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Title: High rates of perinatal Group B Streptococcus clindamycin and erythromycin resistance 1 in an Upstate NY hospital 2 3 Running Title: High rates of perinatal GBS clindamycin resistance 4 5 Authors: 6 Ephraim E. BACK, MD, MPH*, Department of Family Medicine, Ellis Hospital, Schenectady, 7 NY 8 Elisa J. O'GRADY, MT(ASCP), Clinical laboratory, Ellis Hospital, Schenectady, NY 9 Joshua D. BACK, BA, Department of Family Medicine, Ellis Hospital, Schenectady, NY 10 11 Address of Institution: 12 Ellis Hospital 13 624 McClellan Street 14 Schenectady, NY 12304 15 518-347-5067 business phone 16 518-452-0971 home phone 17 518-347-5007 fax 18 19 Corresponding Author:* 20 Ephraim E. Back, MD, MPH 21 Chairman, Department of Family Medicine 22 Ellis Hospital 23 624 McClellan Street 24 Schenectady, NY 12304 25 518-347-5067 phone 26 518-347-5007 fax 27 [email protected] 28 29 30 Abstract word count: 149 31 Text word count: 2364 32 33 Key Phrases: 34 Group B Streptococcus 35 Antibiotic resistance 36 Clindamycin 37 Erythromycin 38 Infection 39

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Copyright © 2011, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.Antimicrob. Agents Chemother. doi:10.1128/AAC.05794-11 AAC Accepts, published online ahead of print on 5 December 2011

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Abstract: 41

OBJECTIVE: To evaluate the rates of clindamycin and erythromycin resistance among Group 42

B Streptococcus (GBS) positive isolates cultured from pregnant women in an Upstate New York 43

community hospital. 44

STUDY DESIGN: All GBS positive perinatal rectovaginal cultures obtained from January 2010 45

through October 2011 were tested for resistance to erythromycin and clindamycin. 46

RESULTS: Among the 688 GBS positive cultures, clindamycin resistance was found in 38.4% 47

and erythromycin resistance was found in 50.7% of isolates. 48

CONCLUSION: Rates of GBS resistance to clindamycin and erythromycin are much higher 49

than reported in earlier US studies, suggesting both increasing resistance as well as regional 50

variation in resistance. These findings lend strong support to the CDC and ACOG 51

recommendations that clindamycin use for intrapartum antibiotic prophylaxis be restricted to 52

penicillin allergic women at high risk of anaphylaxis and that GBS isolates be tested for 53

antibiotic resistance prior to the use of clindamycin in these women. 54

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INTRODUCTION 56

Routine screening for maternal colonization by Group B Streptococcus (GBS) and 57

intrapartum treatment of infected mothers has been a significant public health success. 58

According to the Centers for Disease Control (CDC), the incidence of neonatal GBS infection, a 59

major cause of morbidity and mortality, has declined dramatically over the past 15 years, from 60

1.7 cases per 1,000 live births in the early 1990s to 0.34–0.37 cases per 1,000 live births in recent 61

years. The most recent perinatal GBS guidelines issued by the CDC in November 2010 uphold 62

previous antibiotic recommendations for the prophylactic treatment of GBS colonized women 63

during labor, except for the withdrawal of erythromycin as a second-line prophylactic antibiotic 64

for women with penicillin allergy (6). These recommendations have also been endorsed by the 65

American Congress of Obstetricians and Gynecologists (ACOG) in their recent committee 66

opinion issued in April 2011 (1). Per the CDC and ACOG recommendations, clindamycin is still 67

an acceptable alternative for women with penicillin allergy, provided that the GBS isolates have 68

been tested for clindamycin susceptibility (1,6). Although intrapartum antibiotic prophylactic 69

(IAP) treatment with penicillin and ampicillin has been shown to prevent early-onset GBS 70

disease in clinical trials, concerns have been raised regarding the ability of clindamycin, 71

erythromycin, and vancomycin to reliably reach bactericidal levels in the amniotic fluid, fetal 72

circulation, and fetal tissues. Additionally, according to the CDC guideline report, in vitro 73

resistance to both clindamycin and erythromycin has been increasing, with reports published 74

during 2006-2009 finding GBS resistance ranging from 25% to 32% for erythromycin and from 75

13% to 20% for clindamycin (6). 76

In May 2009, Ellis Hospital the only hospital with maternity services in Schenectady, 77

