alone.
Pharmacodynamics
Pharmacodynamics equations describe the relationships between the drug concentration-time profile and the ability to eradicate the organism, prevent emerging resistance, and minimize adverse effects. Dose and dosing interval determine the minimum concentration, maximum concentration, and overall drug exposure per 24-hour interval (24-hour area under the concentration-time curve = AUC 24 ) ( Figure 37-1 ). Bacterial eradication is typically evaluated in relation to the maximal drug concentration, the AUC, or the percentage of dosing interval time that the drug concentration is above a minimum threshold, as determined by the MIC of the target organism (see Figure 37-1 ).
Pharmacokinetic-Pharmacodynamic Approach
To achieve the best therapeutic response, drug dose should be related to antimicrobial effect through an integrated PK-PD approach, in which a dose is chosen to target a therapeutic drug concentration relative to the MIC of the offending organism. Three important PK parameters are the peak serum level (C max ), the trough level (C min ), and the AUC (see Tables 37-2 and 37-3 ; see Figure 37-1 ). These PK-PD parameters are used to quantify the activity of an antibiotic. Antimicrobial agents are typically associated with one of three patterns of activity (see Table 37-3 and Figure 37-1 ) : (1) those that exhibit concentration-dependent killing and prolonged persistent postantibiotic effects (PAEs) and thus achieve optimal killing when the maximum concentration exceeds a threshold peak/MIC ratio, (2) agents that exhibit time-dependent killing patterns and therefore achieve optimal killing when the duration of drug exposure above a MIC exceeds a percentage of time (T) greater than the MIC, and (3) agents that are most effective when the maximal total drug exposure exceeds a threshold AUC/MIC ratio. Threshold PK-PD therapeutic exposure targets are determined through in vitro experiments, animal models, and human studies that relate drug exposure to MIC and efficacy.
Table 37-3
PK-PD Relationships for Optimal Antimicrobial Treatment
| Antimicrobial Activity | PK-PD Parameter and Goal of Therapy | Definition | Drug Class | Dosing Goal |
|---|---|---|---|---|
| Concentration-dependent killing with postantibiotic effect | C max /MIC | Bacterial killing is proportional to maximal concentration achieved relative to MIC of offending organism | Aminoglycosides Fluoroquinolones Daptomycin |
Enhance peak concentration |
| Time-dependent killing | T > MIC | Bacterial killing is proportional to the amount of time the drug concentration is maintained greater than the MIC of offending organism | β-Lactams: Penicillins Cephalosporins Carbapenems |
Enhance duration of exposure by short dosing intervals |
| Time-dependent killing with postantibiotic effect | AUC/MIC | Bacterial killing is proportional to the amount of total drug exposure relative to MIC of offending organism | Vancomycin Clindamycin Linezolid Azoles |
Enhance amount of drug using both dose and interval |
AUC, Area under the concentration-time curve; C max , maximum drug concentration; MIC, minimal inhibitory concentration; PD, pharmacodynamic; PK, pharmacokinetic; T, time.
Placental Transport of Antimicrobial Drugs
Antimicrobial agents are prescribed for approximately 20% of pregnant women, and many of these drugs are given at the end of pregnancy for amnionitis or intrauterine bacterial infections. Understanding placental transport is therefore an important component of antimicrobial therapy in the neonate.
Drugs may be transported across the placenta either passively, by simple diffusion, or actively through energy-dependent processes. Factors influencing transplacental passage include lipid solubility, degree of ionization, molecular weight, protein-binding affinity, surface area of the fetal-maternal interface, placental blood flow, stage of pregnancy, and placental metabolism. Drug transport across the placenta changes greatly with advancing GA because of the thickness of barrier and also differential expression of drug transporters. Placental drug biotransformation ensues by oxidation, reduction, hydrolysis, or conjugation with endogenous chemicals. In addition, antibiotics can concentrate to various degrees in fetal tissues, depending on lipid solubility, specific binding to biologic constituents, changes in fetal circulation, and GA.
Many antimicrobial drugs rapidly cross the placenta ( Table 37-4 ). Maternal serum concentrations are usually lower than those reported in nonpregnant women because of larger plasma Vd and an increased renal CL during pregnancy. As a result of differences in maternal dosage, route of administration, GA, timing of sample collection, and methods of measuring antimicrobial activity, a wide range of serum values for pregnant women and infants and of percentages of transplacental penetration is obtained for most drugs. Most penicillins and cephalosporins are considered compatible with pregnancy, typically cross the placenta rapidly, and quickly achieve fetal levels that approach or even exceed those in maternal serum. The high and rapidly attainable fetal penicillin serum concentrations explain, in part, the benefit of intrapartum administration of penicillins to pregnant women colonized with group B streptococci in reducing early-onset neonatal sepsis. Antibiotics with lower transplacental penetration with fetal to maternal ratios of 10% to 50% include dicloxacillin, erythromycin, nafcillin, and aminoglycosides.
Table 37-4
Transplacental Passage of Antimicrobial Agents ∗
| Antimicrobial Agent | Trimester | Serum Infant-to-Maternal Ratio(s) (%) | Potential Adverse Effects on Fetus or Infant |
|---|---|---|---|
| Ampicillin | 1, 2 | 50-250 | None |
| 3 | 20-200 | ||
| Penicillin G | 1, 2 | 26-70 | None |
| Cefazolin | 1, 2 | 2-27 | None |
| 3 | 36-69 | ||
| Cefotaxime | 2 | 80-150 | None |
| Ceftriaxone | 3 | 9-120 | None |
| Cefuroxime | 3 | 18-108 | None |
| Cephalexin | 3 | 33 | None |
| Clindamycin | 2 | 10-25 | None |
| 3 | 30-50 | ||
| Gentamicin | 2, 3 | 21-44 | Very rare association with ototoxicity; potentiation of MgSO 4 -induced neuromuscular weakness |
| Tobramycin | 1, 2 | 20 | Ototoxicity |
| Amikacin | 1, 2 | 8-16 | Ototoxicity |
| 3 | 30-50 | ||
| Imipenem | 3 | 14-52 | Seizure activity |
| Nitrofurantoin | 3 | 38-92 | Hemolysis in G6PD deficiency |
| Chloramphenicol | 3 | 30-106 | Circulatory collapse |
| Sulfonamides | 3 | 13-275 | Hemolysis in G6PD deficiency; jaundice and potential kernicterus |
| Tetracyclines | 3 | 10-90 | Depressed bone growth; abnormal teeth; possible inguinal hernia |
| Trimethoprim | 1, 2 | 27-131 | Teratogenic in animals |
G6PD, Glucose-6-phosphate dehydrogenase; MgSO 4 , magnesium sulfate.
Serious adverse fetal and maternal events have been associated with antibiotic use in pregnancy. Examples include kernicterus (sulfonamides), ototoxicity (streptomycin), inhibition of infant bone growth (tetracyclines), and discoloration of teeth (tetracyclines). Anecdotal clinical experience is not sufficient to assess properly the safety of antibiotic administration during pregnancy. Rather, carefully planned prospective toxicity studies in the fetus and neonate, first in animals and then in humans, are warranted. Briggs and coworkers published an up-to-date online reference that allows searching for a drug of interest by name and provides succinct summaries of the research on drugs used in pregnancy and lactation and provides pregnancy recommendations and fetal risk summaries.
Aminoglycosides are considered low risk in pregnancy, although caution is especially advised for kanamycin and streptomycin. Aminoglycosides rapidly cross the placenta into the fetal circulation. Eighth nerve toxicity in the human fetus has been reported after exposure to kanamycin and streptomycin but not other aminoglycosides. Although possible, ototoxicity has not been directly reported after fetal exposure to tobramycin, amikacin, and gentamicin.
Carbapenems are considered low risk in pregnancy based on animal data and sparse human data. Imipenem-cilastatin crosses the placenta and achieves fetal levels of about 30% of that seen in maternal circulation. No significant fetal toxicity has been observed in different animal models. Placental transfer of meropenem has apparently not been studied; however, the molecular properties of the drug suggest placental transfer will occur with subsequent distribution into the fetus.
Medications Contraindicated or Considered to be High Risk in Pregnancy
Sulfonamides should be avoided in the third trimester, particularly if close to delivery. Sulfonamides cross the placenta and the fetal levels are 70% to 90% of maternal levels after 2 to 3 hours. Significant fetal levels can persist for several days after birth. Fetal toxicities include jaundice, hemolytic anemia, and, theoretically, kernicterus.
Tetracyclines are associated with both maternal and fetal risk and are therefore contraindicated in pregnancy, particularly in the second and third trimester. Tetracycline-induced hepatotoxicity is a rare, although serious, adverse event that does not spontaneously resolve after delivery of infant. Tetracyclines readily cross the placental barrier and concentrate in many tissues of the developing fetus. Of particular interest is the deposition of tetracycline in fetal bones and deciduous teeth. Calcification of deciduous teeth begins during the fourth month of gestation, and crown formation of the anterior teeth is almost complete at term. Tetracycline administered during this gestational period produces yellow discoloration, enamel hypoplasia, and abnormal development of those teeth. These effects have been documented for tetracycline, oxytetracycline, and demethylchlortetracycline.
Chloramphenicol crosses the placenta and achieves fetal levels 30% to 100% of maternal levels. Chloramphenicol use in pregnancy has not been associated with major or minor fetal anomalies. However, chloramphenicol is not recommended in newborns because it has been associated with circulatory collapse (gray baby syndrome) and death. Therefore many suggest that chloramphenicol should only be administered to pregnant women near term with caution and if alternative medicines are not available.
