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Discontinuation of Secondary Prophylaxis for Pneumocystis carinii Pneumonia in Human Immunodeficiency Virus—Infected Patients: A Randomized Trial by the CIOP Study Group

  1. Cristina Mussini1,
  2. Patrizio Pezzotti4,
  3. Andrea Antinori6,
  4. Vanni Borghi1,
  5. Antonella d'Arminio Monforte7,
  6. Alessandra Govoni6,
  7. Andrea De Luca5,
  8. Adriana Ammassari5,
  9. Nicola Mongiardo1,
  10. Maria Chiara Cerri1,
  11. Andrea Bedini1,
  12. Cristina Beltrami8,
  13. Maria Alessandra Ursitti3,
  14. Teresa Bini7,
  15. Andrea Cossarizza2,
  16. Roberto Esposito1, and
  17. Changes in Opportunistic Prophylaxis (CIOP) Study Groupa
  1. 1Clinic of Infectious and Tropical Diseases, Azienda Ospedaliera Policlinico, Modena
  2. 2Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena
  3. 3Department of Infectious Diseases, S. Maria Nuova Hospital, Reggio Emilia
  4. 4Istituto Superiore di Sanita`, Rome
  5. 5Clinic of Infectious Diseases, Catholic University, Rome
  6. 6National Institute for Infectious Diseases “L. Spallanzani”, Rome
  7. 7Clinic of Infectious Diseases, University of Milan, Milan
  8. 8Clinic of Infectious Diseases, University of Bologna, Bologna, Italy
  1. Reprints or correspondence: Dr. Cristina Mussini, Clinic of Infectious and Tropical Diseases, Azienda Ospedaliera Policlinico, University of Modena and Reggio Emilia, Via del Pozzo, 71, 41100 Modena, Italy (crimuss{at}unimo.it).

  • ↵a Members of the study group are listed at the end of the text.

 
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Abstract

To evaluate whether bacterial vaginosis predicts the acquisition of sexually transmitted diseases (STDs), we studied 255 nonpregnant female subjects aged 15–30 who reported recent sexual contact with a male partner in whom either gonococcal or chlamydial urethritis or nongonococcal urethritis was diagnosed. Compared to subjects with normal vaginal flora, subjects with bacterial vaginosis were more likely to test positive for Neisseria gonorrhoeae (odds ratio [OR], 4.1; 95% confidence interval [CI], 1.7–9.7) and Chlamydia trachomatis (OR, 3.4; 95% CI, 1.5–7.8). Subjects colonized vaginally by hydrogen peroxide–producing lactobacilli were less likely to receive a diagnosis of chlamydial infection or gonorrhea than subjects without such lactobacilli. Bacterial vaginosis was a strong predictor of gonorrhea and chlamydial infection among subjects who reported recent exposure to a male partner with urethritis. These data support the importance of vaginal flora in the defense against STD acquisition.

Bacterial vaginosis is a common vaginal condition associated with an alteration of the Lactobacillus-predominant normal vaginal flora to an environment dominated by anaerobes, Gardnerella vaginalis, and Mycoplasma hominis. Recent studies have associated bacterial vaginosis with an increased susceptibility to sexually transmitted diseases (STDs). In a cross-sectional study in Uganda, Sewankambo and colleagues [1] demonstrated an association between altered vaginal flora and HIV-1 infection. Abnormal vaginal flora was also associated with HIV-1 acquisition in a prospective trial of Kenyan commercial sex workers [2]. Data that link abnormal vaginal flora to non-HIV STD acquisition are limited. Studies of pregnant women demonstrated that women with Lactobacillus-predominant vaginal flora were less likely to be infected with Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis than women with altered flora [3, 4]. Saigh et al. [5] reported that among 61 women exposed to N. gonorrhoeae, the organism was recovered more frequently from women who lacked endocervical lactobacilli than from women who had endocervical lactobacilli. The purpose of this study was to examine the relationship between bacterial vaginosis and STDs among female subjects recently exposed to men with urethritis.

