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Αλέξανδρος Γ. Σφακιανάκης
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Παρασκευή 26 Μαΐου 2017

leven Broad-Spectrum Antibiotics Investigated Antibiotic Description Year of Initial FDA Approval Amoxicillin Semi-synthetic beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1974 Chloramphenicol Broad-spectrum antibiotic isolated from Streptomyces venezuela in 1947, now synthetically available. Binds to the 50S subunit of bacterial ribosomes, inhibiting peptide bond formation and protein synthesis. 1950 Ciprofloxacin Fluoroquinolone antibiotic. Exerts its bactericidal effect by disrupting DNA replication, transcription, recombination, and repair by inhibiting bacterial DNA gyrase. 1987 Clindamycin Antibiotic derived from lincomycin that has wide-ranging antimicrobial activity. Binds to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. 1970 Doxycycline Broad-spectrum antibiotic that binds to the 30S bacterial ribosomal subunit. Blocks the binding of transfer-RNA to messenger-RNA, thereby disrupting prote

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
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​Reviews Antibiotic Use in Pregnancy and Lactation What Is and Is Not Known About Teratogenic and Toxic Risks Gerard G. Nahum, MD , CAPT Kathleen Uhl, USPHS, and CAPT Dianne L. Kennedy, USPHS OBJECTIVE: Over ten million women are either pregnant or lactating in the United States at any time. The risks of medication use for these women are unique. In addition to normal physiologic changes that alter the pharmaco- kinetics of drugs, there is the concern of possible terato- genic and toxic effects on the developing fetus and newborn. This article reviews the risks and pharmacoki- netic considerations for 11 broad-spectrum antibiotics that can be used to treat routine and life-threatening infections during pregnancy and lactation. DATA SOURCES: Information from the U.S. Food and Drug Administration (FDA) product labels, the Teratogen Information Service, REPROTOX, Shepard's Catalog of Teratogenic Agents, Clinical Pharmacology, and the peer- reviewed medical literature was reviewed concerning the use of 11 antibiotics in pregnant and lactating women. The PubMed search engine was used with the search terms "[antibiotic name] and pregnancy," "[antibiotic name] and lactation," and "[antibiotic name] and breast- feeding" from January 1940 to November 2005, as well as standard reference tracing. METHODS OF STUDY SELECTION: One hundred twen- ty-four references had sufficient information concerning numbers of subjects, methods, and findings to be in- cluded. TABULATION, INTEGRATION, AND RESULTS: The ter- atogenic potential in humans ranged from "none" (pen- icillin G and VK) to "unlikely" (amoxicillin, chloramphen- icol, ciprofloxacin, doxycycline, levofloxacin, and rifampin) to "undetermined" (clindamycin, gentamicin, and vancomycin). Assessments were based on "good data" (penicillin G and VK), "fair data" (amoxicillin, chlor- amphenicol, ciprofloxacin, doxycycline, levofloxacin, and rifampin), "limited data" (clindamycin and gentamicin), and "very limited data" (vancomycin). Significant phar- macokinetic changes occurred during pregnancy for the penicillins, fluoroquinolones and gentamicin, indicating that dosage adjustments for these drugs may be neces- sary. With the exception of chloramphenicol, all of these antibiotics are considered compatible with breastfeed- ing. CONCLUSION: Health care professionals should con- sider the teratogenic and toxic risk profiles of antibiotics to assist in making prescribing decisions for pregnant and lactating women. These may become especially impor- tant if anti-infective countermeasures are required to protect the health, safety, and survival of individuals exposed to pathogenic bacteriologic agents that may occur from bioterrorist acts. (Obstet Gynecol 2006;107:1120–38) A ntibiotics are among the most commonly pre- scribed prescription medications for pregnant and lactating women. 1 More than 10 million women are either pregnant or lactating in the United States at any one time, and they are administered antibiotics for many reasons. 