The use of metronidazole in pregnancy is controversial because the drug is mutagenic in bacteria and carcinogenic in rodents. However, these properties have not been shown in humans. Most published evidence suggests that metronidazole does not pose significant risk; however, carcinogenic potential cannot be excluded. The use of metronidazole for trichomoniases or vaginosis during the second and third trimester is acceptable. For other indications, alternative drugs with acceptable profiles would be preferred.
Antiviral and Antifungal Medications in Pregnancy
Many antiviral medications can be administered to pregnant women, particularly when the maternal benefit outweighs the potential for fetal risk. Valacyclovir and acyclovir are the most common antiviral medications used in pregnancy, often administered to women for treatment or prophylaxis of genital herpes infections. No increase in fetal abnormalities has been ascribed to acyclovir. Because valacyclovir is quickly converted to acyclovir, the placenta and fetus are most exposed to acyclovir. Acyclovir readily crosses the placenta and achieves a cord blood–to-maternal ratio of approximately 1.3.
Pregnancy is also a risk factor for morbidity and mortality caused by severe influenza infections. Oseltamivir is recommended in pregnant women with influenza to decrease mortality and hospital intensive care unit (ICU) admission. Oseltamivir exhibits low transplacental permeability to the fetus, with fetal concentrations predicted to be less than 20%, with even lower concentrations of the active drug oseltamivir carboxylase. Drug transporters may be important in the apparent restrictive placental transfer of oseltamivir and its metabolites. Case series and a review of the Roche Company safety database suggest that oseltamivir is unlikely to cause adverse pregnancy or fetal outcomes, but available data are limited.
Ganciclovir is rarely indicated in pregnancy, and its use is restricted to pregnant women with severe cytomegalovirus (CMV) infections, typically in immunocompromised pregnant women. Both ganciclovir and valganciclovir are associated with concerns for bone marrow toxicity and animal reports of mutagenesis. Very rare cases of ganciclovir use during pregnancy of women with a history of organ transplant have described healthy infant outcomes.
Most antifungal medications must be used with caution in pregnant women. Amphotericin B is the only antifungal agent thought to be compatible with pregnancy. Amphotericin does cross the placenta with cord blood–to-maternal serum ratios ranging from 40% to 100%. No evidence of adverse fetal effects has been reported.
Alternatively, fluconazole at doses greater than or equal to 400 mg/day in the first trimester is associated with teratogenicity in human and animal models, similar to the skeletal anomalies seen in Antley-Bixler syndrome. Exposure to short-course, low-dose fluconazole has not been associated with increased congenital anomalies. Fluconazole is a small enough molecule that placental transfer is expected; however, placental transfer across the human placenta has not been evaluated.
The echinocandin class of antifungal medications has not been adequately studied in pregnancy. Animal data suggest moderate risk for embryotoxicity and teratogenicity. The physical/chemical properties of caspofungin and micafungin, specifically their relatively large size, low lipid solubility, and high protein binding, may limit placental transfer. However, given the absence of human data and suggestion of risk in animal models, most clinicians would attempt to avoid echinocandins, specifically in the first trimester if alternative agents are available.
Excretion of Antibiotics in Human Milk
Postpartum women are often prescribed an antibiotic. However, the concentration of antimicrobial agents in breast milk is typically so low that neither therapeutic nor harmful effects are likely to occur. The amount of drug could be significant if the drug accumulates in breast milk, the infant ingests a large volume of milk, infant feeding times correlate with maximal maternal plasma concentrations, or the drug has reasonable bioavailability in the infant. Assessment of the safety of antibiotics in milk has relied primarily on anecdotal clinical experience, rather than on carefully controlled long-term studies. Two important, updated and referenced sources of information to aid clinicians about medications in breastfeeding mothers are LactMed from the National Library of Medicine ( http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT ) and Dr. Thomas Hale’s Medications and Mother’s Milk ( http://www.medsmilk.com/ ).
Most drugs are transferred into breast milk by passive diffusion, exocytosis, or reverse pinocytosis. Factors influencing the transfer of antibiotics from plasma to milk include maternal serum concentration of unbound drug and the physiochemical properties of the drug, for instance, molecular weight, lipid solubility, degree of ionization, and protein-binding capability. Small, lipid-soluble, non-ionized drugs traverse the lipid bilayers into milk more readily than larger, ionized, water-soluble drugs. Although drugs with high lipid solubility tend to accumulate in milk, the extent varies with the fat content of the milk. The ionization power of drugs depends on the pH of the milk and the drug dissociation constant (pKa). Weak bases become more ionized with decreasing pH. Early postpartum human milk has a pH of 7.0 to 7.1, whereas mature milk after 2 weeks has a pH of approximately 7.3 to 7.4, each compared with the normal serum pH of 7.35 to 7.45. Therefore drugs that are weak bases (pKa > pH), such as erythromycin, isoniazid, metronidazole, and tetracyclines, would be expected to ionize and accumulate in the lower pH environment of colostrum. Weak acids, such as ampicillin, are more likely to be ionized in maternal serum and therefore not transferred at high levels into breast milk. Drugs that are highly serum-protein bound, such as ceftriaxone, tend to remain in the intravascular space in the maternal circulation. Data pertaining to antibiotic concentrations in the colostrum are not available. Because blood flow and permeability are increased during the colostral phase, it is possible that these drugs are present in concentrations equal to or greater than those found in mature milk.
The maternal serum and breast milk concentrations of commonly used antimicrobial agents have been reviewed. Milk-to-plasma ratios show considerable variability because of the extremely small number of women studied and the differences in age, gestation, dosing regimen, and underlying pathophysiology. In general, the concentrations of metronidazole, sulfonamides, and trimethoprim in breast milk are similar to those in maternal serum (milk-to-serum ratio of 1.0), whereas those of chloramphenicol, erythromycin, and tetracycline are approximately 50% of maternal serum values. The concentrations of penicillin, oxacillin, various cephalosporins, and aminoglycosides in milk are low.
Although the milk-to-plasma ratio is frequently quoted to predict drug distribution into breast milk, its utility for those drugs with higher milk-to-serum ratios is suspect. The milk-to-plasma ratio is typically obtained at a single point in time; however, the concentration of drug in breast milk and plasma is not constant, and the ratio of milk-to-plasma concentrations varies greatly over time. Most studies are not performed at steady state. Furthermore, most studies usually do not expose the infant to the breast milk and cannot comment on infant systemic exposure. Instead, Chung and coworkers recommend that the milk-to-plasma ratio be used as a qualitative estimate of the possible magnitude of infant drug exposure. By taking the peak breast-milk concentration and an assumed ingestion of breast-milk intake (150 mL/kg/day), they have derived an estimated potential infant dose correlated with predicted infant exposure ( Table 37-5 ). In addition, infant maturity, developmental characteristics of drug disposition, and tolerance of drug when given directly to the infant, and the possible extent to which the drug may modify the infant’s intestinal gut flora need to be taken into consideration.
Table 37-5
Summary of Reported Breast Milk Concentrations of Selected Antibiotic and Estimated Maximal Potential Infant Daily Dose for Medications That Distribute Into Breast Milk ∗
| Drug | Maternal Dose Regimen † | Peak Milk (μg/mL) ‡ | Corresponding Potential Infant Dose § (mg/kg/day) |
Infant Clinical Dose (mg/kg/day) |
Theoretical Safety Concerns |
|---|---|---|---|---|---|
| Drugs for Which the Effect on Nursing Infants Is Unknown but May Be of Concern; Consider Discarding Milk in Some Cases of Repeated Dosing | |||||
| Metronidazole | 2 g once | 45.8 | 6.87 | 7.5-30 | In vitro mutagen |
| Metronidazole | 400 mg tid for 3-4 days | 15.5 | 2.44 | 7.5-30 | |
| Chloramphenicol | 250 mg q6h for 7-10 days | 2.8 | 0.43 | 50-75 | Idiosyncratic bone marrow suppression; extremely unlikely to achieve levels to cause gray baby syndrome |
| Chloramphenicol | 500 mg q6h for 7-10 days | 6.1 | 0.92 | 50-75 | |
| Maternal Medication Usually Compatible With Breastfeeding With Ongoing Observation of Infant | |||||
| Erythromycin | 2 g/day | 3.2 | 0.48 | 15-50 | GI distress Pyloric stenosis |
| Azithromycin | 1 g then 500 mg/day for 3 days | 2.8 | 0.42 | 5-10 | GI distress |
| Clindamycin | 600 mg q6h | 3.8 | 0.57 | 25-40 | Clostridium difficile colitis |
| Clindamycin | 150 mg tid for at least 7 days | 3.1 | 0.47 | 25-40 | C. difficile colitis |
| Co-trimoxazole (trimethoprim/sulfamethoxazole 80/400) | 3 tablets bid for 5 days | 2.0 (trim) 5.3 (sulf) |
0.3 (trim) 0.8 (sulf) |
6-10 (trim) 75-150 (sulf) |
Hemolytic anemia with sulfa drugs in infants with G6PD deficiency |
| Nitrofurantoin | 100 mg tid for 4 doses | 2.2 | 0.33 | 5-7 | Hemolytic anemia in infants with G6PD deficiency |
| Tetracycline | 2 g /day | 0.4-2 | 0.3 | 25-50 | Teeth staining |
| Ciprofloxacin | 750 mg q12h for 3 doses | 8.2 | 1.23 | 100-150 | Arthropathy, none reported |
| Ofloxacin | 400 mg q12h for 3 doses | 2.4 | 0.36 | none | Arthropathy, none reported |
BID, Twice daily; GI, gastrointestinal; G6PD , glucose-6-phospate dehydrogenase; qxh, every x hours; sulf, sulfamethoxazole; tid, three times daily; trim, trimethoprim.
