Ampicillin Vs. Penicillin for in Uterotherapy

Ampicillin Vs. Penicillin for In Utero Therapy

Douglas D. Glover, David Lalka, and Gilles R.G. Monif Department of Obstetrics and Gynecology, West Virginia University School of Medicine (D.D.G.), and Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy (D.D.G., D.L.), Robert C. Byrd Health Sciences Center, Morgantow)n, WV; Department of Obstetrics and Gynecology, Creighton University School of Medicine, Omaha, NE (G.R.G.M.)

ABSTRACT

KEy WORDS Pharmacokinetics, benzylpenicillin, penicillin G, [3-1actams, GBS prophylaxis

he molecular structure of the penicillins con- LITERATURE REVIEW sists of a thiazolidine ring connected to a A review of the literature on penicillin G and ampi- [3-1actam ring attached to a side chain. The side cillin reveals a dearth of pharmacokinetic data on chain determines many of the pharmacologic char- penicillin G in pregnant subjects and extensive data acteristics of a given penicillin. The presence of an on ampicillin in such patients. 2-9 A partial explana- amino group on the benzyl side chain distinguishes tion emanates from the fact that penicillin G was ampicillin from benzylpenicillin (penicillin G), widely used prior to the evolution of pharmacoki- which is one example of the many chemical variants netics into a distinct discipline. When ampicillin of penicillin resulting from alterations of this side was introduced in the early 1960s, pharmacokinetics chain attached to the basic 6 amino-penicillinoic was the "new kid on the block," thus having the acid molecule. benefit of investigation through these newly Recently, the issue of the relative superiority evolved scientific methods. Being the focus of at- of penicillin G vs. ampicillin for in utero therapy tention in the literature, ampicillin came to be con- has been raised. Amstey and Gibbs wrote an edi- sidered the [3-1actam of choice and the utilization torial opinion stating that the "favorable pharmaco- of penicillin G gradually faded. kinetics of penicillin G and its narrower and specific spectrum make this a better choice for THEORETICAL FACTORS GOVERNING group B streptococcal (GBS) prophylaxis than TRANSPORT OF ANTIBIOTICS ACROSS ampicillin This editorial opinion has stimu- THE PLACENTAL BARRIER lated a growing ambiguity about the peripartal use Anatomically, the placenta is composed of ectoder- of ampicillin. The purpose of this review is to exam- mal cells, a basement membrane, mesodermally de- ine the key points of these contentions and, in so rived tissue, another basement membrane, and fetal doing, clarify the issue of ampicillin vs. penicillin endothelial cells. The only other embryologic G for in utero therapy and GBS prophylaxis. structure in the human body derived from ectoderm

