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New treatments for Chlamydia trachomatis
Chlamydial infections in pregnancy
Volume 164 Number 6, Part 2
romycin for chlamydial infections in pregnancy. N Engl J Med 1986;314:276-9. 59. Black-Payne C, Ahrabi MM, Bocchini JA, Ridenour CR, Brouillette RM. Treatment of Chlamydia trachomatis identified with chlamydiazyme during pregnancy: impact on perinatal complications and infants. J Reprod Med 1990; 35:362-6. 60. McMillan JA, Weiner LB, Lamberson HV, et al. Efficacy of maternal screening and therapy in the prevention of chlamydial infection of the membranes. Infection 1985; 13:263-6.
61. Crombleholme WR, Schachter J, Grossman M, Landers DV, Sweet RL. Amoxicillin therapy for Chlamydia trachomatlS in pregnancy. Obstet Gynecol 1990;75:752-6. 62. Centers for Disease Control. 1989 Sexually transmitted diseases treatment guidelines. MMWR 1989;38(suppl 8):27-8. 63. McNeely SG, Ryan GM, Baselski V. Treatment of chlamydia infection of the cervix during pregnancy. Sex Transm Dis 1989;16:60-2.
New treatments for Chlamydia trachomatis Robert B. Jones, MD, PhD Indianapolis, Indiana Standard regimens of tetracycline, doxycycline, or erythromycin, if complied with, appear to be effective against Chlamydia trachomatis infections under most circumstances. However, the organism may sometimes persist despite what would seem to be adequate therapy. How often this occurs, to what extent noncompliance is the issue, and the role antibiotic resistance plays remain to be determined. Among newer antibiotics, azithromycin appears to be effective in the treatment of uncomplicated urogenital C. trachomatis infections. Single-dose therapy with azithromycin may be especially useful in overcoming compliance problems associated with the treatment of sexually transmitted disease. (AM J OSSTET GVNECOL 1991 ;164:1789-93.)
Key words: C. trachomatis, recurrent infection, antibiotics, azithromycin
Chlamydia trachomatis infections of the genital tract are prevalent among young, sexually active persons. They are associated with considerable morbidity, including infertility, ectopic pregnancy, infant pneumonia, and co~unctivitis.l.2 Efforts at controlling transmission and preventing complications have focused on the identification of infected persons and treatment with effective antibiotics. Selection of the antibiotic has been based primarily on demonstrated efficacy in clinical trials and on cost. 3.4 The treatment presently recommended for uncomplicated genital tract infection with C. trachomatis is doxycycline, 100 mg orally twice a day for 7 days, or tetracycline, 500 mg orally 4 times a day for 7 days.5 The essential therapeutic equivalency of tetracycline,
doxycycline, and minocycline has been established in several clinical trials.' Doxycycline has become the preferred agent, because less frequent dosing is required. 5 Minocycline has been used less often because of vestibular side effecs, particularly at higher doses. Of interest has been the observations that clindamycin in combination with an aminoglycoside has been effective in eradicating C. trachomatis in women with salpingitis,6 whereas clindamycin alone was ineffective in treating men with chlamydial urethritis. 7 A possible explanation may lie in the recent demonstration of in vitro synergy of clindamycin and gentamicin or tobramycin against C. trachomatis despite the fact that the aminoglycosides are inactive when used alone. s
From the Department ofMedIcine, IndIana UniversIty School ofMed-
Although the present treatment regimens appear effective in most patients who are compliant, there has been a failure rate of approximately 5% in most studies in which a test-of-cure culture is obtained 4 to 7 days
iCine. Reprint requests: Robert B. Jones, MD, PhD, Department of MedIcine, EM 435, 545 Barnhill Dr., Indianapolis, IN 46202-5124. 6/0/29339
Recurrent or persistent infections
1789
1790 Jones
June 1991 Am J Obstet Gyneco1
Table I. Time to recurrence of C. trachomatis infection in adolescent girls Recurrence rate Mo after initial infection 0-3
3-6 6-9
9-12 12-15 15-18 18-21 21-24 Cumulative
No. positive/No. tested
%
4/34* 20/79 13/34 13/34 4/20
12 25 38 38 20 54
7/l3 4/7
3/5
68/176
57 60 39
*Test of cure visits not included. Each subject counted only at the time of first recurrence, if she had more than one.