∗ As described and referenced in Chung AM, Reed MD, Blumer JL: Antibiotics and breast-feeding: a critical review of the literature, Paediatr Drugs 4:817-837, 2002; Hale TW: Medications and mothers’ milk online, Amarillo, Tex, 2012, Hale Publishing; and Academy of Pediatrics Committee on Drugs: Transfer of drugs and other chemicals into human milk, Pediatrics 108:776-789, 2001.
† Highest possible concentration was used.
‡ Assuming infant consumes approximately 150 mL/kg/day of breast milk.
Most drugs are predicted to yield limited exposure to newborns (see Table 37-5 ). Penicillin, amoxicillin, ampicillin, ticarcillin, cephalosporins, and aminoglycosides are detected in very low concentrations in breast milk. Clavulanic acid was not detected in breast milk. One study observed higher-than-expected concentrations of ceftazidime in breast milk from women receiving a high-dose regimen at steady state. The predicted infant ceftazidime exposure remains limited, especially given the poor bioavailability of ceftazidime. The overall tolerability profile of penicillin and cephalosporins, along with the low concentration of these drugs in breast milk, support their use in breastfeeding infants. The rare possibility of hypersensitivity reactions or altered intestinal flora–associated diarrhea in breastfeeding infants remains a theoretical concern.
Broad-acting agents should be reserved for the most serious infections. A recent review of antibiotics in breastfeeding reported personal communication with Merck of limited data on detectable low levels of imipenem in breast milk of women; typically 0.2 to 0.5 μg/mL. Cilastatin was not detected. Despite this low exposure in breast milk, infant exposure would be further limited by poor bioavailability and drug inactivation at alkaline or acidic pH. Meropenem is also detected at very low levels in breast milk, with a maximal infant exposure reported to be less than 1%. The physiochemical properties of aztreonam suggest limited transfer into breast milk because it is inactivated in acidic solutions and exhibits moderate protein binding and low lipid solubility. Single-dose PK studies confirmed a minimal amount of aztreonam in breast milk of women.
The physiochemical properties of fluoroquinolones (weak acid, low molecular weight, high lipid solubility, low protein binding, and good bioavailability) suggest that fluoroquinolones can accumulate in breast milk ; however, the predicted infant dose exposure is limited to 2% to 6% (see Table 37-5 ). A case report of one infant revealed negligible ciprofloxacin infant serum concentrations (<0.03 μg/mL) despite accumulation in breast milk after 10 days of maternal exposure (maternal serum, 0.21 mg/mL; breast milk, 0.98 μg/mL). This report highlighted the difficulty of predicting infant exposure from maternal plasma and milk concentrations. The risk of fluoroquinolone-induced arthropathies or cartilage erosion in neonates has not been explored. The predicted fluoroquinolone exposure to an infant is predicted to be negligible and the American Academy of Pediatrics (AAP) and Hale’s Medications in Mother’s Milk have determined that the medication is usually compatible with breastfeeding and moderately safe.
Sulfonamides and tetracycline both distribute relatively poorly into breast milk yet have theoretical concerns for associated adverse events in neonates. The amount of sulfamethoxazole and tetracyclines in breast milk is low and of unclear clinical significance. One breastfed infant with glucose-6-phosphate dehydrogenase (G6PD) deficiency experienced hemolytic anemia while the mother was receiving sulfamethoxypyridazine. The adverse effects of tetracyclines on developing teeth and bones are well documented when the drug is given directly to infants and children; however, the limited exposure in breast milk has not been directly associated with abnormalities. The AAP and Hale agree that most sulfamethoxazole (with trimethoprim) and tetracyclines are usually compatible with breastfeeding and moderately safe. Caution is advised for infants with jaundice, G6PD deficiency, severe illness, or significant prematurity.
Macrolides, including azithromycin, and clindamycin distribute into breast milk. However, the actual amount the infant would receive from breastfeeding remains very small (see Table 37-5 ). Neonatal exposure may be further limited by bioavailability. One case report of erythromycin-induced pyloric stenosis during breastfeeding exposure in a 3-week-old infant has been reported. One report incriminated the administration of clindamycin to a mother in the development of antibiotic-induced colitis in her breastfed infant. The AAP has described erythromycin and clindamycin as usually compatible with breastfeeding and moderately safe. Azithromycin is likely to be compatible with breastfeeding as well.
Metronidazole effectively distributes into breast milk and achieves infant plasma concentrations approximately one fifth of the exposure observed in the mother’s plasma. The relative infant dose is estimated to be 13% of maternal dose, and metronidazole has been detected in infant plasma. Given the mutagenesis and carcinogenicity in animal models, its use in lactation is controversial. Breastfed infants whose mothers were administered metronidazole therapy had no difference in adverse events compared with infants whose mothers received ampicillin or no antibiotics. The AAP considers metronidazole to have an unknown effect on nursing infants but may be of concern. Hale, on the other hand, reports metronidazole as “safer” and thus usually compatible with breastfeeding.
The decision to allow or stop breastfeeding is based on the likelihood that high milk concentrations are attained for a particular antibiotic, whether the drug is expected to be absorbed into neonatal plasma, and whether significant adverse events are commonly associated with this agent. Online resources are now available to rapidly review the most up-to-date knowledge about specific drugs and their use in lactating mothers. In general, the severity of the woman’s infection, rather than the drug that she is receiving, most often is the more important contraindication to breastfeeding.
Penicillin
Penicillin has been used for treatment of neonatal bacterial infections for more than 3 decades. It is safe and well tolerated. However, its efficacy is limited by the development of resistance. Many species of streptococci, Listeria monocytogenes , meningococci, and Treponema pallidum remain susceptible to penicillin, whereas most species of staphylococci, pneumococci, and gonococci have become resistant.
Microbiologic Activity
Penicillin and other β-lactam derivatives interfere with bacterial cell wall synthesis by reacting with one or more penicillin-binding proteins (PBPs) to inhibit transpeptidation. The transpeptidase activity of PBPs is essential for cross-linking adjacent peptides and for incorporating newly formed peptidoglycan into an already existing strand. Subsequently, this event promotes bacterial cell lysis.
Several mechanisms of bacterial resistance to penicillin and other β-lactams have been identified. The most important is by inactivation through enzymatic hydrolysis of the β-lactam ring by β-lactamases. These enzymes are produced by most staphylococci and enteric gram-negative bacilli and by many Neisseria gonorrhoeae strains. Another mechanism of resistance involves decreased permeability of the outer membrane of gram-negative bacteria, which can prevent this drug from reaching its target site. In addition, by poorly defined mechanisms, some group B streptococci are inhibited but not killed by penicillin, a phenomenon termed tolerance. The first group B streptococci isolates with elevated MIC to β-lactamase antibiotics by a mutation in the PBP have recently been described. Usual MICs of penicillin against streptococci are between 0.005 and 0.1 μg/mL. For T. pallidum , the corresponding concentration ranges are between 0.02 and 0.2 μg/mL. Many pneumococcal strains isolated around the world are considered to be relatively (MICs of 0.1-1 μg/mL) or highly (MICs of 2 μg/mL or greater) resistant to multiple antibiotics, including penicillins, macrolides, and third-generation cephalosporins.
Pharmacokinetic Data
Most of the penicillin dose is excreted in the urine in unchanged form. Tubular secretion accounts for approximately 90% of urinary penicillin, whereas glomerular filtration contributes the remaining 10%. Biliary excretion also occurs, and this may be an important route of elimination in newborns with renal failure. A review of the clinical PK of penicillin in neonates has recently been published and serves to reference historical publications.
Aqueous Penicillin G
A mean peak serum concentration of 24 μg/mL (range, 8-41 μg/mL) is observed after a dose of 25,000 units/kg of penicillin G is given intramuscularly to infants with birth weights of less than 2000 g. The peak values do not change appreciably with increasing birth weight or chronologic age up to 14 days. After a dose of 50,000 units/kg, peak serum values of 35 to 40 μg/mL were detected in neonates of different ages. The concentrations at 4 and 8 hours after the dose were not substantially different from those after a dose of 25,000 units/kg. The half-life of penicillin in serum becomes longer in smaller and younger infants. Half-life values of 1.5 to 10 hours are observed in the first week of life, with the longer half-lives being in the smallest infants, having birth weights less than 1500 g. A shorter half-life of 1.5 to 4 hours was observed after 7 days of age. The half-life of penicillin also decreases as creatinine clearance improves.
Procaine Penicillin G
In the first week after birth, a 50,000 units/kg IM dose of procaine penicillin G produces mean serum values of 7 to 9 μg/mL for up to 12 hours and a 24-hour trough concentration of 1.5 μg/mL. Older neonates have lower 24-hour trough concentrations (0.4 μg/mL) because of their increased clearance and shorter half-lives. These serum values are approximately twice those obtained in the original study (22,000 units/kg) and suggest a linear relationship between dose and serum concentration. No accumulation of penicillin in serum is observed after 7 to 10 days of daily doses of procaine penicillin G. The drug was well tolerated, without evidence of local reaction at the site of injection.
