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ORIGINAL RESEARCH |
From the Department of Epidemiology and Center for Molecular and Clinical Epidemiology of Infectious Diseases, University of Michigan School of Public Health, Ann Arbor, Michigan; Department of Pathology, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas; and Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan.
Address reprint requests to: Mark D. Pearlman, MD, University of Michigan Medical School, L4000 Women’s Hospital, Department of Obstetrics and Gynecology, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0276; E-mail: pearlman{at}umich.edu.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: A total of 117 sequential group B streptococcus isolates were obtained between August 1999 and March 2000 from pregnant women at the University of Michigan Medical Center. Serotype and susceptibility to ten antimicrobials using disk diffusion with E-test for confirmation were determined, and the association between several host factors and colonization with a resistant strain was evaluated.
RESULTS: Group B streptococcus was frequently resistant to erythromycin (29%) and clindamycin (21%) but was susceptible to all other antimicrobials tested. A stepwise logistic regression model revealed that black ethnicity (P = .02) and carriage of a serotype V strain (P = .01) were associated with group B streptococcus resistance.
CONCLUSION: Among this population of pregnant women, black ethnicity and serotype V were the strongest predictors of colonization with an erythromycin- or clindamycin-resistant group B streptococcus strain. A better understanding of factors associated with antibiotic resistance is needed to minimize group B streptococcus disease risks and to maximize effective chemoprophylaxis.
Since the widespread adoption of intrapartum chemoprophylaxis, the incidence of early-onset neonatal disease caused by group B streptococcus has decreased significantly.1,2 Nonetheless, group B streptococcus disease still remains a problem: An active, population-based surveillance system identified 345 pregnant woman and 2196 newborns with invasive group B streptococcus disease between 1993 and 1998.2 Obstetric care providers use one of two strategies to identify candidates for antibiotics during labor and delivery: a screening approach using vaginal and rectal cultures for group B streptococcus collected between 35 and 37 weeks’ gestation, and a risk-based approach targeting women with factors enhancing risk of neonatal group B streptococcus disease. Consequently, 27% of women receive antibiotics during labor and delivery1,3; some argue that this may increase the risk of the development of antibiotic resistance.
Penicillin is currently the chemoprophylactic agent of choice, but penicillin-resistant group B streptococcus may emerge, and this possibility causes concern. Alternative antibiotics, such as erythromycin and clindamycin, are currently used among as many as 12% of women who report an allergy to penicillin4; however, many group B streptococcus strains are resistant to these agents as well. In 1997, 15% and 16% of genitourinary group B streptococcus isolates from pregnant women presenting to the University of Michigan Medical Center were resistant to erythromycin and clindamycin, respectively.4 Two years later, resistance rates among group B streptococcus isolates from healthy young men and women living in Michigan were 29% to erythromycin and 18% to clindamycin.5 Resistance to these agents appears to be increasing nationwide.6,7
Although there are no studies specifically addressing factors influencing macrolide and lincosamide resistance in group B streptococcus, studies of other organisms have identified previous antibiotic use as the primary factor.8 For Streptococcus pneumoniae, host characteristics, such as young age, female gender, winter season,9 and having a child attend day-care,10 also are associated with decreased antibiotic susceptibilities. Here, we describe the frequency of erythromycin and clindamycin resistance among sequential group B streptococcus isolates from pregnant women at the University of Michigan Medical Center and its association with several patient characteristics.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We obtained group B streptococcus isolates from 103 pregnant women; five of these women were cultured during labor and delivery. Forty women were undergoing routine prenatal group B streptococcus screening, 50 had urine cultures performed, most likely because of a positive dipstick test or because they presented with symptoms, and the remaining 13 were cultured for unknown reasons. Several women were cultured more than once during their pregnancy and therefore had several specimens from different dates. Because of this, the woman rather than the isolate was used as the unit of analysis (each person was included only once) for all statistical analyses examining associations between sociodemographic factors and group B streptococcus resistance. The Institutional Review Board at the University of Michigan Medical School approved the study protocol.