after completion of therapy" Furthermore, a high proportion of persons with chlamydial infections who come to a sexually transmitted diseases clinic have recurrent infections. 9 In a study performed in Indianapolis between Sept. 1, 1983, and April 15, 1986,5722 persons attending a sexually transmitted diseases clinic were identified by culture as having a chlamydial infection. Of these, 2224 (39%) returned at least once during the same period because of symptoms or concern about having a sexually transmitted disease, and 573 (26%) were again infected with C. trachomatis-some on as many as five separate occasions. 9 These observations led to a closer evaluation of recurrent chlamydial infection, particularly in the setting of concurrent gonococcal infection at the time of recurrence. It was observed that a high proportion of persons (47%) with concurrent gonococcal infection were again infected with the same serovar of C. trachomatis. 9 In patients with no gonococcal infection, recurrence of the same serovar was considerably less frequent (22%). This association between gonococcal infection and the same serovar recurrence persisted for more than a year. By contrast, in persons without gonococcal infection, same serovar recurrence was infrequent beyond 6 months. 9 The most likely explanation of these findings is that a number of patients had not been cured of the original chlamydia infection, which was somehow reactivated by the gonococcal infection. In patients without gonorrhea, the occurrence of same serovar reinfections at less than 6 months may represent either relapses or reinfections from untreated partners. In this group, however, most reinfections after more than 6 months involve a different serovar and presumably represent a new exogenous infection. If the original serovar was still present at the time of the second infection, it would
have been replaced by the newly infecting serovar, perhaps by further stimulation of the immune response. Preliminary data from another study in adolescent girls also indicate a high rate of recurrence. lO Adolescent girls attending county health department clinics, primarily for contraception, pregnancy testing, and other gynecologic services, were cultured for C. trachomatis and followed up, respectively. One hundred seventy-six girls with positive cultures had a negative culture result within 3 months after treatment and had a second culture taken at a subsequent return visit, which was usually for contraceptive purposes (Table I). At each evaluation after the first 3 months, a recurrence rate greater than 20% was observed, with a cumulative rate of 39% for the entire 2-year follow-up period. Distinguishing relapse from same serovar reinfection is particularly difficult in this population. None of the women was abstinent during the interval between infections, and many resumed sexual activity with a former partner who had not been treated for a chlamydial infection. Nevertheless, these data suggest that little if any protection against reinfection results from a natural infection and that persistence may represent more of a problem than is generally recognized. Other evidence supporting such a concept includes the documentation of persistent C. trachomatis infection in infants for as long as 2 years, II as well as persistent infection with lymphogranuloma venereum strains for as long as 20 years in persons not likely to have been reinfected. 12 In addition, there is an animal model in which persistence of sexually transmitted chlamydia infection is observed. Guinea pigs infected intraurethrallY with low doses of the guinea pig inclusion conjunctivitis agent may have no evidence of infection and become culture negative. Yet they remain capable of transmitting the agent to other guinea pigs. 13 Infertility and antibiotic resistance
Persistent infection may also be a contributing factor to infertility in women. We recently reported the recovery of C. trachomatis from the fallopian tubes and endometrium of 8 of 52 women (15%) undergoing microtuboplasty for tubal infertility.l4 In two women who had received tetracycline before microtuboplasty, the organisms were relatively resistant to tetracycline in vitro.'5 These isolates were also resistant to erythromycin, clindamycin, and sulfamethoxazole but were sensitive to ciproftoxacin, oftoxacin, and rifampin. One of the patients was treated with minocycline after microtuboplasty. She had a culture negative result in the lower genital tract and conceived. The other patient was lost to follow-up.