Benzathine Penicillin G
Penicillin can be detected in serum and urine for up to 12 days after a single IM injection of 50,000 units/kg of benzathine penicillin G in newborns. Peak serum concentrations of 0.4 to 2.5 μg/mL (mean, 1.2 μg/mL) are observed 12 to 24 hours after administration, and levels of 0.07 to 0.09 μg/mL are present at 12 days. This preparation has been well tolerated by infants. Muscle damage from IM injection as judged from creatinine values does not appear to be appreciably different from that after IM administration of procaine penicillin.
Cerebrospinal Fluid Penetration
Penicillin does not penetrate CSF well, even when meninges are inflamed. Peak concentrations of 1 to 2 μg/mL occur after an IV dose of 40,000 units/kg of penicillin G is given to infants and children with bacterial meningitis. Although these values are 2% to 5% of concomitant serum concentrations, the concentrations exceed the MIC values for streptococci and susceptible pneumococci by 50- to 100-fold. CSF concentrations of penicillin are not optimal to treat neonatal meningitis caused by penicillin-resistant pneumococci. CSF concentrations decrease as meningeal inflammation is reduced. Concentrations of penicillin in CSF during the first several days of therapy are maintained in the range of 0.5 to 1 μg/mL; thereafter the values are 0.1 μg/mL or less by 4 hours after the dose.
Procaine penicillin G administered by IM injection in newborns provides sufficient CSF exposure for the treatment of congenital neurosyphilis. Procaine penicillin G administered intramuscularly at a dose of 50,000 units/kg provides mean CSF concentrations ranging from 0.12 to 0.7 μg/mL between 4 and 24 hours after a dose. These CSF values are at least severalfold greater than the required minimal spirocheticidal concentration. Benzathine penicillin G does not provide adequate CSF exposure and is not recommended for the treatment of congenital neurosyphilis.
Safety
All forms of penicillin are typically well tolerated in newborns. Cutaneous allergic manifestations to penicillin are rare in the newborn and young infant.
PK-PD and Clinical Implications for Dosing
Penicillin remains effective for therapy for infections caused by group B streptococci and T. pallidum . The dosage recommended for neonatal sepsis or pneumonia is 50,000 to 100,000 units/kg/day administered in two to four divided doses, whereas that for meningitis is 250,000 to 450,000 units/kg/day in two to four divided doses, depending on birth weight and chronologic age. The PD target for β-lactam antibiotics is the T greater than MIC. The trough penicillin levels ideally will remain above the MIC for streptococci.
Penicillin remains effective therapy for congenital syphilis. However, because CNS involvement in congenital syphilis is difficult to exclude with certainty, benzathine penicillin G is not routinely used for therapy. Benzathine penicillin G is reserved for asymptomatic infants with normal findings on CSF examination and radiographic studies and who have positive results on treponemal serologic studies (presumably from maternal origin), and only if follow-up can be ensured. For symptomatic infants and for asymptomatic infants with laboratory or radiologic evidence suggestive of congenital syphilis, the recommended regimen is either aqueous crystalline penicillin G, 100,000 to 150,000 units/kg/day (divided every 12 hours for first 7 days and then every 8 hours thereafter) and administered IV for 10 to 14 days. Alternatively, procaine penicillin G, 50,000 units/kg/day, can be administered intramuscularly for at least 10 days.
Ampicillin
Antimicrobial Activity
Ampicillin remains the preferred penicillin for initial empirical therapy for neonatal septicemia and meningitis because it provides broader antimicrobial activity without sacrificing safety. Ampicillin is commonly used in combination with aminoglycosides. Compared with penicillin G, ampicillin has increased in vitro efficacy against most strains of enterococci and L. monocytogenes , as well as against some gram-negative pathogens, such as Haemophilus influenzae, Escherichia coli, Proteus mirabilis, and Salmonella spp. It is only rarely active against S. aureus . Approximately 90% of group B streptococci and L. monocytogenes organisms are inhibited by 0.06 μg/mL or less of ampicillin. Almost two thirds of the gram-negative enteric bacilli isolated from CSF cultures of infants enrolled in the Second Neonatal Meningitis Cooperative Study (1976-1978) were inhibited by 10 μg/mL or less of ampicillin. However, an increased rate of ampicillin-resistant gram-negative bacilli has been reported.
Pharmacokinetic Data
Ampicillin, similar to many β-lactam antibiotics, is cleared by renal elimination. Therefore drug CL and half-life are dependent on renal maturation. Plasma drug CL increases (and half-life decreases) with increasing birth weight, GA, and chronologic age. Despite its frequent use, the PK of ampicillin in extremely-low-birth-weight (ELBW) infants remains sparse.
Serum ampicillin concentration-time curves have been determined after IM doses in newborns. The mean peak serum concentrations 0.5 to 1 hour after 5-, 10-, 20-, and 25-mg/kg doses were 16, 25, 54, and 57 μg/mL, respectively, whereas the values at 12 hours were from 1 to 15 μg/mL (mean, 5 μg/mL). After 50-mg/kg doses, the mean peak values were higher in LBW infants (100-130 μg/mL) compared with larger-term infants (80-85 μg/mL). Peak serum concentrations as high as 300 μg/mL (mean values, 180-216 μg/mL) are observed 1 to 2 hours after a 100-mg/kg dose. These latter values exceed the MIC 90 values of group B streptococci by at least 3000-fold. Half-life decreases with advancing age from 3 to 6 hours in the first week of life to 2 to 3.5 hours thereafter.
Serum ampicillin concentration-time curves after IV doses have been characterized for preterm and term infants. After a 100-mg/kg IV dose, premature infants of 26 to 33 weeks of gestation had a lower mean peak serum concentration (135 μg/mL) compared with more mature 34- to 40-week infants (153 μg/mL). When the loading dose was followed by maintenance ampicillin doses of 50 mg/kg IV at 12- to 18-hour intervals, the mean peak and trough serum concentrations in steady-state conditions were 113 and 30 μg/mL, respectively, for premature neonates, and 140 and 37 μg/mL, respectively, for full-term neonates. Despite the lower peak concentration in premature infants, the trough value was maintained, likely given the longer half-life in premature newborn (9.5 hours) compared with full-term newborns (7 hours). Trough values of 30 μg/mL exceed the MIC 90 value for group B streptococci by 300-fold.
Cerebrospinal Fluid Penetration
Concentrations of ampicillin in CSF vary greatly. The largest concentrations (3-18 μg/mL) occur approximately 2 hours after a 50-mg/kg IV dose and exceed the MIC 90 values for group B streptococci and L. monocytogenes by 50- to 300-fold. By contrast, these peak concentrations equal or exceed the MIC values against many E. coli strains by only severalfold. The values in CSF are lower later in the course of meningitis, when meningeal inflammation subsides.
Safety
Ampicillin is well tolerated when administered parenterally to newborns. Nonspecific rashes and urticaria are rarely observed, and diarrhea is uncommon. In older children and adults, very large doses can result in CNS excitation or seizures. Moderately prolonged bleeding times have been reported with repeated doses. Elevations of serum glutamic-oxaloacetic aminotransferase and creatinine values frequently are detected in neonates and probably represent local tissue destruction at the site of IM injection. Mild eosinophilia may be noted in newborns and young infants. Alteration of the microbial flora of the bowel may occur after parenteral administration of ampicillin, but overgrowth of resistant gram-negative organisms and Candida albicans occurs more frequently after oral administration. Diarrhea usually subsides on discontinuation of therapy.
PK-PD and Clinical Implications for Dosing
Vast clinical experience has demonstrated that ampicillin is a safe and effective drug for therapy for neonatal bacterial infections caused by susceptible organisms. Combined ampicillin and aminoglycoside therapy is appropriate initial empirical management of suspected bacterial infections of neonates because it provides broad antimicrobial activity and potential synergism against many strains of group B streptococci, L. monocytogenes , and enterococci. β-Lactam antibiotics exhibit time-dependent killing; therefore the PK-PD target is T greater than MIC. Frequent dosing intervals are used to maintain drug exposure over the dosing interval. For systemic bacterial infections other than meningitis, a dosage of 25 to 50 mg/kg per dose given two to three times per day in the first week of life, and then three to four times per day thereafter, is recommended. For therapy of bacterial meningitis, we recommend a dosage of at least 200 mg/kg/day, although some consultants use dosages as high as 300 mg/kg/day. Premature infants may continue to receive ampicillin 2 to 3 times per day for up to 4 weeks, depending on GA, chronologic age, and renal function ( Table 37-6 ).