NY, initiated testing of all GBS isolates for resistance to both erythromycin and clindamycin. 78


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This initiative was started due to the inherent difficulties in determining which submitted isolates 79

were obtained from pregnant women with known penicillin allergy. Initial observations 80

following the adoption of this routine sensitivity testing revealed a higher rate of both 81

clindamycin and erythromycin resistance than had been reported elsewhere in the literature. As a 82

result, we began to collect GBS resistance data for all perinatal GBS isolates. This paper 83

summarizes our findings. 84

85

MATERIALS AND METHODS 86

All rectovaginal cultures obtained from pregnant women for GBS screening that were 87

submitted to the Ellis Hospital laboratory from January 2010 through October 2011 were 88

included in this study. GBS culture results and results of GBS isolate antimicrobial susceptibility 89

testing were reviewed retrospectively. Age and race of patients were ascertained from hospital 90

computerized registration records. Data was compiled onto a Microsoft Excel spreadsheet and 91

analyzed using EpiInfo 3.5.3 (CDC) epidemiologic software. Anova was used to test for 92

significant difference in ages between antibiotic resistant and antibiotic susceptible women. Chi-93

square was used to test for differences in racial composition between the groups. The study was 94

approved by the hospital’s institutional review board. 95

The Ellis Hospital laboratory followed accepted GBS culture techniques, as summarized 96

in the CDC recommendations (6). All rectovaginal swabs were tested by both direct plating and 97

enriched broth culture techniques. A sheep blood agar plate (BAP) was inoculated, followed by a 98

Lim broth. The BAP was incubated in 5% CO2; the Lim broth was incubated in ambient air. 99

Both were incubated at 35-37˚C for 18-24 hours. The BAP was then examined for colonies 100

morphologically consistent with GBS. A streptococcal grouping latex agglutination test was 101


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performed to definitively identify GBS. Negative cultures from the BAP direct plating were 102

incubated for another 18-24 hours in 5% CO2 at 35-37˚. In addition, the corresponding Lim broth 103

was then subcultured to a BAP and incubated in 5% CO2 at 35-37˚ for 18-24 hours. If both the 104

48 hour direct culture BAP and the 24 hour broth enrichment BAP were negative for GBS, the 105

culture was recorded as being GBS negative. If GBS was isolated from either the direct plating 106

or enriched broth culture techniques, the culture was recorded as being GBS positive. 107

Antibiotic susceptibility and inducible clindamycin testing were performed concurrently 108

on all GBS positive cultures. The disk diffusion methodology followed the recommendations of 109

the Clinical and Laboratory Standards Institute (CLSI) (8). 110

A 0.5 McFarland turbidity standard suspension of GBS was prepared from isolated GBS 111

colonies and used to inoculate a plate of Mueller-Hinton agar (with 5% sheep blood). After the 112

entire surface of the plate was swabbed three times, clindamycin (2 μg) and erythromycin (15 113

μg) disks were placed on the plate 15 mm apart, and the plates were then incubated at 35-37˚C in 114

5% CO2 for 20-24 hours. Presence of a “D-zone” on the plate (flattening of the zone of inhibition 115

adjacent to the erythromycin disk) was interpreted as evidence of inducible clindamycin 116

resistance. If there was no “D-zone” present, the zone size of each drug was measured and 117

recorded. Interpretation of GBS resistance followed CLSI recommendations. For clindamycin, a 118

zone size of ≥19mm is susceptible; 16-18 mm is intermediate; and ≤15 mm is resistant. For 119

erythromycin, a zone size of ≥21 mm is susceptible; 16-20 mm is intermediate; ≤15 mm is 120

resistant. Any intermediate susceptibility result was considered resistant for the purposes of this 121

study. 122

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RESULTS 125

The results of GBS and susceptibility testing are summarized in Figure 1. Physicians who 126

deliver patients at Ellis Hospital use either the Ellis Hospital laboratory or outside reference 127

laboratories to process rectovaginal GBS samples which are routinely obtained during the during 128

the third trimester of prenatal care. From January 2010 though October 2011, a total of 3,055 129

rectovaginal cultures were processed by the Ellis Hospital laboratory, representing 75.1% of all 130

women who delivered babies at the hospital during that time frame. Of the 679 (22.2%) GBS 131

positive isolates, 344 (50.7%; range 39.3% - 72.7%/month) were resistant to erythromycin and 132

