Group B streptococcus emerged during the 1970s as the leading cause of serious neonatal infection in the United States.1 Perinatal transmission can occur in 10–30% of women who are colonized, whereas invasive infection may result in 1–3% of cases. A 1990 US population study estimated the incidence of infant group B streptococcus infection to be 1.8 per 1000 live births, resulting in 310 deaths.2,3
During the 1990s, the incidence of disease caused by vertical transmission of group B streptococcus fell by 65%, to 0.6 cases per 1000 live births.4 The decline was attributed mainly to the effectiveness of intrapartum prophylaxis for women at risk for transmitting group B streptococcus infection. Several randomized, controlled clinical trials have demonstrated a significant reduction of neonatal sepsis by intrapartum chemoprophylaxis with ampicillin or penicillin.5–8 The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics both embraced the concept of intrapartum prophylaxis for group B streptococcus in 1992, but initially recommended different strategies for implementation. The Centers for Disease Control and Prevention, in concert with multiple organizations, issued consensus guidelines for intrapartum chemoprophylaxis in 1996.3 These guidelines identify patients at risk who would benefit most from intrapartum penicillin or ampicillin for group B streptococcus prophylaxis and recommend erythromycin or clindamycin as alternatives for mothers with a history of penicillin allergy.
Reports of high degrees of resistance to clindamycin and erythromycin by group B streptococcus have prompted significant concern about their selection as alternatives for women with significant penicillin allergy.9–11
Additionally, several reports have noted limited to poor transplacental delivery of erythromycin and clindamycin compared with the excellent delivery of penicillin to cord blood and amniotic fluid (AF).12–15
Recently, cefazolin has been suggested as a better alternative for women with a history of significant penicillin allergy because group B streptococcus resistance is rare, and risk of significant cross-allergenicity with penicillin is low (ranging from 2% to 7%).16 At this time, minimal pharmacokinetic data exist for cefazolin during pregnancy. In this study, we aimed to evaluate the intrapartum pharmacokinetics of cefazolin, including delivery to AF and cord plasma, and to ascertain whether adequate cefazolin concentrations are attained to meet or exceed the mean inhibitory concentration to suppress 90% of group B streptococcus strains (MIC90). According to the National Committee for Clinical Laboratory, minimal concentration of cefazolin that inhibits 90% or more of group B streptococcus strains (MIC90) is 0.5 μg/mL, whereas the MIC50 (concentration inhibiting more than 50% of strains) is 0.25 μg/mL. The MIC90 for ampicillin is 0.12 μg/mL and 0.25 μg/mL for both erythromycin and clindamycin.
MATERIALS AND METHODS
Term patients undergoing scheduled elective cesarean delivery between September 1999 and January 2001 were candidates for the study. Specific inclusion criteria comprised pregnant patients at term who were 18 years of age or older and not in labor. Women who had ruptured membranes, serious maternal illness, signs of infection, or a history of allergy to penicillin or cephalosporin were excluded. Twenty-six patients enrolled in the study. The Institutional Review Board of the University of Michigan Hospitals and Health Centers approved the study protocol, and informed consent was obtained from all patients and fathers of the babies.
Cefazolin was administered at five predetermined time intervals (0.5, 1, 2, 4, and 6 hours) before undergoing elective cesarean delivery (Table 1). A standard 1 g of cefazolin was infused intravenously. A convenience sampling (ie, nonrandomized and nonconsecutive) of at least five women were recruited for each predelivery dosing period. The women were selected and placed into the various time groups based on their availability to participate in the different time frames of the study. The concentration of cefazolin was then measured in maternal and umbilical cord plasma and in AF in relation to the time when the infusion was initiated. Amniotic fluid was aspirated with a sterile needle and syringe, either just before or just after uterine incision, but before amniotomy. Care was taken to avoid contamination with maternal blood. Amniotic fluid specimens contaminated with blood or meconium were excluded. Umbilical cord blood was collected by transumbilical puncture immediately after the delivery of the neonate with a sterile needle and syringe. A sample of maternal blood was drawn at the time of delivery in all cases. Although cefazolin dosing was given at a projected time before operative delivery, the results are reported as actual time elapsed from administration to delivery.
All samples were placed immediately on ice and were processed within 30 minutes of collection. The samples were centrifuged at 6000 G for approximately 2–3 minutes. The supernatants were then transferred into plastic centrifuge storage tubes and frozen at −70C until analyzed.