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Patients and Methods

Our study, which was approved by the Institutional Review Board at the University of Pittsburgh, enrolled females who sought care during 1998–2001 at the Sexually Transmitted Diseases Clinic at the Allegheny County Health Department (Pittsburgh, Pennsylvania) and the ambulatory clinics of the Family Health Council (a major provider of reproductive health care in western Pennsylvania). Females aged 15–30 years were eligible for participation if they reported or were advised by health department officials of sexual activity with men who received a diagnosis of gonococcal or chlamydial urethritis or nongonococcal urethritis. Females were eligible regardless of the duration of time that had passed since the sexual encounter with the infected male partner. We excluded from analysis those females for whom test results for bacterial vaginosis, gonorrhea, or chlamydial infection were unavailable. Additional exclusion criteria included pregnancy, receipt of antibiotic treatment within the preceding 14 days, gynecologic surgery within the past 6 weeks, and previous hysterectomy.

After informed consent was obtained, a standardized interview was completed, which elicited medical, sexual, social, and demographic information. All participants then underwent a comprehensive gynecologic examination. Samples of vaginal fluid from the lateral vaginal walls were obtained for pH measurement, Whiff amine testing, and microscopy. An additional vaginal swab was streaked on a glass slide and air dried for Gram stain interpretation. A polyester fiber–tipped swab was used to obtain a sample from the posterior vaginal fornix for culture for T. vaginalis growth. Endocervical samples were obtained to test for the presence of N. gonorrhoeae and C. trachomatis. All patients were uniformly treated with single doses of azithromycin (1 g), cefixime (400 mg), and metronidazole (2 g), in accordance with standard STD treatment guidelines [6].

Microbiologic analysis. Air-dried slides of vaginal fluid were stained with Gram stain and interpreted for the presence of bacterial vaginosis, in accordance with standardized scoring criteria [7]. Bacterial vaginosis was diagnosed if the score was 7–10; a score of 4–6 indicated intermediate vaginal flora; and a score of 0–3 indicated normal vaginal flora. Swabs of vaginal fluid were transported to the laboratory in Amies transport medium (MML Diagnostics Packaging). Swabs were plated for growth of lactobacilli, and the organism's H2O2 production was tested by means of a qualitative assay on tetramethylbenzidine agar plates, as described elsewhere [8]. For T. vaginalis culture, vaginal swabs were placed in modified Diamond's media, incubated at 37°C, and examined every second day, for a maximum of 1 week, for the presence of motile trichomonads. Endocervical samples were streaked on modified Thayer-Martin medium and chocolate medium to test for N. gonorrhoeae growth; identification of N. gonorrhoeae was confirmed by means of Gram stain examination, oxidase testing, and Gonochek-II analysis (EY Laboratories). C. trachomatis was identified by PCR amplification of endocervical samples, performed in accordance with the manufacturers' recommendations (Roche Diagnostics).

Statistics. The characteristics used for comparison of subjects with and without N. gonorrhoeae and C. trachomatis infection were chosen because they have been associated with STDs by other investigators or because of their biological potential to increase or decrease the risk of these STDs. The unadjusted ORs were estimated from an unconditional, binary logistic model with only the 1 covariate of interest in the model [9]. The unadjusted ORs are presented because the 95% CI is more informative than a P value; unadjusted ORs also permit comparison with adjusted ORs. The 95% CIs were derived from Wald's test, and statistical significance was verified by maximum likelihood estimation. The adjusted ORs are presented as adjusted point estimates of the log odds with 95% CIs, rather than as approximations of the risk ratio. The models were constructed with potential confounding variables found to be associated with N. gonorrhoeae or C. trachomatis infection. The estimation of the log odds for statistically significant covariates was obtained from a final model from which the covariates that were not statistically significant had been removed. The unadjusted and adjusted log odds were obtained by computer software (SPSS).