Address correspondence/reprint requests to Dr. Gilles R.G. Monif, Department of Obstetrics and Gynecology, Creighton University School of Medicine, 601 No. 30th Street, Suite 4700, Omaha, NE 68131. Received December 18, 1995 Review Article Accepted December 19, 1995 AMPICILLIN VS. PENICILLIN FOR IN UTERO THERAPY GLOVER ET AL. and mesoderm as opposed to mesoderm and endo- tally, these characteristics simply slow the rate of derm is the choroid plexus. Not surprisingly, the placental transfer but do not prevent such transfer. antibiotic transports across these 2 membranes strongly parallel each other. The factors governing COMPARATIVE PHARMACOKINETICS OF antibiotic transport across the placental are 1) mo- AMPICILLIN AND PENICILLIN G IN lecular size, 2) degree of protein binding, 3) degree PREGNANCY of ionization, and 4) lipid solubility. Intravenous Administration A review of the literature failed to identify any Molecular Size comparative pharmacokinetic studies of ampicillin The comparability of the size of penicillin G and and penicillin G in pregnant subjects receiving both ampicillin is such that this factor per se is not a drugs intravenously. Hence, direct intraindividual significant determinant for differential transport of comparison of parameters such as volume of distri- these 2 antibiotics. bution, clearance, and half-life has not been made. Indeed, a recent review of this topic suggested that Degree of Protein Binding much of our knowledge of penicillin G pharmacoki- Penicillin G is moderately bound to albumin in the netics in pregnancy is based on a number of very sera of normal and pregnant subjects (65% bound early and semiquantitative reports, compared with ampicillin's 20%). 3,5,7 To be pharmacologically active, an antibiotic must exist in its Intramuscular Administration unbound state. The amount of antibiotic available In what is perhaps the most comprehensive compar- for transport in a given time is a direct function of ative study of these 2 drugs, identical intramuscular the concentration of free drug. Once the antibiotic doses were given at various times during pregnancy is removed by transport, the equilibrium between with maternal, fetal, and amniotic-fluid sampling. bound and unbound drug is reestablished. The free Ampicillin appears to yield consistently higher (ap- drug entering the fetal vascular compartment and proximately 50%) maternal and fetal serum concen- amniotic fluid is once again subjected to similar trations than penicillin G. However, its level in protein binding interactions which reduce the amniotic fluid is substantially lower than that of amount of antibiotic available for biologic activity. penicillin G during the first 2 h following adminis- One of the keys to effective in utero therapy con- tration. After 3 h, superior and ultimately therapeu- cerns how much pharmacologically active antibiotic tic concentrations of ampicillin appear in the amni- appropriate to the bacteria in question can be deliv- otic fluid. ered in a relatively limited time. Ampicillin Pharmacokinetics Degree of Ionization In contrast to penicillin G, the pharmacokinetics of Both penicillin G (pKa 2.8 for its free carboxylic- ampicillin have been studied thoroughly, z'8'9 It has acid group) and ampicillin (pKa 2.5 for its free been established that pregnant women exhibit renal carboxylic-acid group and pKa 7.2 for its free clearances and total body clearances that are about amino group) are highly ionized (>99.9%) under 50% greater than those under control conditions. physiologic conditions. 1 Thus, this factor has little These control studies were performed 3-12 months impact on defining the relative rate of placental after delivery when normal menstruation had re- transfer. sumed and breast-feeding had ceased. The oral bio- availability was very similar during pregnancy and Lipid Solubility 3-12 months postpartum (approximately 50%), and Both penicillin and ampicillin antibiotics exhibit the recovery of the drug in the urine was essentially only moderate lipophilicity. The oil/water partition unaffected by pregnancy. 6'7 Furthermore, studies of coefficients (Ko/w) are 0.55 and 0.16 for penicillin G the reproducibility of ampicillin levels following and ampicillin, respectively (isobutanol vs. repeated administration of the drug to the same pH 7.4 aqueous buffer). 1 However, in general, a subject have demonstrated the dose proportionality difference of a factor of 3-4 in Ko/w will have only of the area under the plasma-concentration time moderate effects on drug permeability. Fundamen- curve. Studies of the serum concentration in the

44 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY AMPICILLIN VS. PENICILLIN FOR IN UTERO THERAPY GLOVER ET AL. mother following the administration of the drug into gence of a resistant subpopulation of a previously the amniotic fluid have been performed. susceptible strain which then becomes the domi- Finally, MacAulay et al. studied the transfer- nant population. A prime example of this phenome- ence of ampicillin within the maternal serum, fetal non was the abuse of kanamycin during the 1970s serum, and amniotic-fluid compartments. A transfer in newborn intensive care units (NICUs) which occurs from mother to fetus within minutes, but resulted in K. pneumoniae isolates that were resistant the antibiotic concentrations in the amniotic fluid to virtually all the aminoglycosides available at that are minimal for 60 min and potentially therapeutic time. Another prime example of induced resistance levels for susceptible bacteria are not achieved until is the change in the avidity of binding of penicillin 90 min has elapsed. Therefore, the amniotic fluid to the penicillin-binding proteins of selected strains appears to become a depository for the ampicillin. of Streptococcus pneumoniae. USE OF PENICILLIN G VS. AMPICILLIN FOR Intrinsic Resistance GBS PROPHYLAXIS If an antibiotic is used against a bacterium whose Spectrum of Susceptibility spectrum of susceptibility is not encompassed by Once pharmacologically significant levels of an anti- that drug, one cannot anticipate having a true bio- biotic are attained in the fetal compartment, the key logic effect. Approximately 35-40% of all current question governing the biologic effectiveness is the E. coli isolates are resistant to ampicillin. This resis- spectrum of susceptibility of the organism involved. tance is mediated primarily by the presence of sig- Both penicillin G and ampicillin share a common nificant quantities of [3-1actamases within the peri- spectrum of activity against gram-positive bacteria. plasmic space. More than 95% of all K. pneumoniae However, minor differences exist. For example, the isolates are similarly inherently resistant to ampicil- minimum inhibitor concentrations (MIC) for ampi- lin. When isolated instances of disease due to En- cillin are lower for enterococci and Listeria monocyto- terobacteriaceae occur in the face of ampicillin ther- logenes, whereas penicillin G is more effective than apy, the probability is that the same pattern of ampicillin for hemolytic streptococci. This superior disease would have been observed had ampicillin MIC for the [3-hemolytic streptococci does not nec- not been given. Unless one is dealing with a phe- essarily translate into biologic significance. The clear nomenon such as anaerobic progression or the use difference between penicillin G and ampicillin is the of antibiotics which has an impact on 30S or 50S latter's extended spectrum for gram-negative bacte- ribosomes, ineffective antibiotics will not alter the ria, specifically Escherichia coli, Proteus mirabilis, Sal- progress of monoetiologic disease. monella species, and Haemophilus influenzae. Drug chemoprophylaxis with ampicillin alters The concept of ampicillin's selecting for resis- the incidence of disease by diminishing the denom- tance emanates from a case series published by inator, thus magnifying the impact of the numera- McDuffie et al. lz These authors reported 4 cases of tor. As a consequence, perception of the relative Enterobacteriaceae chorioamnionitis in gravidas who importance of an isolate is changed. McDuffie et had received ampicillin prophylaxis for premature al. lz could not adequately approximate the number rupture of the fetal membranes and GBS carriage. of cases of perinatal septicemia adequately treated Three of the isolates were E. coli. The fourth case with ampicillin. Therefore, no rigorous risk/benefit was due to Klebsiella pneumoniae. Two of the resul- analysis can be performed. tant neonates died with fulminant perinatal septicemia. The rationale for publication of their manu- CONCLUSIONS script was the contention that these isolates were Because of the limited comparative data available examples of "adverse perinatal outcomes due to for penicillin G, it is overly assertive to contend selection or overgrowth of resistant organisms re- that the pharmacokinetic advantages of penicillin sulting from the use of ampicillin." G in pregnancy warrant its selection over ampicillin. Similary, the data regarding the spectrum of suscep- Induced Resistance tibility clearly show that ampicillin is the more ver- Prolonged use (especially associated with subopti- satile antibiotic, while the available data on the mal dosing) of an antibiotic can select for the emer- selection of resistant stains are best regarded as

INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 45 AMPICILLIN VS. PENICILLIN FOR IN UTERO THERAPY GLOVER ET AL. tentative such that validation through prospective women following administration of ampicillin and pi- study is required. Thus, it appears that ampicillin vampicillin. Am J Obstet Gynecol 130:674-683, 1978. 8. Mandell GL, Sande MA: Antimicrobial agents: Penicil- is to penicillin G in the clinical settings of superior lins, cephalosporins and other beta-lactam antibiotics. in utero therapy. In Gilman AG, Rall TW, Nies AS, et al. (eds): The Pharmacological Bases of Therapeutics. 8th ed. Elms- REFERENCES ford, NY: Pergamon Press, pp 1080-1085, 1990. 1. Amstey MS, Gibbs RS: Is penicillin a better choice than 9. MacAulay MA, Abour-Sabe M, Charles D: Transplacen- ampicillin for prophylaxis of neonatal group B streptococ- tal transfer of ampicillin. Am J Obstet Gynecol 96:943- cal infections? Obstet Gynecl 84:1058-1059, 1994. 950, 1966. 2. Nau H: Clinical pharmacokinetics in pregnancy and peri- 10. Williams DA: pkA values for some drugs and miscellane- natology. II. Penicillins. Dev Pharmacol Ther 10:176- ous organic acids and bases. In Foye WO, Lemke TL, 188, 1987. Williams DA (eds): Principles of Medicinal Chemistry. 3. Eleck E, Ivan B, Arr M: Passage of the penicillins from 4th ed. Media, PA: Williams & Wilkins, pp 948-961, mother to fetus in humans. Int Clin Pharmacol Ther 1995. Toxicol 63:223-228, 1972. 11. Weihrauch TR, Kohler H, Hoffler D: Cerebral toxicity 4. Hockert O, Nummi S, Vuopala S, Jarvinen P: Transpla- of penicillins in relation to their hydrophobic character. cental passage of azidocillin, ampicillin and penicillin to Naunyn-Schmiedebergs Arch Pharmakol 289:55-64, an early and late pregnancy. Scand J Infect Dis 2:125- 1975. 130, 1970. 12. McDuffie RS, McGregor JA, Gibbs RS: Adverse perina- 5. Campbell B, Cox S: The penicillins. Obstet Gynecol tal outcome and resistant Enterobacteriaceae after antibi- Clin North Am 19:435-447, 1992. otic usage for premature rupture of the membranes and 6. Philipson A: Pharmacokinetics of ampicillin during preg- group B streptococcus carriage. Obstet Gynecol 82:487- nancy. J Infect Dis 136:370-376, 1977. 489, 1993. 7. Philipson A: Plasma levels of ampicillin in pregnant

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