Cefazolin concentrations were determined using high-pressure liquid chromatography, which consisted of a LDC SpectroMonitor 3200, a Hitachi L6000 high-pressure pump, and a Shimadzu auto injector SIL-9A (Japan). The samples for plasma and AF were prepared according to a previously described method.17 The plasma sample (1 mL) was mixed with 0.5 mL of 0.4 M of hydrochloric acid and 0.2 mL of internal standard (cephalexin 3 mg/mL). This sample was then extracted with a mixture of chloroform-1-pentanol (3:1) and back extracted into 0.1 M of phosphate buffer (pH 7). The aqueous phase was injected into the chromatographic column. Cefazolin samples for a standard curve were prepared by dissolving and diluting analytical grade cefazolin in water to obtain the desired concentrations. These samples were run in parallel with the study samples.
The wavelength for optimal detection of the drug was 275 nm. The analytical sensitivity at this wavelength was 50 ng/mL. The mobile phase was a mixture of 0.02 M of sodium phosphate buffer (pH 3.8) and methanol (23:77). The flow rate was 1.0 mL/min. All sample results were determined with the use of a standard curve generated with known criteria. Proportions and 95% confidence intervals (CI) were performed in accordance with standard descriptions.18
Twenty-six women provided informed consent to participate in this investigation. The women ranged in age from 22 to 40 years (31 ± 5 years [mean ± standard deviation]). The gestational age at delivery was 39 ± 1 week (mean ± standard deviation). Of the 26 women, 20 were white, five were black, and one was Asian. The majority of the patients received regional spinal anesthesia (n = 18), whereas the remainder received epidural anesthesia (n = 8). Six underwent a primary cesarean delivery, five for breech presentation, and one for suspected macrosomia in a gestational diabetic. The remaining 20 women had elective repeat cesarean delivery. All but two women were multiparous. Eight women received their prenatal care through the resident clinic service, whereas the remaining women received their care through the various faculty practices.
The actual time intervals between cefazolin administration and delivery varied from 20 minutes to 7 hours (Figure 1). Cefazolin concentrations in maternal plasma ranged from 0.2 to 37.7 μg/mL. In 25 of 26 maternal specimens, the cefazolin concentration exceeded the mean inhibitory concentration to suppress 90% of group B streptococcus growth (MIC90), that is, 0.5 μg/mL.
Cord blood samples were obtained from 40 minutes to 7 hours after maternal administration (Figure 2). All except one cord plasma cefazolin concentration exceeded the MIC90 for group B streptococcus. Cefazolin concentrations in these specimens ranged from 0.1 to 11.9 μg/mL.
Six of the AF specimens were discarded because of contamination with blood, meconium, or both. Cefazolin concentrations in the remaining 20 specimens ranged from 0.3 to 3.9 μg/mL (Figure 3). Cefazolin levels in the AF exceeded the MIC90 in all except two cases. The maternal plasma cefazolin concentrations that equaled or exceeded the MIC90 were 25 of 26 or 0.96 (95% CI 0.89, 1.00). The cord plasma cefazolin concentrations that equaled or exceeded the MIC90 were 25 of 26 or 0.96 (95% CI 0.89, 1.00). Finally, the AF cefazolin concentrations that equaled or exceeded the MIC90 were 18 of 20 or 0.9 (95% CI 0.77, 1.00).
Of all specimens assayed, four (one maternal plasma, one cord plasma, and two AF) had cefazolin concentrations less than the MIC90 for group B streptococcus. It is notable that three (one maternal plasma, one cord plasma, and one AF) of these four came from one individual patient.