2 Because of the special consider- ations associated with fetal and newborn develop- ment, these women constitute a uniquely vulnerable population for which the risks of medication use must be separately assessed. In addition to the pharmacokinetic and pharma- codynamic changes that may occur during pregnancy and lactation that can alter the effectiveness of drugs, 3 there is the added concern of the possible teratogenic and toxic effects that medications may have on the developing fetus and newborn. In general, there is a dearth of pharmacokinetic and pharmacodynamic information regarding the use and proper dosing of Food and Drug Administration (FDA)–approved From the Department of Obstetrics and Gynecology, Uniformed Services Uni- versity of the Health Sciences, Bethesda, Maryland; Office of Women's Health, U.S. Food and Drug Administration, Rockville, Maryland; FDA Center for Drug Evaluation and Research, Silver Spring, Maryland. Presented in part at the FDA Science Forum in Washington, DC, April 27–28, 2005. The views, opinions, interpretations, and conclusions expressed in this article are those of the authors only and do not reflect either the policies or positions of the Center for Drug Evaluation and Research, the U.S. Food and Drug Adminis- tration, or the U.S. Department of Health and Human Services. Corresponding author: Gerard G. Nahum, MD, FACOG, FACS, Box 2184, Rockville, MD 20847; e-mail: GNahum2003@yahoo.com. © 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/06 1120 VOL. 107, NO. 5, MAY 2006 OBSTETRICS & GYNECOLOGY drugs in pregnant and lactating women, as well as limited data pertaining to the teratogenic potential and the fetal or neonatal toxicity of these marketed medications. Accordingly, sparse information must sometimes be assembled from diverse sources to address these issues. Recently, the threat of bioterrorism has expanded the context in which the potential use of antibiotic medications may be needed. 4 Although the possibility of a large-scale bioterrorist attack in the United States is unlikely, the potential for widespread antibiotic use in this situation emphasizes the need for health care professionals to be familiar with the risks and benefits of administering antibiotics to pregnant and lactating women. This article reviews the available information concerning the risks and special circumstances to be considered in pregnant and lactating women for a group of 11 broad-spectrum antibiotics (amoxicillin, chloramphenicol, ciprofloxacin, clindamycin, doxy- cycline, gentamicin, levofloxacin, penicillin G, peni- cillin VK, rifampin, and vancomycin). By using this information, better choices can be made for the treatment of different types of bacterial pathogens in these particularly vulnerable populations. DATA SOURCES AND METHODS OF STUDY SELECTION Information from FDA-approved product labels, the Teratogen Information Service, Shepard's Catalog of Teratogenic Agents, REPROTOX, Clinical Pharma- cology, and the peer-reviewed literature were re- viewed for information concerning the use of 11 antibiotics in pregnant and lactating women. The medical literature was queried with the PubMed search engine. Papers searched were published from January 1940 to November 2005, in any language. The search terms "[antibiotic name] and pregnancy," "[antibiotic name] and lactation,", and "[antibiotic name] and breastfeeding," were used, as was standard reference tracing. A total of 124 references were accessed through these sources that contained suffi- cient information concerning the numbers of subjects, methods of investigation, and findings to be useful for the purpose of drawing conclusions concerning phar- macokinetic parameters, teratogenic potential, and toxicity assessments of these drugs. All materials were restricted to information from nonproprietary sources that were available in the public domain. Addition- ally, information concerning the potential treatment options for exposures and diseases caused by possible agents of bioterrorism were obtained from materials published by the Centers for Disease Control and Prevention in Atlanta. RESULTS A description of the 11 broad-spectrum antibiotics and their general modes of action are provided in Table 1. All 11 antibiotics cross the placenta and enter the fetal compartment. For 5 of these, human umbilical cord blood levels are of the same order of magnitude as circulating maternal blood concentrations (chlor- amphenicol, clindamycin, gentamicin, rifampin, and vancomycin). For 4, the concentrations are of the same magnitude or higher in amniotic fluid as in maternal blood (ciprofloxacin, clindamycin, levo- floxacin, and vancomycin) (Table 2). All 11 antibiotics are excreted in human breast milk. Limited information concerning the amount in breast milk was available for 8 antibiotics (ciprofloxa- cin, clindamycin, doxycycline, gentamicin, levofloxa- cin, penicillin G, penicillin VK, and rifampin). No quantitative data concerning breast milk concentra- tions were available for 3 (amoxicillin, chloramphen- icol, and vancomycin) (Table 2). Using the Teratogen Information Service clas- sification system for teratogenic risk, 44 the terato- genic potential of the 11 antibiotics during human pregnancy ranged from "none" in 2 cases (penicil- lin G and VK) to "unlikely" in 6 (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levo- floxacin, and rifampin) to "undetermined" in 3 (clindamycin, gentamicin, and vancomycin). As- sessments were based on data that were "good" for 2 (penicillin G and VK) to "fair" for 6 (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levo- floxacin, and rifampin) to "limited" for 2 (clinda- mycin and gentamicin) to "very limited" for 1 (vancomycin). A summary of the human and ani- mal data contributing to these assessments is shown in Table 3. The Food and Drug Administration Pregnancy Category classifications for the 11 anti- biotics (as defined under 21 CFR [Code of Federal Regulations] 201.57 for the A, B, C, D, X Preg- nancy Category system) (Table 4) were "B" in 5 cases (amoxicillin, clindamycin, penicillin G, peni- cillin VK, and vancomycin), "C" in 5 cases (chlor- amphenicol, ciprofloxacin, gentamicin, levofloxa- cin, and rifampin), and "D" in 1 case (doxycycline) (Table 3). In addition to the published literature, proprietary data were used to establish the FDA pregnancy category for these drugs. Despite numerous concerns regarding the poten- tial for maternal and fetal or neonatal toxicity of these VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1121 11 drugs—including idiosyncratic and dose-related bone marrow suppression with chloramphenicol, ar- thropathies and bone and cartilage damage with ciprofloxacin and levofloxacin, dental staining and hepatic necrosis with doxycycline, and ototoxicity and nephrotoxicity with gentamicin and vancomy- cin—none of these toxicities has been documented in human mothers or offspring either during preg- nancy or breastfeeding with these antibiotics (Table 3). Very limited information was available pertain- ing to maternal pharmacokinetics in pregnancy for 8 antibiotics (amoxicillin, ciprofloxacin, clindamycin, gentamicin, levofloxacin, penicillin G, penicillin VK, and vancomycin), and none was available for 3 (chloramphenicol, doxycycline, and rifampin) (Table 2). For 4 antibiotics (amoxicillin, gentamicin, penicil- lin G, and penicillin VK), lower circulating drug concentrations were measured in pregnant women than nonpregnant, suggesting that a shorter dosing interval or increased maternal dose or both may be necessary to obtain similar circulating drug concen- trations as for women in the nonpregnant state. In the case of ciprofloxacin and levofloxacin, circulating concentrations were generally reduced in pregnant women, also suggesting that an increased maternal dose or a shorter dosing interval or both may be necessary. In 3 cases (chloramphenicol, gentamicin, and vancomycin), therapeutic drug monitoring of serum peak and trough levels is recommended to assess circulating drug levels. In 1 case (clindamycin), the standard pharmacokinetic parameters did not change appreciably during the first, second, or third trimester of pregnancy (Table 2). Very little pharma- Table 1. Description of the Eleven Broad-Spectrum Antibiotics Investigated Antibiotic Description Year of Initial FDA Approval Amoxicillin Semi-synthetic beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1974 Chloramphenicol Broad-spectrum antibiotic isolated from Streptomyces venezuela in 1947, now synthetically available. Binds to the 50S subunit of bacterial ribosomes, inhibiting peptide bond formation and protein synthesis. 