261 (38.4%; range 25.0% - 54.5%/month) were resistant to clindamycin. Two GBS positive 133

isolates exhibited intermediate resistance to clindamycin and nine isolates had intermediate 134

resistance to erythromycin. Dual resistance of isolates to both organisms was high, with 94.3% 135

of clindamycin resistant isolates also exhibiting resistance to erythromycin and 71.5% of 136

erythromycin resistant isolates exhibiting resistance to clindamycin. 137

138

From April through October 2011, data was recorded separately for constitutive versus 139

inducible resistance. During this period, 94/105 (89.5%) of the clindamcyin resistant isolates 140

exhibited constitutive resistance and 11/105 (10.5) of the isolates exhibited inducible resistance. 141

142

The median age of women with GBS positive cultures was 28 years (range 15 to 48 143

years) with no significant difference in age between women with clindamycin and/or 144

erythromycin resistant isolates and those with susceptible isolates. Sixty six percent of the 145

women with GBS positive cultures were white, 17% were African American, 6% were Hispanic, 146


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and 11% were “other” or unknown. There was no significant difference in race between the 147

women with resistant isolates and those with susceptible ones. 148

149

DISCUSSION 150

While the rate of colonizing GBS among pregnant women in this study falls within the 151

range reported in the literature, the rates of resistance to both erythromycin and clindamycin 152

(50.7% and 38.4% respectively) are much higher than those reported in the studies published 153

during 2006-2009, which are cited in the 2010 CDC guidelines (25%-32% and 13%-20% 154

respectively) (1,4,6,8,17). Since the CDC first issued guidelines for universal perinatal GBS 155

screening in 2002 (5), studies from Texas, Michigan, Rhode Island, Connecticut, and Utah 156

reported rates of GBS resistance to erythromycin ranging from 10%-44% and resistance to 157

clindamycin ranging from 11%-26 % (2,7,10,12-13,16). We identified only one published study 158

which reported a rate of clindamycin resistance almost as high as the rate that we report. This 159

study from Ohio reported that of the 200 GBS isolates obtained between 2001-2004, 54% were 160

resistant to erythromycin and 33% were resistant to clindamycin (9). 161

It is likely that resistance rates for GBS, like those for other bacteria, vary regionally and 162

are influenced by antibiotic usage. The increase in clindamycin resistance parallels the marked 163

increase in methicillin-resistant Staphlococcus aureus (MRSA) and may be driven at least partly 164

by the reported 300% increase in clindamycin use for the treatment of MRSA infections over the 165

past decade (11). There is considerable evidence of increasing resistance of GBS to 166

clindamycin and erythromycin in both the general population (4,6) and among pregnant women 167

(15,16). For example, investigators from Connecticut reported a 400% increase in GBS 168

clindamycin resistance (from 5.3% to 21%) over a 7 year period from 2000-2007 (16,18). A 169


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2010 study from Utah which reports a relatively high rate of GBS resistance to erythromycin 170

(44%) and clindamycin (24%) for isolates collected between 2007-2008 is the most recent study 171

in the literature prior to our report (2). Our data was collected in 2010 and 2011 and may reflect 172

the increasing rate of GBS resistance, not yet reported from other areas of the US. 173

Although not explicitly discussed, the current CDC recommendation that erythromycin 174

should no longer be used for IAP is likely due to the high observed rate of erythromycin 175

resistance, a rate which is actually lower than the 38% clindamycin resistance rate that we found 176

among our GBS positive isolates. Even if the rates reported in the present study are not yet being 177

observed in other regions, the trend of increasing clindamycin resistance widely reported in the 178

last decade should prompt discussion regarding the elimination of clindamycin, like 179

erythromycin, as an option for IAP. 180

The high rates of antibiotic resistance that we found, along with the widely observed 181

trend of increasing antibiotic resistance, underscores the need for universal implementation of 182

the CDC guidelines recommending that GBS isolates be tested for antibiotic resistance prior to 183

initiating prophylaxis with clindamycin. Several studies have shown that although antenatal 184

screening and the use of IAP for GBS has increased, healthcare providers are not adequately 185

testing GBS isolates for resistance prior to administering erythromycin or clindamycin and are 186

not following the recommendations to use cefazolin in penicillin allergic women at low risk for 187

anaphylaxis. A 10-state study evaluating the implementation of the 2002 CDC guidelines among 188

women who delivered in 2003 and 2004 found that less than 1% of isolates from GBS colonized 189

women with reported penicillin allergy were tested for GBS susceptibility prior to IAP (19). In 190

this study, clindamycin was overwhelmingly used even in women who were at low risk for 191

anaphylaxis, while vancomycin was used in only 0.3% of all women receiving IAP. Similar 192