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Results

We enrolled 255 females (mean age, 22 years) in this study. Fifty-nine percent of the cohort participants were African American, 37% were white, and 4% were of other racial backgrounds. Forty-two percent of the participants were uninsured, 23% had private health care insurance coverage, and 25% were enrolled in a Medicaid managed care plan. The mean time between the last episode of intercourse and presentation to the clinic was 11 days. Seventy-five subjects reported sexual contact with a man with gonorrhea, 32 subjects (13%) were exposed to chlamydia, and 148 subjects (58%) had a sexual partner who had received a diagnosis of nongonococcal urethritis. The overall rate of chlamydial or gonococcal infections in our cohort was 35% (88 of 255 subjects); fifty (20%) and 57 (22%) of the subjects tested positive for N. gonorrhoeae and C. trachomatis, respectively. Among subjects who reported sexual contact with a partner infected with N. gonorrhoeae, 42 (56%) of 75 tested positive for gonorrhea. C. trachomatis was identified in 13 (41%) of 32 subjects who reported contact with a man infected with chlamydia and in 18 (12%) of 148 subjects who had a partner in whom nongonococcal urethritis was diagnosed.

Participant characteristics stratified by results of tests for N. gonorrhoeae infection are presented in table 1. After adjustment for confounding variables, a test result positive for gonorrhea was associated with younger age (15–20 years of age, compared with ⩾21 years of age) and having had a new sexual partner within the preceding 3 months. We did not identify associations between a test result positive for N. gonorrhoeae infection and race, menstrual cycle phase, contraceptive use, douching within the preceding 30 days, alcohol intake, or use of illicit drugs. Subjects who reported consistent condom use with each coital act were not less likely to be infected with N. gonorrhoeae than were subjects who reported inconsistent condom use, with infection rates of 20% (5 of 25) and 25% (45 of 180) among consistent and inconsistent condom users, respectively (P, not significant).

Table 1
Table 1

Characteristics of subjects, stratified by presence or absence of Neisseria gonorrhoeae.

Results of C. trachomatis tests are outlined in table 2. A nonsignificant trend was observed between positive C. trachomatis test results and young age (OR, 1.7; 95% CI, 0.9–3.1). There were no associations between chlamydial infection and race, menstrual phase, contraceptive use, douching within the preceding 30 days, alcohol ingestion, or illicit drug use. Subjects who reported that they had had a new sexual partner within the preceding 3 months had infection rates comparable to those for subjects who did not report a new partner (22% vs. 23%; P, not significant). Similar to our findings for self-reported condom use and gonorrhea test results, self-reported condom use was not associated with protection against chlamydial infection.

Table 2
Table 2

Characteristics of subjects, stratified by presence or absence of Chlamydia trachomatis.

We enrolled 118 subjects (46%) with bacterial vaginosis, and these subjects were more likely to be infected with N. gonorrhoeae or C. trachomatis than were subjects without bacterial vaginosis (tables 1 and 2). Of subjects with bacterial vaginosis, 29% (34 of 118) were infected with N. gonorrhoeae, and 31% (37 of 118) tested positive for chlamydia. Forty-eight percent of the subjects (57 of 118) with bacterial vaginosis were infected with 1 of these 2 sexually transmitted organisms, compared with an infection rate of 23% (31 of 137) for subjects without bacterial vaginosis. After controlling for potentially confounding factors, subjects with bacterial vaginosis were 4.1 times more likely to be infected with N. gonorrhoeae than were subjects without bacterial vaginosis (95% CI, 1.7–9.7). Likewise, subjects with bacterial vaginosis were significantly more likely to test positive for C. trachomatis than were subjects without bacterial vaginosis (OR, 3.4; 95% CI, 1.5–7.8).

When vaginal flora patterns were further defined as bacterial vaginosis (those with Gram stain analysis scores of ⩾7), intermediate vaginal flora (scores of 4–6), and normal vaginal flora (scores of 0–3), we observed a trend toward the increased likelihood of test results positive for either N. gonorrhoeae or C. trachomatis as the abnormality of the vaginal flora increased. N. gonorrhoeae was present in 10% of subjects (8 of 84) with normal vaginal flora, 15% of subjects (8 of 53) with intermediate vaginal flora, and 29% of subjects (34 of 118) with bacterial vaginosis (P <.001; test for trend). A similar trend was seen when we stratified vaginal flora with chlamydial infections, as 12% of subjects (10 of 84) with normal flora, 19% of subjects (10 of 53) with intermediate vaginal flora, and 31% of subjects (37 of 118) with bacterial vaginosis were infected with C. trachomatis (P <.001; test for trend). The associations between bacterial vaginosis and both gonorrhea and chlamydial infection were also seen when clinical criteria were used for the diagnosis of bacterial vaginosis, in lieu of Gram stain analysis criteria (data not shown) [10].