1950 Ciprofloxacin Fluoroquinolone antibiotic. Exerts its bactericidal effect by disrupting DNA replication, transcription, recombination, and repair by inhibiting bacterial DNA gyrase. 1987 Clindamycin Antibiotic derived from lincomycin that has wide-ranging antimicrobial activity. Binds to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. 1970 Doxycycline Broad-spectrum antibiotic that binds to the 30S bacterial ribosomal subunit. Blocks the binding of transfer-RNA to messenger-RNA, thereby disrupting protein synthesis. 1967 Gentamicin Aminoglycoside antibiotic with broad-spectrum activity. Binds irreversibly to 30S bacterial ribosomal subunit, thereby inhibiting protein synthesis. 1966 Levofloxacin Fluoroquinolone antibiotic. L-isomer of ofloxacin, which provides its principal antibiotic effect. Inhibits bacterial DNA replication, transcription, recombination, and repair by inhibiting bacterial type II topoisomerases. 1996 Penicillin G Beta-lactam antibiotic that is primarily bactericidal. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1943 Penicillin V (phenoxymethyl penicillin) Naturally derived beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. Considered preferable to penicillin G for oral administration because of its superior gastric acid stability. 1956 Rifampin Rifamycin B derivative that inhibits bacterial and mycobacterial DNA-dependent RNA polymerase activity. Used primarily for the treatment of tuberculosis, with additional utility for the treatment of both leprosy and meningococcal carriers. 1971 Vancomycin Glycopolypeptide antibiotic. Binds to the precursor units of bacterial cell walls, inhibiting their synthesis and altering cell wall permeability while also inhibiting RNA synthesis. Because of its dual mechanism of action, bacterial resistance is rare. 1964 FDA, U.S. Food and Drug Administration. 1122 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Amoxicillin Gram-positive aerobes, most gram-positive anaerobes, gram- negative aerobes including some enteric bacilli, Helicobacter, spirochetes, actinomyces* Crosses the human placenta. 5–7 Penicillins transferred to the fetus and amniotic fluid reach therapeutic levels. 5 Excreted in human breast milk in small amounts. 8 Considered "usually compatible with breastfeeding." 9† Following therapeutic doses, mean human milk concentrations were 0.1–0.6 g/mL. 10 No adverse effects seen in nursing infants whose mothers have been treated with amoxicillin. Shorter dosing interval and/ or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 Chloramphenicol Gram positives, gram negatives, anaerobes, chlamydia, rickettsiae Crosses the human placenta readily. Umbilical cord serum concentrations 29–106% of maternal levels. 12 Excreted in human breast milk. 13–15 In 5 patients with minor obstetrical lacerations who receive d1gPOqDfor8 days, mean milk concentrations were 0.5–2.8 g/mL. In 5 patients receivin g2gPOqDfor8 days for mastitis, mean milk concentrations were 1.8–6.1 g/mL. 13 Human milk concentrations are 51–62% of blood levels. 14 Percentage of administered dose in human breast milk per day is 1.3%. 15 Effect on breastfed infants considered "unknown but may be of concern." 16 Unknown whether dose adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Serum concentrations can be monitored to keep peak and trough levels in the ranges of 10–20 and 5–10 g/mL, respectively. CBC monitored to detect bone marrow depression. Ciprofloxacin Gram-negative aerobes, some staphylococci Crosses the human placenta and concentrates in amniotic fluid (Product information Cipro, 2001). 17 In 20 women at 19–25 weeks of gestation who received two 200-mg IV doses q 12 hours, the mean amniotic fluid level 2–4 hours after dosing was 0.12 0.06 g/mL (n 7; amniotic fluid: maternal serum concentration [AF:MS ratio] 0.57), 0.13 0.07 g/mL at 6–8 hours (n 7; AF:MS ratio 1.44), and 0.10 0.04 g/mL at 10–12 hours (n 6; AF: MS ratio 10.00). 17 Excreted in human breast milk (Product information Cipro, 2001). 17 Considered usually compatible with breastfeeding." 9† In 10 women given 750 mg q12 hours PO, serum and milk concentrations were obtained 2, 4, 6, 9, 12, and 24 hours after the 3rd dose. Concentrations were 3.79 1.26, 2.26 0.75, 0.86 0.27, 0.51 0.18, 0.20 0.05, and 0.02 0.006 g/mL at these times and the ratios of breast milk: serum concentration were 1.84, 2.14, 1.60, 1.70, 1.67, and 0.85, respectively. 