Various clinical units at University of Michigan Medical Center collected the urine, vaginal, cervical, rectal, perineal, endometrial, and placental specimens using a transport swab (CultureSwab Collection and Transport System; Becton-Dickinson, Sparks, MD). After collection, the swab was inserted into Todd-Hewitt broth containing 15 µg/mL of amikacin. The University of Michigan Medical Center Microbiology Laboratory incubated the swab overnight at 37C in CO2. Specimens with evident bacterial growth were subcultured to 5% sheep blood trypticase soy agar and incubated in 5% CO2 overnight. Plates were inspected for colonies having morphology and hemolysis consistent with group B streptococcus; typical isolates were confirmed as group B streptococcus using the Slidex Strepto B Kit (BioMerieux Vitek, Hazlewood, MO) as described previously.11,12
Serotyping of group B streptococcus strains by capsular type Ia, Ib, II–VII was conducted as described previously11,12 using the Lancefield capillary precipitin method.
All group B streptococcus isolates were tested for susceptibilities to the following ten antimicrobials: penicillin (10 IU), ampicillin (10 µg), levofloxacin (5 µg), quinupristin-dalfopristin (15 µg), imipenem (10 µg), cefazolin (30 µg), vancomycin (30 µg), clindamycin (2 µg), erythromycin (15 µg) (Baltimore Biological Laboratories, Sparks, MD), and linezolid (30 µg) (Pharmacia Upjohn, Kalamazoo, MI). The disk diffusion method was used as described previously.5 Those strains demonstrating resistance or intermediate resistance were retested using E-test strips (AB Biodisk, NA, Piscataway, NJ) to obtain the minimum inhibitory concentration. The National Committee for Clinical Laboratory Standards guidelines were used to interpret the disk diffusion13 and minimum inhibitory concentration results.14 Break points for cefazolin and imipenem were described previously5; those used for linezolid were 21 or more mm = susceptible, 18–20 mm = intermediate, and up to 17 mm = resistant.
Proportions were used to describe the frequency of antibiotic resistant group B streptococcus strains at the time the 103 women were first identified as carrying a group B streptococcus strain. Associations between carriage of a resistant strain and gestational age of fetus at time of culture, age, ethnicity, marital status, number of children, number of pregnancies, medical procedure performed, and serotype were tested using the 
2 test. Crude prevalence ratios were calculated for each variable. We used stepwise logistic regression to identify the strongest predictors of colonization with a resistant strain. SAS 8e for Windows (SAS Institute Inc., Cary, NC) was used for all statistical analyses.
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RESULTS |
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A total of 117 group B streptococcus isolates were obtained from 103 pregnant women who had a specimen submitted for culture for any reason. These isolates were obtained from different sites at various times. At the initial visit, 52 of the group B streptococcus strains (50%) were isolated from the urine, whereas 24 (23%) were isolated from the rectum and its surrounding area (ie, the perineum, anal orifice). Twenty-two isolates (21%) were obtained from the vagina and cervix and thus were considered to have originated from the same area. A vaginal/rectal specimen using the same swab was obtained from four women; for our analyses these were categorized as rectal specimens. A placental specimen was obtained from five women at delivery. Six (6%) of these women had more than one specimen obtained from more than one site at the first visit. An additional 14 isolates were obtained from women receiving a repeat culture on a different date. Half of these originated from the urine.
Thirty (29%) of the consecutive group B streptococcus isolates collected from 103 pregnant women were resistant to erythromycin, and 22 (21%) were resistant to clindamycin at the initial visit. All 22 isolates resistant to clindamycin also were resistant to erythromycin, whereas eight were resistant only to erythromycin. Each group B streptococcus isolate was susceptible to penicillin, ampicillin, levofloxacin, cefazolin, imipenem, quinipristine-dalfopristine, vancomycin, and linezolid. Several strains, however, had intermediate resistance to erythromycin (n = 12) and penicillin (n = 8) by disk diffusion. The minimum inhibitory concentration results demonstrated that these strains with intermediate resistance actually were resistant to erythromycin but susceptible to penicillin. Among those women who returned for another visit (n = 10), four had group B streptococcus that remained susceptible to every antibiotic tested, five continued to carry a group B streptococcus-resistant strain, and one acquired a resistant strain between the first and second office visit. Three of the five women who continued to carry a resistant group B streptococcus strain had repeat cultures performed at three different office visits.
Eight of the nine group B streptococcus serotypes were represented in this sample. Among the 103 group B streptococcus isolates obtained from the 103 women at the initial visit, serotypes III (n = 20) and V (n = 21) predominated, whereas serotypes Ia (n = 19), Ib/c (n = 11), II (n = 11), IV (n = 1), VI (n = 2), and nontypeable (n = 18) were also found. All six women who were colonized in more than one site at the initial visit had the identical serotype in both sites. Similarly, all 14 women cultured at multiple time points were colonized with the identical serotype as at the first visit. Those women colonized with a serotype V group B streptococcus strain were 13 times (P = .01) more likely to be carrying a strain resistant to erythromycin or clindamycin (41%) than those women colonized with a serotype II strain (3%). Nine black women carried resistant group B streptococcus strains, two with serotype V, both resistant. Seventeen white women were colonized with resistant strains; seven of the 14 strains from the women with serotype V strains were resistant.