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findings were reported from a hospital system in Utah, where only 4% of 3,698 GBS positive 193

isolates obtained during 2007-2008 were tested for antimicrobial susceptibility (2). Although the 194

authors of this study did not state what percentage of women reported a history of penicillin 195

allergy, they analyzed a subset of hospitals with pharmacy information and found that GBS 196

susceptibility was known for only 38% of the women in these hospitals who received 197

clindamycin. 198

Although 10-30% of pregnant women are colonized with GBS, the attack rate of early 199

onset disease among infants was only 1.7 cases per 1,000 births even in the pre-IAP era (6). 200

Thus, even when using clindamycin prophylaxis in a woman colonized with clindamycin 201

resistant GBS, the vast majority of babies will not develop GBS infection. Yet, the consequences 202

will be dire for the rare infant who becomes infected, as illustrated by a case report from Utah 203

which described an infant who developed early onset clindamycin resistant GBS disease after his 204

mother had received prophylactic clindamycin (2). Both the failure to test the susceptibility of 205

GBS isolates from penicillin allergic women and the under-use of cefazolin to treat women at 206

low risk for anaphylaxis has led to the overuse of clindamycin, thereby increasing both the 207

number of infants inadequately protected from GBS infection and likely contributing to the 208

increased rates of antibiotic resistant GBS which have been reported over the past decade. 209

Both the 2002 and 2010 CDC guidelines recommend susceptibility testing only for GBS 210

positive isolates from penicillin allergic women who are at high risk for anaphylaxis (5,6). “Real 211

world” compliance with guidelines, though, is often suboptimal, especially without significant 212

institutional intervention. Following release of the 2002 CDC guidelines, our institution 213

developed a GBS laboratory requisition form that requested ordering physicians to identify 214

whether the patient had a penicillin allergy, but this information was not consistently provided 215


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and isolates from penicillin allergic women were not routinely tested for antibiotic susceptibility. 216

We were only successful in determining susceptibility for all GBS positive cultures from 217

penicillin allergic women by initiating universal susceptibility testing for all GBS isolates. This 218

approach, while slightly more expensive (estimated $3.38 to $5.88 per isolate at our institution, 219

accounting for both labor and supplies), may be a cost-effective alternative to be considered by 220

other institutions who are also grappling with attaining 100% compliance with CDC 221

recommendations. Although there is little recent data regarding the cost of caring for a child 222

with GBS disease, a California study published in 1999 estimated an economic cost (medical and 223

long-term sequelae) of $70,000 per case of early-onset GBS disease in a term infant, not 224

accounting for life-years lost (14). In addition to preventing the inappropriate use of 225

clindamycin, universal susceptibility testing has alerted us to the high rates of clindamycin 226

resistance at our institution, a benefit that we believe will be important in monitoring local GBS 227

resistance patterns in other institutions as well. 228

A strength of this study is that it is the largest published study in the past decade to report 229

GBS resistance data for rectovaginal cultures obtained from pregnant women. In addition, the 230

data for rates of antibiotic resistance was consistent during the 22 month data collection period. 231

The study is limited, however, by the fact that the sample was completely derived from a single 232

hospital in Upstate NY. As a result, it is not known how our results compare with those from 233

other geographic locations. We do believe, though, that it is likely that some geographic regions 234

have very high rates of GBS clindamycin resistance, similar to those that we found. Further 235

research is needed to determine if other local and regional rates of GBS antibiotic resistance are 236

indeed higher than those used by the CDC to formulate its IAP guidelines. If research confirms 237

higher and increasing rates of clindamycin resistance, the CDC and ACOG may need to consider 238


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revising the guidelines to limit the use of clindamycin as an acceptable antibiotic option for 239

intrapartum antibiotic prophylactic treatment. 240

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Figure Legends 306

Fig. 1: Total number of rectovaginal cultures and GBS positive cultures, and percentage of GBS 307

positive isolates resistant to erythromycin or clindamycin. 308


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