17 For breastfeeding infants consuming 150 mL/kg per day, the estimated maximum dose is 0.569 mg/kg per day or 2.8% the approved dose for infants of 20 mg/kg per day. 18 Circulating fluoroquinolone concentrations are lower in pregnant than in nonpregnant women, but no specific pharmacokinetic data is available regarding ciprofloxacin in pregnant women. 19 It is unknown whether dose adjustments during pregnancy are necessary. Approximately 50–70% of a dose is excreted in the urine and, if renal function is impaired, the serum half- life is slightly prolonged (Product information Cipro, 2001). ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1123 Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Clindamycin Gram-positive anaerobes, gram- negative anaerobes, aerobic gram-positive cocci, streptococci, Clostridia strains Crosses the human placenta readily. 44,20–23 In 54 women undergoing cesarean delivery who received 600 mg IV 30 minutes before surgery, umbilical cord blood concentrations were 46% of maternal serum levels. 20 After multiple oral doses prior to therapeutic abortion, fetal blood concentrations were 25% and amniotic fluid levels were 30% of maternal blood levels. 21 Excreted in human breast milk (Product information Clindamycin, 1970). Considered "usually compatible with breastfeeding." 9† At maternal doses of 150 mg orally to 600 mg IV, breast milk concentrations range from 0.7 to 3.8 g/mL (Product information Clindamycin, 1970). Pharmacokinetic parameters do not change during pregnancy in women studied during the 1st, 2nd, and 3rd trimesters of gestation. 20,24 There are no studies to indicate that dosing should be modified during pregnancy. C max and T max (after a single standard dose) and C ss (after multiple doses) do not change appreciably at any time during pregnancy. Doxycycline Gram-positives, gram- negatives, rickettsiae, chlamydiae, mycoplasma, spirochetes, actinomyces Crosses the placenta (Product information Vibramycin, 2001). Excreted in human breast milk. 25 Use for a short period (1 week) during breastfeeding is considered probably safe. 9,16 Breast milk concentrations are 30–40% of that found in maternal blood. 25 Unknown whether dose adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Enterohepatically recirculated. Excreted in urine and feces as unchanged drug. From 29% to 55.4% of a dose can be accounted for in the urine by 72 hours (Product information Vibramycin, 2001). Gentamicin Gram-negative aerobic rods, many streptococci, Staphylococcus aureus , mycobacteria Crosses the human placenta. 20,26–28 In 2 different studies, peak umbilical cord blood levels were 34% 26 and 42% 20 of associated maternal blood concentrations. Excreted in human breast milk. 29,30 Considered "usually compatible with breastfeeding." 9† Poorly absorbed from the GI tract. 29 Only half of nursing newborns had detectable serum levels, which were low and not likely to cause clinical effects. 29 No adverse signs or symptoms in nursing infants as a result of maternal treatment. 9 Increased dosage suggested due to decreased serum half-life in pregnancy and lower maternal serum levels. 20,31 In 54 women undergoing cesarean delivery, levels were lower than nonpregnant women. 20 Eliminated mainly by glomerular filtration (Product information Gentamicin, 1966). Clearance decreased in preeclamptic patients. 32 Dose/ dosing interval adjusted via peak and trough levels (Product information Gentamicin 1966). ( continued ) 1124 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Levofloxacin Gram-positives and gram-negatives Crosses the human placenta and concentrates in amniotic fluid (based on data for racemic ofloxacin) (Product information Levaquin, 1996). 17 In 20 women at 19–25 weeks of gestation receiving two IV 400-mg doses of ofloxacin q12 hours, mean amniotic fluid concentration 3–6 hours after dosing was 0.25 0.11 g/mL (n 6; amniotic fluid: maternal serum concentration [AF:MS ratio] 0.35), 0.15 0.11 g/mL at 6–10 hours (n 8; AF:MS ratio 0.67), and 0.13 0.11 g/mL at 11–12 hours (n 6; AF:MS ratio 2.57). 17 Excreted in human breast milk in high concentrations (based on data for racemic ofloxacin) (Product information Levaquin, 1996). 17 Considered "usually compatible with breastfeeding." 