Table 37-6
Suggested Dosage Schedules for Systemic Antibiotics Used in Newborns ∗
| Dosage (mg/kg) and Interval of Administration by Weight | ||||||
|---|---|---|---|---|---|---|
| Weight | <1200 g ∗ | 1200-2000 g | >2000 g | |||
| Antibiotics | Route | Age 0 to 28 Days | Age 0 to 7-14 Days | Age >7 to 14 Days | Age 0 to 7 Days | Age >7 Days |
| Amikacin † (ODD) | IV, IM | 15-18 q36-48h | 18 q36-48h | 15 q24-36h | 15 q24h | 15 q12-24h |
| Ampicillin | IV, IM | |||||
| Meningitis | 100 q12h | 100 q12h | 75-100 q8h | 100 q8-12h | 75 q6h | |
| Other infections | 50 q12h | 50 q12h | 50 q8h | 50 q12h | 50 q8h | |
| Aztreonam | IV, IM | 30 q12h | 30 q12h | 30 q8h | 30 q8-12h | 30 q8h |
| Cefazolin | IV, IM | 25 q12h | 25 q8h | 25 q8h | 25 q12h | 25 q8h |
| Cefepime | IV, IM | 30-50 q12h | 30-50 q12h | 30-50 q8h | 30-50 q12h | 30-50 q8h |
| Cefotaxime | IV, IM | 50 q12h | 50 q12h | 50 q8h | 50 q12h | 50 q8h |
| Clindamycin | IV, IM | 5 q12h | 5 q12h | 5 q8h | 5 q12h | 5 q8h |
| Gentamicin † (ODD) | IV, IM | 4-5 q48h | 4-5 q36-48h | 4 q24h | 4 q24h | 4 q24h |
| Linezolid | IV | 10 q8-12h | 10 q12h | 10 q8h | 10 q8h | 10 q8h |
| Metronidazole ‡ | IV | 7.5 q24h | 7.5 q12h | 7.5 q12h | 7.5 q12h | 7.5 q8h |
| Meropenem | IV, IM | 20 q12h | 20 q12h | 20 q8h | 20 q8h | 20-30 q8h |
| Nafcillin | IV | 25 q12h | 25 q12h | 25 q8h | 25 q8h | 25-50 q6-8h |
| Oxacillin | IV, IM | 25 q12h | 25 q12h | 25 q8h | 25 q8h | 25-50 q6-8h |
| Penicillin G (units) | IV | |||||
| Meningitis | 50,000 q12h | 50,000 q12h | 50,000 q8h | 50,000 q8h | 50,000 q6h | |
| Other infections | 25,000 q12h | 25,000 q12h | 25,000 q8h | 25,000 q8h | 25,000 q6h | |
| Piperacillin-tazobactam | IV, IM | 50-100 q12 | 100 q12h | 100 q8h | 100 q12h | 100 q8h |
| Rifampin | IV | 5-10 q12 | 5-10 q12h | 5-10 q12h | 5-10 q12h | 5-10 q12h |
| Ticarcillin-clavulanate | IV | 75 q12h | 75 q12h | 75 q8h | 75 q8-12h | 75 q6-8h |
| Tobramycin † (ODD) | IV, IM | 4-5 q36-48h | 4-5 q36h | 4 q24h | 4 q24h | 4 q24h |
| Vancomycin † | IV | 15 q18-24h | 15 q12h | 15 q8-12h | 15 q12h | 15 q8h |
IM, Intramuscular; IV, intravenous; ODD, once-daily dosing.
∗ Based upon anecdotal clinical experience, neonatal and hospital formularies, and notable references cited in text. Dosing for infants < 1200 g or often infants with gestational age < 29 weeks is typically based upon limited pharmacokinetic (PK) information and many prefer to use postmenstrual age–based dosing for these infants. Use of most of these drugs remains off-label in neonates because of the need for more pharmacokinetic and safety information. Higher dosing may be indicated for treatment of meningitis or microorganisms with higher minimal inhibitory concentration, such as Pseudomonas . In the absence of complete pharmacokinetic information across gestation age and postnatal ages, interhospital variability in dosing guidance is expected. National Institute of Child Health and Development–sponsored Pediatric Trials Network ( https://pediatrictrials.org/ ) has several ongoing PK studies to evaluate dosing of antimicrobial drugs in neonates to improve labeling of drugs by the U.S. Food and Drug Administration.
† Adjustments of further dosing intervals should be based on therapeutic drug monitoring.
Antistaphylococcal Treatment
S. aureus infections occur in nurseries either as sporadic cases or in the form of disease outbreaks. In recent years, multiply-resistant strains, especially MRSA and coagulase-negative staphylococcal species, such as methicillin-resistant Staphylococcus epidermidis (MRSE), have been responsible for an increasing number of nosocomially-acquired staphylococcal infections in many neonatal care units.
Antistaphlococcal Penicillins ( Table 37-7 )
Antimicrobial Activity
Nafcillin and oxacillin are the mainstays of methicillin-sensitive staphylococcal therapy. These semisynthetic agents are engineered to be resistant to hydrolysis by most staphylococcal β-lactamases by virtue of a substituted side chain that acts by steric hindrance at the site of enzyme attachment. Most penicillinase-producing staphylococci are inhibited by less than 0.5 μg/mL of nafcillin and oxacillin.
Table 37-7
Drugs Used in Treatment of Staphylococcus aureus
Dose, peak, and half-life as reported in references .
| Drug | Route Elimination | Peak (μg/mL) | Half-Life (hr) | CLSI Sensitivity Breakpoint MIC ∗ | PK-PD Target | CSF Penetration | Safety and Clinical Pearls |
|---|---|---|---|---|---|---|---|
| MRSA | |||||||
| Vancomycin 15 mg/kg |
Renal | 25-30 | PNA<7d 6.7 (<2 kg) 5.9 (>2 kg) 4 at ≈90 days |
≤2 | AUC/MIC > 400 Trough 10 (15 if MRSA pneumonia) Keep level > the MIC |
30%-50% inflamed 0%-20% noninflamed |
Check levels in renal insufficiency or change renal function. Steady state before fourth to fifth dose 10%-20% penetration epithelial lung fluid Consider increased trough target (15-20) with difficult-to-treat infection Limited protein binding Very high variability |
| Clindamycin 5-6.5 mg/kg |
Hepatic | 10 | 8.7 (preterm) 3.6 (term) |
≤0.5 | AUC/MIC | Poor | Good bone penetration, often effective against MSSA (check D-test) |
| Linezolid 10 mg/kg |
Renal 30% Nonrenal 65% Metabolites renally excreted |
12 | 5.6 (PNA<7d, GA<34wk GA) 2.8 (PNA<80d, 25-40wk GA) |
≤4 | AUC/MIC > 80 |
27%-100% | Monitor blood counts to evaluate for rare thrombocytopenia and anemia if used > 14 days. Enhanced lung penetration with accumulation in epithelial lung lining fluid CSF penetration unreliable; case report of linezolid efficacy in treatment of ventriculostomy related CSF infection in preterm infants |
| Rifampin 10 mg/kg/day |
Hepatic | 4 | Not defined | ≤1 | Not defined | 5%-20% | Light sensitive Use in combination therapy due to induction of resistance |
| Daptomycin 6 mg/kg |
Hepatic | 25 | 6.2 (range, 3.7-9.0) | ≤1 | C max /MIC AUC/MIC |
Low | Myopathy, elevated CPK Sparse PK, safety evaluation No lung penetration |
| MSSA | |||||||
| Oxacillin 50 mg/kg |
Renal | 100 | 3 (day 0-7 PNA<7d) 1.5 (day > 7 PNA>7d) |
≤2 | T > MIC > 50% | Low | Bone marrow suppression Monitor CBC |
AUC, Area under the concentration-time curve; CBC, complete blood count; CPK, creatine phosphokinase; CSF, cerebrospinal fluid; CLSI, Clinical and Laboratory Standards Institute; C max , maximum drug concentration; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive S. aureus; PD, pharmacodynamic; PK, pharmacokinetic; T, time.
∗ CLSA. Performance Standard for Antimicrobial Susceptibility Testing; Twenty-Fourth Informational Supplement. CLSI document M100-S24. Wayne, Pa: Clinical and Laboratory Standards Institute; 2014. Bacteria with intermediate sensitivities have higher MIC.
Pharmacokinetic Data (See Table 37-7 )
Nafcillin . Unlike other penicillins, nafcillin exhibits primarily hepatic CL rather than renal CL. The administration of 5-, 10-, 15-, and 20-mg/kg IM doses of nafcillin to full-term newborns in the first 4 days of life produces mean peak serum concentrations 1 hour later of 10, 25, 30, and 37 μg/mL, respectively. These concentrations are significantly higher than those obtained in older children receiving comparable amounts of this drug. Preterm infants weighing less than 2000 g had higher steady-state peak concentrations—100 to 160 μg/mL after receiving 33- to 50-mg/kg IV doses. In these preterm infants, the half-life ranged from 2.2 to 5.5 hours.
Oxacillin . Oxacillin exhibits primarily renal CL. Despite this difference in clearance mechanism, the PK of oxacillin in neonates is similar to that of nafcillin. Mean peak serum concentrations of approximately 50 and 100 μg/mL are produced by 20- and 50-mg/kg IM doses, respectively. The serum half-life of oxacillin in premature infants is about 3 hours in the first week of life and 1.5 hours thereafter.
Safety
The antistaphylococcal penicillins are well tolerated in newborn and young infants. Repeated IM injections can result in muscle damage, sterile muscle abscess, and elevation of creatinine concentrations. Nephrotoxicity (interstitial nephritis or cystitis) is rare in newborns but occurs in 3% to 5% of children who receive large doses of methicillin and possibly the other antistaphylococcal penicillins, with the exception of nafcillin. Reversible hematologic abnormalities, such as neutropenia or eosinophilia, commonly are observed in children undergoing treatment with these drugs, but their incidence in newborns is unknown. Because nafcillin has a predominant biliary excretion, accumulation of this drug in serum can occur in jaundiced neonates, and potential adverse effects can develop. Extravasation of nafcillin at the injection site can result in necrosis of local tissue.