The placental transfer of cefazolin appears quite similar to that of ampicillin, with concentrations greater than the MIC90 achieved rapidly in maternal, cord, and AF compartments. This contrasts with the poor or unpredictable delivery of erythromycin and clindamycin to cord blood and AF. The attainment of the MIC90 for cefazolin against group B streptococcus in the body compartments at 4 hours after infusion is compared with that of other recommended antimicrobial agents for group B streptococcus prophylaxis in Figure 4.12,13,19
The cefazolin MIC90 for group B streptococcus was attained or exceeded by 30 minutes after completion of cefazolin infusion in all three compartments assayed. Samples obtained at later intervals also demonstrated concentration greater than the MIC90 as late as 7 hours after infusion, with the exception of the four specimens previously noted. Three of these four specimens came from a single patient. This patient had no unusual obstetric or medical problems that should affect cefazolin metabolism or distribution (eg, obesity or hypertension). Although these results cannot be explained with certainty, it is hypothesized that either the patient received considerably less cefazolin than anticipated, or she was an unusually rapid metabolizer of cefazolin. In all other study participants, the MIC90 was quickly and predictably attained in the maternal and cord plasma, though more variability was observed in the AF concentration. Bloom et al saw a similar phenomenon in ampicillin levels drawn in 40 women during elective cesarean delivery.19 We speculate that the variability in cefazolin levels may reflect the variability in fetal micturition or fetal antibiotic metabolism.
The disturbing increase in the frequency of resistance of group B streptococcus by clindamycin and erythromycin combined with data suggesting limited transplacental passage of these antibiotics have prompted concern about the efficacy of these agents in penicillin-allergic women. Fernandez et al studied 224 group B streptococcus isolates from neonates with either bacteremia or meningitis between 1992 and 1996, and found that all were susceptible to penicillin G, but 7.4% and 3.4% were resistant to erythromycin and clindamycin, respectively.9 Among 100 group B streptococcus strains isolated in 1997, Pearlman et al reported 16% and 15% resistance to erythromycin and clindamycin, respectively.10 Morales et al reported similar results, with 20% resistance to erythromycin and 15% resistance to clindamycin among 164 isolates in 1999.11 Neonatal deaths despite intrapartum prophylaxis with clindamycin have been attributed to group B streptococcus subsequently found to be resistant to this agent.
There has also been significant concern about the transplacental passage of clindamycin and erythromycin. Heikkinen et al studied 21 term placentas after delivery and found the mean transplacental transfer of erythromycin to be 3%.12 Philipson et al investigated the placental transfer of erythromycin and clindamycin and found that clindamycin attained therapeutic concentrations in cord blood but not in AF, whereas erythromycin failed to attain effective concentrations in either compartment.14
The use of a first-generation cephalosporin, such as cefazolin, may be a reasonable and cost-effective alternative to patients with a history of penicillin allergy, especially with the frequency of marked resistance and limited placental transfer of erythromycin and clindamycin. It has been reported that up to 80% of patients with penicillin allergies have a negative skin test when later tested for that allergy.20,21 Moreover, cefazolin, with its low frequency of cross-allergenicity to penicillin, appears to offer greater promise than erythromycin or clindamycin for preventing transmission of group B streptococcus infection. Although there is some concern about the cross-allergenicity of cephalosporin in patients with penicillin allergy, the potential risk of anaphylactic reaction appears to be low. The risk of anaphylaxis to penicillin has been estimated to occur in approximately one to five per 10,000 patients treated.20 The incidence of systemic anaphylaxis to cephalosporin drugs is less clear. However, one review involving 9388 patients who took either cephaloridine, cephalothin, or cephalexin and who had no history of prior penicillin allergy had a rate of anaphylaxis of two per 10,000.21 There have been several articles on the cross-allergenicity between penicillins and cephalosporins. In a study of 15,708 patients, Petz found that 4.5% had a history of allergy to penicillin, and 8.1% of these had an allergic reaction to administration of cephalosporin.22 Of the patients who did not have a penicillin allergy, 1.9% had an allergic reaction to cephalosporin. When looking at the specific cephalosporin used, the lowest amount of cross-allergenicity was with cefazolin (4%). In a report provided by Glaxo Pharmaceuticals in 1991, there were 3948 patients treated with ceftazidime, with 521 patients reporting a history of a penicillin allergy.20 Of the 11 penicillin-allergic patients who gave a history of anaphylactic or urticarial reactions, none had a reaction to ceftazidime. Of the remaining 510 penicillin-allergic patients, 14 patients had an allergic reaction when given ceftazidime. Three of these were anaphylactic or urticarial type reactions. There were no fatalities among any of these patients. Of the 3427 patients who had no history of penicillin allergy, 57 patients had an allergic reaction. Thus, the relative risk of developing any reaction to ceftazidime for penicillin-allergic patients was 1.66 compared with patients without reported allergies.