Test results for N. gonorrhoeae and C. trachomatis were also stratified by vaginal Lactobacillus colonization (tables 1 and 2). When compared to subjects without lactobacilli, subjects with H2O2-producing lactobacilli in the vagina were significantly less likely to test positive for C. trachomatis (OR, 0.4; 95% CI, 0.2–0.8). A similar but nonsignificant trend was seen between the recovery of H2O2-producing lactobacilli and a lower rate of N. gonorrhoeae infection (OR, 0.6; 95% CI, 0.2–1.3). Gonorrhea and chlamydial infection rates were similar for subjects colonized with H2O2-negative strains of lactobacilli and for subjects from whom no vaginal lactobacilli were recovered.

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Discussion

This study adds to the growing body of literature that characterizes the adverse reproductive consequences of bacterial vaginosis, and it demonstrates strong associations between the presence of bacterial vaginosis and both gonococcal and chlamydial infection. In a cohort of female subjects with a recent exposure to an STD, who were thus at high risk for STD acquisition, subjects with bacterial vaginosis were 4 times more likely to test positive for gonorrhea and 3.4 times more likely to test positive for chlamydial infection than were subjects without bacterial vaginosis. Nearly one-half of the subjects (48%) with bacterial vaginosis at the time when STD tests were performed also tested positive for either N. gonorrhoeae or C. trachomatis, whereas 23% of subjects without bacterial vaginosis tested positive for at least 1 of these organisms. We have also shown that there was an incremental increase in the likelihood of positive test results for gonorrhea or chlamydial infection as the abnormality of vaginal flora increased, which suggests that females with altered vaginal flora but without bacterial vaginosis may also be at risk for sexually transmitted infections.

Normal vaginal flora has long been believed to be important in the protection against genital pathogens. Much emphasis has been placed on the importance to host defense of H2O2-producing lactobacilli, which are significant constituents of a normal vaginal environment. Saigh et al. [5] reported that, among women exposed to N. gonorrhoeae, those with lactobacilli identified in cultures of endocervical samples were less likely to test positive for N. gonorrhoeae than were women without lactobacilli. A large cross-sectional study of American pregnant women demonstrated that those with normal vaginal flora were less likely to be infected by C. trachomatis or N. gonorrhoeae than were those with abnormal flora [3]. A similar pattern was recently reported in a cohort of nonpregnant women [11]. Martin et al. [2], in a study of commercial sex workers in Kenya, documented an increased likelihood of acquisition of gonorrhea among women without vaginal lactobacilli. In the current study, subjects colonized with H2O2-producing lactobacilli were less likely to be infected with an STD than were subjects without lactobacilli. Normal vaginal flora is also believed to be an important defense against HIV acquisition; studies conducted in Africa have documented an association between HIV infection and abnormal vaginal flora [1, 2, 12]. Taken together, the data from the current study and the aforementioned studies are consistent with the hypothesis that H2O2-producing lactobacilli are an important defense against STD infection. This association has fostered the development and study of vaginal microbicides and the use of Lactobacillus organisms to reduce STD and HIV acquisition.

The mechanisms by which normal vaginal microflora protect against STD acquisition and bacterial vaginosis are not well characterized. Hydrogen peroxide–producing lactobacilli, typically absent in women with bacterial vaginosis, have the capability to inhibit the growth of N. gonorrhoeae in vitro [13]. Although normal vaginal flora may be directly involved in the prevention of STD acquisition, an abnormal vaginal microenvironment, mediated by microbial products, may also alter the host defense against infection. Succinate is produced by anaerobic gram-negative rods commonly associated with bacterial vaginosis. This acid alters leukocyte function and may compromise host defenses [14]. Sialidase and other glycosides are found at increased levels in the vaginal fluid of women with bacterial vaginosis. These glycosides are associated with decreased vaginal fluid viscosity, which can potentially alter mucosal integrity and facilitate infection with genital pathogens (S. Hillier, unpublished data). In addition to strong associations between abnormal vaginal flora and both gonococcal and chlamydial infection, our study also demonstrates that the absence of H2O2-producing lactobacilli was associated with STDs. These data further support the important role that the vaginal microenvironment plays in the pathogenesis of STDs. The association between bacterial vaginosis and STDs likely involved both an alteration in host defense against infection due to the loss of protection in a Lactobacillus-deficient environment and an enhanced susceptibility to STDs due to the presence of bacterial vaginosis–associated organisms and their products.