PK-PD and Clinical Implications for Dosing (See Tables 37-6 and 37-7 )
Nafcillin and oxacillin are the antistaphylococcal drugs most often used for treatment of methicillin-sensitive staphylococcal infections in neonates. Like other β-lactam antibiotics, it is important to maintain the drug concentrations over the dosing interval (T > MIC). Therefore, as infants mature, drug CL improves and dosing intervals shorten. The dosage of oxacillin is 25 to 50 mg/kg every 12 hours (50-150 mg/kg/day) in the first week of life and every 6 to 8 hours (75-200 mg/kg/day) thereafter. The larger dosage is indicated for infants with disseminated staphylococcal disease or meningitis. For nafcillin, the dosage is 25 mg/kg (50 mg/kg for meningitis) per dose given every 12 hours in the first week of life and every 6 to 8 hours thereafter. Depending on GA at birth and chronologic age, extremely preterm infants may have delayed clearance and therefore should continue twice daily dosing for 2 to 4 weeks (see Table 37-6 ). If an infant does not respond to antimicrobial therapy as anticipated, one should consider an occult site of staphylococcal disease (e.g., abscess, osteomyelitis, endocarditis), pathogen resistance, or the need to shorten the dosing interval to maintain the drug concentration above the MIC throughout the dosing interval. Appropriate drainage of purulent foci, addition of an aminoglycoside or rifampin to the regimen, and use of vancomycin are among several options to consider in management of unresponsive infections.
Methicillin-Resistant Staphylococcal Infections (MRSE and MRSA) (See Table 37-7 )
MRSA now constitutes a relatively common cause of infection outbreaks in some nurseries, and MRSE strains are an important cause of catheter-associated disease, particularly among LBW premature infants. Glycopeptide antibiotics such as vancomycin or teicoplanin (in Europe) are the drugs of choice for infections caused by these resistant strains. Infections may be treated with combination therapy: a glycopeptide with an aminoglycoside or rifampin. More recently, the use of linezolid, clindamycin, and daptomycin have been explored for the treatment of MRSA infections.
Vancomycin (See Table 37-7 )
Antimicrobial Activity
Vancomycin is bactericidal against most aerobic and anaerobic gram-positive cocci and bacilli. The drug interferes with the phospholipid cycle of cell wall synthesis, alters plasma membrane function, and inhibits RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics. Synergistic bacterial killing has been demonstrated for vancomycin with aminoglycosides.
Pharmacokinetic Data (See Table 37-7 )
Vancomycin is not metabolized by the body and is excreted unchanged in the urine primarily by glomerular filtration. Vancomycin CL reflects renal maturation and increases with GA and chronologic age. Vancomycin is approximately 55% protein bound.
Neonates have increased extracellular fluid volume and limited renal elimination capacity and therefore are expected to have lower C max and delayed clearance of vancomycin. The PK of vancomycin in preterm and term infants has been thoroughly reviewed by Pacifici and Allegaert. Clearance estimates are lowest in the most preterm neonates (≈0.9 mL/min/kg), with a two- to threefold increase in clearance within the neonatal age range, reflecting renal maturation and improvement in renal function, with clinical stability over time. Serum creatinine (SCr) remains an important predictor of renal clearance, even after accounting for GA and postchronologic age. The use of neonatal creatinine is controversial, however, because it is affected by maternal creatinine load, the natural decline with PNA, analytic variation in creatinine measurement, and concomitant diseases and medications. Currently, creatinine remains the best clinically available estimate of renal function despite these limitations. Vancomycin CL is also reduced in growth restriction and in the setting of indomethacin exposure for patent ductus arteriosus (PDA). Infants on extracorporeal membrane oxygenation (ECMO) have delayed CL and increased Vd.
In the first week after birth, peak concentrations of 17 to 30 μg/mL are produced at the end of a 30-minute infusion of a 15-mg/kg dose given to neonates weighing less than 2000 g. Slightly higher values are observed in larger infants. In infants up to 12 months of age, doses of 10 mg/kg produce similar peak serum concentrations.
Population PK studies have attempted to explain the observed variability of vancomycin with chronologic age, maturity, and renal function. In a large population PK study of 1103 vancomycin concentrations from 374 newborns and infants less than 2 years of age, creatinine levels were strongly correlated with vancomycin elimination, whereas chronologic age and prematurity (<28 weeks) were significant but less important predictors of vancomycin CL. Vancomycin CL for a typical 27-day-old, 1.8-kg, ex–33-week-GA infant with creatinine at 0.6 mg/dL is estimated to be 0.10 to 0.12 L/hr. The Vd (0.5- 0.8 L/kg) varies with weight and is larger than that reported in older children.
Traditional and population PK studies consistently report improved clearance and shorter half-lives with advancing GA and chronologic age. However, PK studies in preterm infants still show remarkable variability. Vancomycin half-life is prolonged in the first week of life, ranging from 6 to 10 depending on prematurity and renal function. The half-life then decreases to 4 to 7 hours in the first 1 to 2 months, then eventually to 2 to 2.5 hours in childhood.
Neonates undergoing ECMO receiving vancomycin have a larger Vd, lower CL, and longer half-life. However, because infants on ECMO typically have renal insufficiency, some of the delayed vancomycin CL may be explained by elevated SCr.
Vancomycin does not readily penetrate the CSF unless the meninges are inflamed. The CSF concentrations of vancomycin are 10% to 15% of the concomitant serum concentrations in infants with minimal meningeal inflammation. In premature infants born at 26 to 31 weeks of GA, dosages of 20 mg/kg every 18 to 24 hours were associated with CSF vancomycin concentrations of 2.2 to 5.6 μg/mL, 26% to 68% of their corresponding serum values.
Safety
Initial experience with vancomycin in the 1950s suggested a moderate incidence of ototoxicity and nephrotoxicity. These adverse effects were presumably related to the impurities found in early preparations of the drug. Further studies have indicated that vancomycin is well tolerated and safe when administered intravenously, particularly in newborns and young infants. Rare cases of ototoxicity and nephrotoxicity typically involved excessive doses, underlying hearing loss or renal disease, and concomitant therapy with other ototoxic or nephrotoxic agents. To minimize risk of nephrotoxicity or ototoxicity, vancomycin trough levels are monitored in patients with underlying renal dysfunction or those receiving concomitant therapy with aminoglycoside. There is also no proven association between therapeutic drug monitoring and the prevention of ototoxicity. Renal function should be monitored during vancomycin therapy.
In adults, the most important risk factors for developing nephrotoxicity include trough concentrations greater than 10 μg/mL, concomitant treatment with aminoglycosides, and/or prolonged therapy greater than 21 days. Other risk factors include extremely high peak concentrations greater than 60, high total dose, preexisting renal failure, and concurrent treatment with amphotericin and/or furosemide. Nephrotoxicity is not well characterized in pediatrics but appears to be less common in neonates and young infants. After rapid administration, some older patients develop a histamine reaction characterized by an erythematous pruritic rash that can persist for several hours but tends to resolve with antihistamine medications. Use of a slower infusion rate (i.e., >45-60 minutes) usually avoids this adverse event. Vancomycin is irritating to tissue and is thus always administered through the IV route. In neonates, an association between vancomycin exposure and ototoxicity or renal toxicity has not been described.
PK-PD and Clinical Implications for Dosing (See Tables 37-6 and 37-7 )
The primary indication for vancomycin therapy in newborns is for infections caused by MRSA and by ampicillin-resistant enterococci. Vancomycin is the initial drug of choice for documented infections caused by S. epidermidis because most strains are resistant to penicillin, methicillin, cephalosporins, and aminoglycosides. Of interest, Staphylococcus warneri has a somewhat reduced glycopeptide susceptibility (MIC > 2 μg/mL) compared with S. epidermidis (MIC < 2 μg/mL). The rate of killing of staphylococci is slow for vancomycin compared with β-lactams. If susceptibility data for staphylococcal infections reveals methicillin sensitivity, then the antibiotic regimen should be adjusted. For β-lactam–sensitive staphylococci and enterococci, vancomycin was inferior to nafcillin and ampicillin when comparing bactericidal rate and rapidity of blood sterility.
Vancomycin is a concentration-independent, time-dependent antibiotic with moderate PAE. The continued suppression of bacterial growth against gram-positive bacteria can persist for several hours, depending on the organism and initial antibiotic concentration, typically ranging from 0.6 to 2 hours for S. aureus and 4 to 6 hours for S. epidermidis . Both increased AUC/MIC (>400) and increased T greater than MIC have been shown to promote bacterial clearance. MRSA and S. epidermidis are typically sensitive to vancomycin, with MIC less than 2 μg/mL. Serum bactericidal titers of 1:8 (approximate serum concentrations of 12 μg/mL) have been associated with clinical cures in children. Bactericidal activity appears to be maintained if the vancomycin concentrations exceed the MIC for 100% of the dosing interval, or if the vancomycin trough concentration is greater than 10 μg/mL.
Therapeutic drug monitoring focused on trough serum concentrations can be used to optimize PK-PD efficacy targets. Trough values of at least 10 ensure that the non–protein-bound vancomycin concentration will typically remain above the MIC of the offending organism and should achieve an AUC 0-24 /MIC greater than 400 if the MIC is less than 1 mg/dL. In adults, higher trough concentrations, that is, 15 to 20 μg/mL, are indicated when treating serious MRSA infections, deep-seated infections, or those caused by organisms with a MIC greater than 1 μg/mL. Peak levels are no longer recommended. The safety of these higher exposures has not been evaluated in neonates and children. Extremely preterm infants, infants with renal insufficiency or variable renal function, and infants on ECMO are likely to need more therapeutic drug monitoring.
The timing of trough monitoring is critical. Trough values near steady state are typically drawn around the fourth dose. Trough values evaluated before steady state may need to be repeated after subsequent dosing to evaluate probable drug accumulation until steady state is reached and also with any change in renal function or with prolonged treatment regimens.