9† In 10 women given 400 mg of ofloxacin q12 hours PO, serum and milk concentrations were obtained 2, 4, 6, 9, 12, and 24 hours after the 3rd dose. Concentrations were 2.41 0.80, 1.91 0.64, 1.25 0.42, 0.64 0.21, 0.29 0.10, and 0.05 0.02 g/mL at these times, with breast milk: serum concentration ratios of 0.98, 1.30, 1.39, 1.25, 1.12, and 1.66, respectively. 17 For breastfed infants consuming 150 mL/kg per day, the estimated maximum infant dose of ofloxacin is 0.362 mg/kg per day. 18 Circulating fluoroquinolone concentrations are lower in pregnant than in nonpregnant women, but no specific pharmacokinetic data is available regarding levofloxacin in pregnant women. 19 There are no data to support dosing adjustments during pregnancy. Penicillin G Gram-positive aerobes including most streptococci/ enterococci, gram- positive anaerobes, spirochetes, actinomyces, some gram negatives* Crosses the human placenta. 5,33,34 Penicillins are transferred to the fetus and amniotic fluid reaching therapeutic levels. 5 Excreted in human breast milk in small amounts (Product information Bicillin, 2001; product information Penicillin V, 1997). 15 Considered "usually compatible with breastfeeding." 9† In women with serum concentrations of penicillin ranging from 6 to 120 g/dL, corresponding breast milk concentrations were 1.2–3.6 g/dL, and the amount of the maternal dose appearing in breast milk per day was estimated at 0.03%. 15 Shorter dosing interval and/ or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 Penicillin VK Gram-positive aerobes including most streptococci/ enterococci, gram- positive anaerobes, gram negatives Crosses the human placenta readily. 5,7,10,33,34,35 Penicillins are transferred to the fetus and amniotic fluid reaching therapeutic levels. 5 Excreted in human breast milk in small amounts (Product information Penicillin V, 1997). 15,36 Considered "usually compatible with breastfeeding." 9† In 18 women, penicillin V milk concentration depended on presence of mastitis, with peak levels 2.6–5.4 hours after a single PO 1,320-mg dose. 35 Peak concentration was 30–72 g/dL with mean concentration 26-37 g/dL. AUC over 8 hours after dosing was 2.1–3.0 mg-h/L. 35 Estimated dose of penicillin V ingested per day by breastfed infants is 40–60 g/kg, or 0.09– 0.14% of maternal dose per kg body weight. 35 Shorter dosing interval and/or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillin V is excreted renally, primarily via tubular secretion. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1125 Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Rifampin Mycobacteria, Neisseria meningitidis , S aureus , Haemophilus influenzae , Legionella pneumophila , Chlamydia Crosses the human placenta (Product information Rifampin, 1971). 37–39 Umbilical cord concentrations between 12% and 33% of maternal blood levels, with peak levels occurring concurrently after drug administration. 37–39 Excreted in human breast milk (Product information Rifampin, 1971). 15,40,41 Considered "usually compatible with breastfeeding." 9† After a single oral dose of 600 mg, a nursing infant would ingest approximately 0.05% of the maternal dose per day, or approximately 0.3 mg/day. 15,40,41 Unknown whether dosing adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Hepatically deacetylated to active metabolite. Parent compound and metabolites excreted via biliary elimination (60%). Enterohepatic re-circulation; plasma levels elevated in hepatic disease. Up to 30% excreted in urine; renal clearance is 12% of GFR. 38 Vancomycin Gram positives, S aureus , Staphylococcus epidermidis , streptococci, enterococci, Clostridium , Coryne- bacterium Crosses the human placenta (Product information Vancomycin, 1964). 42,43 Appears in umbilical cord blood after IV maternal treatment (Product information Vancomycin, 1964). 42,43 Amniotic fluid and umbilical cord blood concentrations during the early 3rd trimester comparable to maternal blood levels (fetal-maternal serum concentration ratio of 0.76). 43 Excreted in human breast milk when administered IV (Product information Vancomycin, 1964). 42 When administered orally, vancomycin is poorly absorbed from the GI tract (Product information Vancomycin, 1964). It is, therefore, not likely to cause adverse effects in nursing infants. There are no studies to indicate that vancomycin dosing should be modified during pregnancy. Volume of distribution and plasma clearance both increased, but half-life similar to that for nonpregnant women (4.55 versus 4–6 hours) in a woman administered IV vancomycin twice daily from 26–28 weeks of pregnancy. 