Because only eight women had strains resistant to erythromycin alone, carriage of any resistant strain was the outcome for this analysis, as there was not sufficient power to detect associations with erythromycin resistance separately.
Unmarried women (prevalence ratio: 2.3, P = .006) less than 25 years of age (prevalence ratio: 1.9, P = .03) carried resistant group B streptococcus strains more frequently (Table 1
). Black ethnicity also had a positive crude association with resistance (prevalence ratio: 2.0, P = .04); however, ethnicity was highly associated with marital status and age. Stratifying age by ethnicity and marital status showed that unmarried black women less than 25 years old were more likely to carry a resistant strain (Figure 1). There was no difference in the prevalence of group B streptococcus resistance by age among married and unmarried white women. Women who had been pregnant multiple times also carried a resistant group B streptococcus strain more frequently, although the association was not statistically significant. Culture site, medical procedure performed, and gestational age of the fetus at time of culture were not associated with resistance. Previous history of antibiotic use could not be assessed, as a validation showed that the medical record was not a reliable source for this information.
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Another interesting finding was that women colonized with a resistant group B streptococcus strain at the initial visit were 3.7 times (95% confidence interval, 0.83, 16.84, P = .05) more likely to be cultured again at a second visit. The number of women returning for a second visit is small and all women were not followed throughout their entire pregnancy, therefore this estimate should be interpreted with caution.
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DISCUSSION |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Resistance rates appear to be higher among black women, although our sample size was small and our power to detect the observed crude association of 2.0 for black ethnicity with a two-sided 
of .05 was approximately 53%. Thus, these results require confirmation. In 1998, a random digit dialing survey conducted on women in the United States revealed that 83% of black women compared with 55% of white women consulted a health care professional regarding a recent episode of vaginal symptoms.19 Thus, it is possible that black women were treated previously with antibiotics more frequently than white women because they more readily sought health care. Because previous exposure to antibiotics is the most important factor in the emergence of antibiotic resistance,8 it is one possible explanation for this observation. Unfortunately, we were not able to evaluate the role of recent antibiotic use for this study. Further, black women were more likely than white women to carry group B streptococcus in one study.20 A higher rate of group B streptococcus colonization in conjunction with greater antibiotic exposure rates may increase the selective pressure for developing antibiotic resistance.
The crude analysis suggested that unmarried women (P = .006) less than 25 years of age (P = .03) were more likely to carry a resistant group B streptococcus strain, although only younger age approached statistical significance when added to the model (P = .06). Because most of the younger women in this study were not married, it is possible that they engaged in different behaviors than the older, married women (such as douching) that may alter the balance of the vaginal flora.21 Again, the sample size is small, and further studies are needed to confirm these findings.
Group B streptococcus cultured from different anatomical sites may have different potential for resistance development; for example, some antibiotics concentrate in the urine. Half of the isolates in our collection were cultured from the urine. Presumably the urine cultures were ordered in response to patient symptoms or following a positive urine screen for nitrates and red or white blood cells, which is common during pregnancy. Further, not all pregnant women were screened for group B streptococcus; thus, the frequency of resistance among our strains probably is not generalizable to other pregnant women and certainly not to the general population. Our goal, however, was to describe factors associated with resistant group B streptococcus strains, and we believe these factors would be relevant to group B streptococcus strains isolated from individuals with similar characteristics.
Until a safe and effective group B streptococcus vaccine is marketed, widespread intrapartum chemoprophylaxis is required to reduce the incidence of group B streptococcus disease in newborns less than 7 days of age (early-onset disease). Because resistance rates to alternative antibiotics, such as erythromycin and clindamycin, are rising,6,7 this will be increasingly difficult. A better understanding of risk factors for group B streptococcus disease and for antibiotic resistance is needed to minimize disease risks and maximize effective prevention in the interim. Meanwhile, the use of clindamycin should be reserved only for those women with susceptible strains, and women with penicillin allergies should receive cefazolin to ensure effective disease prevention.22 Because of poor fetal compartment penetration, erythromycin is less desirable than clindamycin for prophylaxis in penicillin-allergic women.23
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Footnotes |
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The authors thank the laboratory staff at the University of Michigan Medical Center Microbiology Laboratory for processing the bacterial specimens, Melissa Hickman for serotyping the isolates, and Pharmacia Upjohn for providing the linezolid at no charge.