Several vancomycin dosing regimens have been proposed. The traditional dosage schedule for vancomycin in neonates is typically 10 to 15 mg/kg every 12 hours (20-30 mg/kg/day) in the first week of life and every 8 hours (30-45 mg/kg/day) thereafter. Extremely premature infants have unique dosing requirements to account for changes in body water composition and postnatal maturation in renal function. It is also reasonable to consider SCr and/or changes in SCr in setting of infection when determining vancomycin dosage. The larger dosage (15 mg/kg) is used for treatment of CSF infection or pneumonia. Extremely preterm infants, infants with renal insufficiency or variable renal function, and infants on ECMO are likely to need more frequent drug monitoring.
Prospective evaluation of these dosing regimens continues to demonstrate the large degree of variability in exposure, consistent with variability seen in PK studies. Until prospectively validated dosing guidelines are available, individual units should consider monitoring the frequency of vancomycin trough concentrations outside of the target range and the MIC of their local organisms to evaluate the appropriateness of their current dosing guidance in their specific population.
To maintain an AUC/MIC PD target and maintain vancomycin concentration above a given threshold, some clinicians have considered dosing by continuous infusion. One study in 145 preterm neonates showed that continuous infusions of either 15 to 25 mg/kg/day or 20 to 30 mg/kg/day both resulted in therapeutic vancomycin exposures. In another study, one group of 27- to 41-week PMA infants received vancomycin 10 to 30 mg/kg/day continuous infusion, whereas a second group of 28- to 51-week PMA infants received a loading dose of 7 mg/kg, followed by a continuous infusion of 10 to 40 mg/kg/day, according to PMA. Both groups had therapeutic vancomycin concentrations at steady state. Group 1 steady-state vancomycin concentration was 11 μg/mL, and group 2 steady-state vancomycin concentration after loading dose was 15 μg/mL. These continuous infusions appear to have been well tolerated; however, the infusions would likely require a dedicated IV line.
The dramatic increase in worldwide prevalence of vancomycin-resistant enterococci (VRE) and the serious threat posed by the spread of vancomycin-resistant staphylococci has discouraged the use of vancomycin for antimicrobial prophylaxis or empirical therapy.
Linezolid (See Table 37-7 )
Antimicrobial Activity
Linezolid is a synthetic oxazolidinone antibiotic that inhibits bacterial protein synthesis in a broad range of gram-positive organisms. In kill-curve experiments, linezolid is bacteriostatic against staphylococci and enterococci but can be bactericidal against streptococci. Linezolid has a unique mechanism of action and therefore does not exhibit cross-resistance with antistaphylococcal penicillins or vancomycin. It is FDA approved for treatment of infections caused by glycopeptide-resistant strains of Enterococcus faecium, S. aureus, and Streptococcus pneumoniae in neonates.
Pharmacokinetic Data (See Table 37-7 )
Linezolid is known for its rapid and nearly complete absorption after oral dosing. Bioavailability is approximately 100% in adults but has not been well characterized in neonates. Only 30% of linezolid is eliminated via the kidneys as active drug in the urine. Nonrenal pathways account for approximately 65% of total body clearance for linezolid. Linezolid is oxidized on the morpholine ring, resulting in two inactive metabolites that are then excreted in the urine. The specific biotransformation pathways in children have not been defined. Linezolid is not a cytochrome P-450 substrate. Single-dose PK for IV linezolid has been assessed in 42 neonates (25-40 weeks of gestation) in the first 80 days of life. Linezolid CL increases rapidly in the first week of life and is relatively constant from day 8 to 79 after birth. The increases in clearance are likely related to the development of biotransformation pathways after birth- and age-associated increases in glomerular filtration for the residual renal elimination of the drug. Linezolid Vd varies inversely with GA. In the first week of life, preterm infants have a slower CL and longer half-life (2.0 mL/kg ∗ min and 5.6 hours, respectively) compared with more mature infants (3.8 mL/kg ∗ min and 3 hours, respectively). Beyond the first week of life, CL and half-life estimates are similar (5.1 mL/kg ∗ min and 1.5 hours, respectively) in preterm and term infants up to 90 days of age. Linezolid trough concentrations at 11 hours are 0 to 4 μg/mL. Infants receiving a 10-mg/kg dose are predicted to have a mean AUC of 54.9 mg ∗ hr/L. Infants have faster CLs and shorter half-lives than older infants such that infants (>7 days of age) dosed every 8 hours achieve AUCs similar to older children. Linezolid rapidly penetrates the CSF in children; however, CSF concentrations are inconsistent; children with ventricular peritoneal shunts receiving the drug did not consistently achieve or maintain therapeutic concentrations in the CSF. In adults, moderate hepatic or renal insufficiency does alter the PK of linezolid. The drug’s metabolites accumulate in adults with renal insufficiency; however, the clinical significance of these metabolites is unknown.
Safety
Linezolid has been well tolerated in the small number of infants and children in PK and efficacy trials. In pediatric comparator trials, the most common drug-related adverse events in children treated with linezolid were diarrhea, nausea, vomiting, anemia, and thrombocytopenia. Drug-related adverse events rarely led to discontinuation of therapy. Linezolid is a reversible, nonselective inhibitor of monoamine oxidase ; therefore it has the potential for interaction with adrenergic and serotonergic agents. Patients receiving linezolid may have an enhanced pressor response to sympathomimetic agents, including dopamine. Myelosuppression has been reported, and therefore complete blood counts should be monitored weekly in patients on linezolid therapy, particularly for therapy beyond 2 weeks. One noncomparative study found good therapeutic outcomes, but a high rate of adverse reactions, in adults with serious gram-positive infections treated with linezolid for a mean of 28 days.
PK-PD and Clinical Implications for Dosing (See Tables 37-6 and 37-7 )
Linezolid is indicated for the treatment of vancomycin-resistant E. faecium (VRE) infections; pneumonia caused by MRSA or S. pneumoniae ; and severe, complicated skin infections caused by susceptible organisms. Linezolid penetrates respiratory secretions and epithelial lining fluid better than vancomycin. Linezolid exhibits time-dependent killing with moderate-to-prolonged persistent antimicrobial effects. The primary PD determinant associated with efficacy in the neutropenic thigh-infection model for S. pneumoniae and S. aureus is an AUC/MIC ratio of 50 and 80, respectively. Susceptible strains of Enterococcus and Streptococcus spp. have MICs less than or equal to 2 μg/mL, whereas the susceptible strains of staphylococci have a MIC less than or equal to 4 μg/mL. In adults with MRSA or VRE, favorable outcomes were experienced in 97% of those who achieved a linezolid AUC/MIC ratio of greater than 95 compared with 75% of those who had lower AUC/MIC ratios. Administration of continuous linezolid infusions, such that drug concentrations are maintained above the MIC for entire dosing interval, has been associated with bactericidal activity. For adults with MRSA infections, there appears to be no significant difference in clinical cure or microbiologic cure between linezolid and vancomycin. However, linezolid was superior to vancomycin in one adult comparator trial of complicated skin and soft tissue infections.
Linezolid clinical trials have been performed in hospitalized young infants and children with documented gram-positive infections. Linezolid was well tolerated at a dosage of 10 mg/kg every 8 hours and as effective as vancomycin for treatment of resistant gram-positive infections. Infants require dosing every 8 hours to maintain AUCs similar to those achieved in adolescents and adults dosed every 12 hours. An AUC of 100 would achieve AUC/MIC ratios of greater or equal to 50 if the MIC of the organism was less than or equal to 2, as would be expected for most enterococcal or streptococcal infections. Higher doses may be needed to achieve this AUC/MIC target in infants with faster CL or infants with MRSA infections, where the MIC may be between 2 to 4 μg/mL; PD targets have not been confirmed in clinical trials. In the first few days of life, infants may accumulate linezolid as CL is rapidly changing. For extremely preterm infants younger than 7 days of chronologic age, we would consider a dose of 10 mg/kg every 12 hours. The risk of drug accumulation is balanced with the need to rapidly achieve and maintain adequate plasma and tissue concentrations of drug during a developmental period of rapidly improving CL. The potential for linezolid resistance has been documented; further emergence and spread of such resistance may depend on its prudent use.
A new oxazolidinone antibiotic, tedizolid (marketed as Sivextro), was approved by the FDA in 2014 for once-daily dosing against acute gram-positive bacterial infections, including MRSA; information on its potential use and safety in pregnancy and infants is not yet available.
Clindamycin (See Table 37-7 )
Antimicrobial Activity
Clindamycin replaced its parent compound lincomycin because it is more completely absorbed from the gut, has fewer adverse effects, and has greater antibacterial activity in vitro. Clindamycin is primarily a bacteriostatic agent that acts by inhibiting protein synthesis through reversible binding to bacterial ribosomes, thus inhibiting bacterial protein synthesis. Clindamycin is active against gram-positive cocci such as S. aureus, S. pneumoniae (including many multidrug-resistant strains), and S. pyogenes . It also maintains notable activity against anaerobic bacteria, especially members of the Bacteroides group. Aerobic gram-negative bacteria are not usually susceptible to this antibiotic. Resistance to clindamycin is related to alterations of its target site and not to reduced uptake or to breakdown of the drug by the resistant bacteria.
Pharmacokinetic Data
Clindamycin pharmacology has been recently reviewed; however, there is a paucity of information in neonates. Clindamycin exhibits significant (94%) protein binding. The drug is eliminated primarily through the liver, with only about 10% excreted in unchanged form in the urine. Clindamycin is reported to be a cytochrome P-450 substrate that may increase the neuromuscular blocking action of tubocurarine and pancuronium. Clindamycin has been shown to accumulate in patients with hepatic dysfunction. It is widely distributed throughout the body, including pleural fluid, ascites, bone, and bile. However, no significant levels (≈20%) are seen in the CSF, even in the setting of meningitis. Experimental meningitis animal models have demonstrated CSF penetration after parenteral administration. In adults, clindamycin exhibits excellent bioavailability after oral administration.