43 CBC, complete blood count; AF, amniotic fluid; MS, maternal serum; GI, gastrointestinal; AUC, area under the curve; GFR, glomerular filtration rate . * Listed in the product label and the clinical pharmacology monograph as active against most strains; bacterial resistance occurs commonly in some sp ecies of otherwise susceptible bacteria due to beta-lactamase production. † Based on assessment by the American Academy of Pediatrics. 1126 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data Antibiotic Human Data: Teratogenic and Toxic Effects Animal Data: Teratogenic and Toxic Fetal Effects Magnitude of Human Teratogenic Fetal Risk (Based on TERIS Assessment) 44 FDA Pregnancy Category* Amoxicillin OR for major congenital anomalies 1.4 (95% CI 0.9–2.0) for women using amoxicillin clavulanic acid during pregnancy in a case-control study of 6,935 malformed infants (no increased risk). 45 OR (adjusted) for congenital anomalies 1.16 (95% CI 0.54– 2.50) in a Danish study (1991–2000) of 401 primiparous women who filled prescriptions for amoxicillin during pregnancy (rate 4.0%) compared with 10,237 controls who did not redeem any prescription drug (rate 4.1%). 46 No increased rate of congenital malformations among 147 women who received prescriptions for amoxicillin during the 1st trimester. 46 No increased rate of congenital anomalies among 284 infants whose mothers were administered amoxicillin or ampicillin during the 1st trimester, or in 1,060 infants whose mothers were treated at any time during pregnancy. 47 No significantly increased rate of major or minor anomalies in the children of 14 women treated with amoxicillin and probenecid during the first 14 weeks of gestation or among 57 women treated after the 14th week in a controlled clinical trial on the treatment of gonorrhea during pregnancy. 48 No adverse effects in offspring exposed to amoxicillin during the 2nd and 3rd trimesters in 3 controlled clinical trials of antibiotic treatment for premature preterm rupture of membranes. 49–51 An association of necrotizing enterocolitis in newborns and maternal amoxicillin and clavulanic acid treatment during the 3rd trimester was observed in a randomized controlled trial including 4,826 pregnant patients. 52,53 No increased congenital malformations in mice treated with 3–7 times the maximum human therapeutic dose of amoxicillin. 54 No adverse reproductive effects in rats given amoxicillin- clavulanic acid at doses of 400 and 1,200 mg/day prior to fertilization and during the first 7 days of gestation (Product information Amoxil, 2001). 55 No adverse fetal effects in pigs given amoxicillin with clavulanic acid at doses of 600 mg/kg on days 12–42. 56 Increased frequency of embryonic death in mice treated with amoxicillin at 6–7 times the maximum therapeutic human dose. 54 Increased risk of teratogenicity is "unlikely," based on "fair" data. B Chloramphenicol OR for major congenital anomalies 1.7 (95% CI 1.2–2.6) for oral administration at any time during pregnancy in a case- control study of 22,865 malformed infants (risk marginally increased). 57 RR for congenital malformations 1.19 (95% CI 0.52–2.31) in 348 offspring born to women who took chloramphenicol at any time during pregnancy (no statistically increased risk). 58 Potential for both dose-related and idiosyncratic bone marrow toxicity. Caution should be used near term, during labor, and while breastfeeding due to the possibility of inducing "gray-baby" syndrome. 59 No increased congenital anomalies in monkeys. 60 No teratogenicity in mice or rabbits at 10–40 times the recommended human dose. 61 No teratogenicity in rats at 2–4 times the usual human dose, 62 but various fetal anomalies at 10–40 times the human dose. 61,63 Increased fetal death and decreased fetal weight in mice, rats, and rabbits. 61–63 Increased risk of teratogenicity is "unlikely," based on "fair" data. "Therapeutic doses of chloramphenicol are unlikely to pose a substantial teratogenic risk." C ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1127

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