Received March 21, 2002. Received in revised form June 6, 2002. Accepted June 27, 2002.
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REFERENCES |
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2. 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.
3. Rouse DJ, Goldenberg RL, Cliver SP, Cutter GR, Mennemeyer ST, Fargason CA Jr. Strategies for the prevention of early-onset neonatal group B streptococcal sepsis: A decision analysis. Obstet Gynecol 1994;83:483–94.[Abstract]
4. Pearlman MD, Pierson CL, Faix RG. Frequent resistance of clinical group B streptococci isolates to clindamycin and erythromycin. Obstet Gynecol 1998;92:258–61.[Abstract]
5. Manning SD, Pearlman MD, Tallman P, Pierson CL, Foxman B. The frequency of antibiotic resistance among group B streptococcus isolated from healthy college students. Clin Infect Dis 2001;33:E137–9.[Medline]
6. 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.[Medline]
7. Farley MM. Group B streptococcal disease in nonpregnant adults. Clin Infect Dis 2001;33:556–61.[Medline]
8. Hoban DJ, Doern GV, Fluit AC, Roussel-Delvallez M, Jones RN. Worldwide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin Infect Dis 2001;32: S81–93.
9. Yagupsky P, Porat N, Fraser D, Prajgrod F, Merires M, McGee L, et al. Acquisition, carriage and transmission of pneumococci with decreased antibiotic susceptibility in young children attending a day care facility in southern Israel. J Infect Dis 1998;177:1003–12.[Medline]
10. Kronenberger CB, Hoffman RE, Lezotte DC, Marine WM. Invasive penicillin-resistant pneumococcal infections: A prevalence and historical cohort study. Emerg Infect Dis 1996;2:121–123.[Medline]
11. Bliss SJ, Manning SD, Tallman P, Baker CJ, Pearlman MD, Marrs CF, Foxman B. Group B streptococcus colonization in male and non-pregnant female University students: A cross-sectional prevalence study. Clin Infect Dis 2002;34:184–90.[Medline]
12. Manning SD, Tallman P, Baker CJ, Gillespie B, Marrs CF, Foxman B. Determinants of co-colonization with group B streptococcus among heterosexual college couples. Epidemiology 2002;13:533–9.[Medline]
13. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk susceptibility tests. Approved standard M2-A7. Wayne, PA: National Committee for Clinical Laboratory Standards, 2000.
14. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: Approved standard-fifth edition. NCCLS document M7-A5. Wayne, PA: National Committee for Clinical Laboratory Standards, 2000.
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16. Hickman ME, Rench MA, Ferrieri P, Baker CJ. Changing epidemiology of group B streptococcal colonization. Pediatrics 1999;104:203–9.
17. Zaleznik DF, Rench MA, Hillier S, Krohn MA, Platt R, Lee ML, et al. Invasive disease due to group B streptococcus in pregnant women and neonates from diverse population groups. Clin Infect Dis 2000;30:276–81.[Medline]
18. Elliott JA, Farmer KD, Facklam RR. Sudden increase in isolation of group B streptococci, serotype V, is not due to emergence of a new pulsed-field gel electrophoresis type. J Clin Microbiol 1998;36:2115–6.
19. Foxman B, Marsh JV, Gillespie B, Sobel JD. Frequency and response to vaginal symptoms among white and African American women: Results of a random digit dialing survey. J Womens Health 1998;7:1167–74.[Medline]
20. Beachler CW, Baker CJ, Kasper DL, Fleming DK, Webb BJ, Yow MD. Group B streptococcal colonization and antibody status in lower socioeconomic parturient women. Am J Obstet Gynecol 1979;133:171–3.[Medline]
21. Onderdonk AB, Delaney ML, Hinkson PL, Dubois AM. Quantitative and qualitative effects of douche preparations on vaginal microflora. Obstet Gynecol 1992;80:333–8.[Abstract]
22. Committee on Infectious Diseases American Academy of Pediatrics. In: Pickering LK, ed. 2000 red book. 2000:543.
23. Philipson A, Sabath LK, Charles D. Transplacental passage of erythromycin and clindamycin. N Engl J Med 1973;288:1219–21.
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