We identified additional factors associated with tests positive for N. gonorrhoeae or C. trachomatis. Younger subjects 15–20 years old were significantly more likely to have gonorrhea than were subjects ⩾21 years old; in addition, there was a similar, but not significant, association between age and chlamydial infection. Younger females in particular are believed to be more susceptible to STD acquisition, in part due to cervical ectopy and the enhanced exposure of endocervical columnar cells, the cellular targets for N. gonorrhoeae and C. trachomatis [15]. We found that subjects who reported having a new sexual partner were more likely to be infected with N. gonorrhoeae than were subjects without a new partner; no such association was seen with chlamydial infection. A new sexual partner has been reported to be a risk factor for STD acquisition by some investigators but not others [16, 17]. Of interest, those subjects who reported consistent condom use (i.e., condom use with every coital act) were not less likely to receive a diagnosis of gonorrhea or chlamydial infection. If condom use protects against STD acquisition, our paradoxical results may be explained by the poor validity of self-reported condom use [18]. Reasons that self-reported condom use is not associated with protection against STDs include improper use and recall bias.

Because our study was cross-sectional, we cannot extrapolate our results to accurately characterize the transmission rate of N. gonorrhoeae or C. trachomatis, for 2 reasons. First, we are limited by our lack of knowledge of the subjects' infection status at baseline; some subjects could have been infected before contact with the partner identified as the source of gonorrhea, chlamydial infection, or nongonococcal urethritis. Second, we did not require verification of the male partner's infection, although we were able to confirm 90% of the male partners' diagnoses by examination of our health department's STD registry. Another weakness of our study is that we cannot assure that bacterial vaginosis preceded the subjects' exposure to gonorrhea or chlamydial infection; it is possible that the vaginal flora was altered only after, and perhaps as a result of, the acquisition of these STDs.

Although studies have documented that the vaginal microenvironment is dynamic, with ecological alteration common during menstruation and intercourse, bacterial vaginosis is often a long-standing, stable condition [3, 19]. In a study of 141 pregnant women with bacterial vaginosis at 23–26 weeks' gestation, only 12% of the women had vaginal flora that had reverted to normal 10 weeks later; in another study of vaginal flora in nonpregnant women, only 54 (25%) of 220 women with bacterial vaginosis had vaginal flora that had spontaneously reverted to normal 4 months later (S. Hillier, unpublished data) [3]. These studies indicate that bacterial vaginosis is commonly present for a long time, in the absence of treatment; therefore, we believe that bacterial vaginosis preceded STD exposure in most instances, and not vice versa. Although causality between bacterial vaginosis and STD acquisition cannot currently be established, the results of our study are consistent with the findings of prospective studies performed in Africa that demonstrated an increased risk of acquisition of gonorrhea and HIV infection among women with altered vaginal flora [2, 12].

In summary, we have demonstrated that females at risk for STD acquisition more commonly test positive for N. gonorrhoeae and C. trachomatis if they have bacterial vaginosis. To our knowledge, this is the largest study of nonpregnant American females that characterizes the relationship between bacterial vaginosis and STDs. The strong relationship between bacterial vaginosis and gonococcal and chlamydial infections provides further insight into the microbial interaction in the lower genital tract and highlights the importance of normal vaginal flora in the defense against STD acquisition.

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Acknowledgements

We thank Ingrid Macio, Anne Rideout, and Christine Donahue, for their invaluable assistance, and Tracy Zamborsky, for statistical support.

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Footnotes

  • Financial support: Istituto Superiore di Sanita` (Programma Nazionale di Ricerca sull'AIDS; grants 50A.0.12, 50B.14, and 50C.8).

  • Received August 14, 2002.
  • Accepted November 21, 2002.
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  1. Clin Infect Dis. (2003) 36 (5): 645-651. doi: 10.1086/367659
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