When weighing the risks and benefits in relation to the severity of neonatal group B streptococcus disease, the benefit of cefazolin with its low rate of cross-allergenicity may outweigh the risk of up to a 20% likelihood of resistance to the current recommended alternatives. Because of the unpredictability of life-threatening allergic reaction with administration of all drugs (including erythromycin and clindamycin), appropriate steps should be taken to assure the ability to respond rapidly in the event of a major allergic reaction.
This study indicates that intravenously administered cefazolin, like penicillin or ampicillin, is rapidly transferred from the maternal circulation to the fetal and AF compartments in concentrations that should offer outstanding antimicrobial efficacy.
1. McCracken GH Jr. Group B streptococci: The new challenge in neonatal infections. J Pediatr 1973;82:703–6.
2. American Academy of Pediatrics. Revised guidelines for prevention of early-onset group B streptococcal infection. Pediatrics 1997;99:489–98.
3. Centers for Disease Control. Prevention of perinatal group B streptococcal disease: A public health perspective. MMWR 1996;45(RR-7):1–24.
4. Schrag SJ, Zywicki S, Farley MM, Reingold AL, Harrison LH, Lefkowitz LB, et al. Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis. N Engl J Med 2000;342:15–20.
5. Siegel JD, Cushion NB. Prevention of early-onset group B streptococcal disease: Another look at single-dose penicillin at birth. Obstet Gynecol 1996;87.
6. Kauffman RE, Boulos BM, Azarnoff DL. Placental transfer of penicillin G during constant-rate infusion in the goat. Am J Obstet Gynecol 1973;117:64–8.
7. Depp R, Kind AC, Kirby WM, Johnson WL. Transplacental passage of methicillin and dicloxacillin into the fetus and amniotic fluid. Am J Obstet Gynecol 1970;107:1054–7.
8. Chamberlain A, White S, Bawdon R, Thomas S, Larsen B. Pharmacokinetics of ampicillin and sulbactam in pregnancy. Am J Obstet Gynecol 1993;168:667–73.
9. Fernandez M, Hickman ME, Baker CJ. Antimicrobial susceptibilities of group B streptococci isolated between 1992 and 1996 from patients with bacteremia or meningitis. Antimicrob Agents Chemother 1998;42:1517–9.
10. Pearlman MD, Pierson CL, Faix RG. Frequent resistance of clinical group B streptococci isolates to clindamycin and erythromycin. Obstet Gynecol 1998;92:258–61.
11. Morales WJ, Dickey SS, Bornick P, Lim DV. Change in antibiotic resistance of group B streptococcus: Impact on intrapartum management. Am J Obstet Gynecol 1999; 181:310–4.
12. Heikkinen T, Laine K, Neuvonen PJ, Ekblad U. The transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin. Br J Obstet Gynaecol 2000;107:770–5.
13. Weinstein AJ, Gibbs RS, Gallagher M. Placental transfer of clindamycin and gentamycin in term pregnancy. Am J Obstet Gynecol 1975;124:688–91.
14. Philipson A, Sabath LD, Charles D. Transplacental passage of erythromycin and clindamycin. Medical intelligence. N Engl J Med 1973;288:1219–21.
15. Kiefer L, Rubin A, McCox JB, Foltz EL. The placental transfer of erythromycin. Am J Obstet Gynecol 1955;69:174–7.
16. Effmeyer JE. Adverse reactions to penicillin. Ann Allergy 1981;47:288–300.
17. Brisson AM, Fourtilan JB. Determination of cephalosporins in biological materials by reverse-phase liquid column chromatography. J Chromatogr 1981;223:393–9.
18. Gardner MJ, Altman DG. Statistics with confidence—Confidence intervals and statistical guidelines. London: British Medical Journal; 1995:28–33.
19. Bloom SL, Cox MD, Bawdon RE, Gilstrap MD. Ampicillin for neonatal group B streptococcal prophylaxis: How rapidly can bactericidal concentrations be achieved? Am J Obstet Gynecol 1996;175:974–7.
20. Lin RY. A perspective on penicillin allergy. Arch Intern Med 1992;152:930.
21. Shephard GM. Allergy to beta-lactam antibiotics. Immun Allergy Clin North Amer 1991;11:611.
22. Petz LD. Immunologic reactions of humans to cephalosporins. Postgrad Med 1971;47:64–9.