When IV clindamycin was administered to infants in the first 4 weeks after birth, in a dosage schedule of 6.5 mg/kg every 8 hours (preterm) or 5 mg/kg every 6 hours (term), the mean peak serum concentration was 10 μg/mL, and trough values ranged from 2.8 to 5.5 μg/mL. The serum elimination half-life was inversely related to GA and birth weight. Premature neonates demonstrated a mean serum half-life of 8.7 hours, compared with 3.6 hours for term newborns. Another study of 12 neonates demonstrated a serum elimination half-life of 3.5 to 9.8 hours (mean, 6.3 hours). Neonates have longer elimination half-lives for clindamycin than the 3-hour half-life observed in infants aged 1 month to 1 year of age.
Safety
Adverse effects of clindamycin include diarrhea, rashes, elevated levels of hepatic enzymes, granulocytopenia, thrombocytopenia, and, rarely, Stevens-Johnson syndrome. The most serious potential complication to consider is pseudomembranous colitis. Many asymptomatic neonates are colonized with Clostridium difficile , the presumed etiologic agent of pseudomembranous colitis. However, evidence for an association of C. difficile colonization with colitis in newborns is lacking, and pseudomembranous colitis is rare in both newborns and young infants. This adverse effect also is observed with the use of β-lactam and other antimicrobial agents.
PK-PD and Clinical Implications for Dosing (See Tables 37-6 and 37-7 )
Clinical information suggests that clindamycin can be effectively used to treat MRSA infections. Caution is advised, however, because resistance to clindamycin can be induced after selective antimicrobial pressure, particularly in MRSA organisms that initially are clindamycin susceptible and erythromycin resistant. Use of clindamycin in selected MRSA-infected newborn patients can obviate the need for vancomycin therapy. For treatment of the rare Bacteroides fragilis infections in newborns, especially those involving the CSF, metronidazole or clindamycin have been used. Clindamycin is said to have poor penetration into the CSF albeit good penetration into brain tissue.
Considerable debate exists regarding the optimal dose of clindamycin. Antibacterial activity is concentration independent and time dependent, with considerable PAE. Clindamycin has antibacterial activity that appears to be maximized as drug concentrations approach one to four times the MIC and also has a considerable PAE (4-6 hours). In the murine thigh infection model, clindamycin has been effective against clindamycin-susceptible (and noninducible) MRSA. One proposed PK-PD target is to maintain the clindamycin concentration above the MIC for greater than or equal to 50% of the dosing interval. Most staphylococcal species have a low MIC (<1 μg/mL) for the drug. Much lower dosing than is currently used in adults was shown to achieve equivalent killing and maintain the clindamycin concentration above the MIC for 100% of the dosing interval. Empirical dosing information based upon the limited PK information available is 5 mg/kg/dose administered every 12 hours in the first week of life and every 6 to 8 hours thereafter. Preterm infants may have decreased CL of clindamycin; therefore dosing interval is typically maintained at 8 to 12 hours for the first 2 weeks after birth. These doses are less than recommended in infants and young children (25-40 mg/kg/day divided every 6-8 hours). More neonatal PK data is needed, especially in ELBW infants with serious bacterial infections in the first 90 days after birth. Because clindamycin is highly protein bound, assays need to clearly quantify the molecularly active non–protein-bound exposure to clindamycin.
Rifampin
In selected neonates with persistent, systemic staphylococcal infections, rifampin has been used to provide a synergistic effect when given with other antistaphylococcal drugs. Resistance rapidly emerges with rifampin monotherapy. In adults, rifampin is widely distributed throughout the body, including the CSF. Rifampin is 80% protein bound and is eliminated in bile after progressive deacetylation to metabolites that remain microbiologically active. No dose adjustment is needed for renal insufficiency. Rifampin is bactericidal through the inhibition of bacterial-specific DNA-dependent RNA polymerase activity. It is active against most strains of Neisseria meningitidis , Mycobacterium tuberculosis , and aerobic gram-positive bacteria, including methicillin-sensitive S. aureus (MSSA), MRSA, and S. epidermidis . Safety concerns regarding rifampin are focused on thrombocytopenia, liver dysfunction and jaundice; liver function and blood count monitoring is recommended. Rifampin has been found to compete with bilirubin for biliary excretion, and increased bilirubin has been observed. Rifampin is also known to induce cytochrome P-450 enzymes, and therefore drug interactions are possible. Rifampin has been shown to accelerate elimination of drugs that are used in the neonatal population, including phenytoin, azole antifungal agents, narcotic analgesics, diazepam, and corticosteroids.
Neonatal PK information for IV rifampin is sparse, and dosing remains empirical. In one small study, infants (mean age, 23 days) received rifampin 10 mg/kg/day and had a mean peak concentration of 4.02 μg/mL and a mean 12-hour trough concentration of 1.11 μg/mL. In children, rifampin CL is induced after 8 days of therapy. As rifampin CL increases and half-life decreases, the dosing interval may need to be shortened to accommodate induced clearance in prolonged therapy. Uncontrolled clinical case series suggest that rifampin used as an adjunct to vancomycin therapy can provide prompt clearance of persistent staphylococcal bacteremia or ventriculitis in high-risk neonates.
Teicoplanin
Teicoplanin is a glycopeptide antibiotic that is almost identical to vancomycin with regard to its antibacterial spectrum of activity. It is used frequently in Europe, where it is approved for the treatment of gram-positive infections ; however, it is not approved for use in the United States. Teicoplanin may have some advantages over vancomycin in terms of tolerability, with a lower propensity to cause nephrotoxicity and histaminic-type reactions. Teicoplanin also has a longer elimination half-life, allowing for longer dosing intervals. It rapidly penetrates into tissue and reaches high concentrations in the kidney, trachea, lungs, and adrenals but does not penetrate well into the CSF. It is excreted unchanged in the urine after a prolonged elimination phase.
Despite these potential advantages, teicoplanin PK data adequate to formulate dosage regimens in neonates are lacking. In one study, four neonates received a single dose of 6 mg/kg, and the mean peak serum teicoplanin concentration was 19.6 μg/mL, with a mean half-life of 30 hours. In several noncomparative trials, the clinical and bacteriologic response rates ranged between 80% and 100% in 173 infected neonates given IV teicoplanin 8 to 10 mg/kg once daily after a loading dose of 10 to 20 mg/kg. A recent study of 37 episodes of staphylococcal bacteremia in neonates treated with a loading dose of 16 mg/kg teicoplanin, followed by a maintenance dose of 8 mg/kg/day, achieved bacterial eradication in 89% and survival of 94% with no documented drug-related adverse events. One neonate was reported to have tolerated teicoplanin overdose (20 mg/kg/day for 5 days).
Daptomycin
Daptomycin is the first-in-class member of the cyclic lipopeptide family. Lipopeptides have a unique mechanism of action. They insert into bacteria membranes and cause a rapid membrane depolarization, leading to inhibition of protein, DNA and RNA synthesis, cell leakage, and ultimately cell death. Daptomycin exhibits rapid, concentration-dependent, bactericidal activity against MRSA, MRSE, vancomycin-resistant S. aureus , and VRE. The product is approved in the United States for the treatment of complicated skin and skin structure infections, and S. aureus bacteremia. Daptomycin is not indicated for the treatment of pneumonia because of its inactivation by surfactant. Daptomycin exhibits a high degree of protein binding and is primarily excreted unchanged by the kidney. In clinical trials, a few adults receiving daptomycin had elevated creatine phosphokinase (CPK) enzyme and, rarely, myopathy. The manufacturer recommends monitoring CPK weekly while on therapy and discontinuing therapy for myopathy, myalgia, or CPK greater than 1000 mg/dL.
Daptomycin is not approved for use in children or neonates. One single-dose PK study of 25 children with suspected or proven gram-positive infections revealed more rapid CL in younger children. Two infants with complicated MRSA infections who received 6 mg/kg dose every 12 hours had peak and trough concentrations that were consistent with concentrations observed in adults treated with a 4-mg/kg daily dose. These infants achieved microbiologic and clinical cure; however, their exposure was less than that achieved in adults receiving daptomycin at the approved dose of 6 mg/kg per day for treatment of MRSA bacteremia.
A single-dose PK study, after giving 6 mg/kg daptomycin IV, was carried out on 20 neonates at risk for infection, having a median gestation age at birth of 32 weeks (range, 23-40 weeks) and median PNA of 3 days (range, 1-85 days). The median AUC at 24 hours, Vd, total-body clearance, and half-life of daptomycin were 262.4 mg ∗ hr/L (range, 166.7-340.2), 0.21 L/kg (range, 0.11- 0.34), 0.021 L/hr/kg (range, 0.016-0.034), and 6.2 hours (3.7-9.0), respectively. CPK concentrations were not elevated. No adverse events related to daptomycin were observed. Daptomycin concentrations were lower than that achieved in adults receiving similar doses. Clearance in young infants was similar to that in children 2 to 6 years of age and higher than that observed in adolescents and adults. Young infants are likely to need higher doses of daptomycin to achieve adult efficacy targets. Additional studies, including multiple-dose PK and safety studies, are needed to derive appropriate PK-PD dosing guidance.
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