New treatments for C. trachomatis
Volume 164 Number 6, Part 2
Table II. Eradication of C. trachomatis by
~-lactam
1791
antibiotics and erythromycin Bactenologzc cure rate
Szte mfected, reference
Urethra (F)/cervix
Urethra (M) Cervix Cervix (postpartum) Cervix (postpartum) Endometrium (Salpingitis)
I
Antzbzotzc
Day 7*
Pivampicillin, 700 mg 2 times a day for 7 days Erythromycin, 500 mg 2 times a day for 7 days Amoxicillin, 750 mg 3 times a day for 7 days Ampicillin, 3.5 gm loading dose, then 500 mg 4 times a day for 7 days Timentin (5), piperacillin (2) Cefoxitin (2), cefotetan (I) Cephalosporin
26/26
26/26
23/23
22/23
Day i4
I
% 19
11/11
20
10/12
21
6/7t 0/3
22
2/10t
23
*After initiation of therapy. tThree to 58 days after completion of therapy. tType of follow-up cultures not specified.
The clinical significance of the type of resistance observed in these isolates remains to be determined. It was heterotypic, because only a small proportion of organisms in each isolate showed high-level resistance to tetracycline after in vitro growth. I5 Consequently, both a high inoculum and immunofluorescent staining of inclusions were necessary to demonstrate resistance. In addition, the resistant isolates did not grow well in vitro and may have had limited in vivo viability.
Erythromycin and p-Iactam antibiotics Treatment of chlamydial infections in pregnancy has proved to be a particularly difficult problem. Tetracycline cannot be used, and many pregnant women cannot tolerate the gastrointestinal side effects associated with erythromycin. However, in one study in which oral erythromycin ethylsuccinate was given to infected pregnant women at a dose of 400 mg four times a day, cure rates of 92% were observed. Only 3% of subjects discontinued medication because of gastrointestinal intolerance. 16 In a subsequent study in pregnant women, oral amoxicillin, 500 mg three times a day for 7 days, was compared with an oral erythromycin base, four times a day for 7 days. There was a slightly higher cure rate in the amoxicillin-treated women, and the regimen was better tolerated. I? In a much smaller study nine infected, pregnant women were treated with comparable doses of amoxicillin for 10 days, and three were not cured. I8 Thus although further evaluation is in order, amoxicillin appears to be an acceptable alternative to erythromycin when erythromycin cannot be tolerated. Limited data indicate that when given for several days, penicillins or erythromycin may also be effective
Table III. In vitro activity of selected antimicrobial agents against C. trachomatis Antzmzcrobial agent
MiC range (pglml)
Tetracycline Doxycycline Erythromycin Clindamycin Azithromycin Ampicillin Sulfamethoxazole Rifampin Ofloxacin Ciprofloxacin Fleroxacin Lomefloxacin Perfloxacin Norfloxacin Enoxacin
0.02-0.5 0.03-0.05 0.05-0.5 0.25-2.0 0.26-1.02 0.2-50 4-50 0.005-0.25 0.5-2.0 1.0-4.0 1.5-2.5 2.0-4.0 2.0-8.0 8.0-16.0 8.0-16.0
- -I- -
See references 24 through 28. MIC, Minimum inhibitory concentration.
for the treatment of chlamydial infections in other situations (Table 11).19.23 However, to date, single-dose or short-course therapy has been ineffective,20 and cephalosporins have not been effective treatment when tried in patients. 23
New antimicrobials Some of the fluoroquinolones and the azalide antibiotic, azithromycin, demonstrate significant promise for the treatment of chlamydial infections. Table III outlines the in vitro susceptibility of C. trachomatis to several of these agents. 24 •28 Ciprofloxacin was one of the first fluoroquinolones to undergo clinical trials for the treatment of chlamy-
1792 Jones
dial infections. 29 • '0 Despite excellent in vitro activity, a substantial incidence of late failures was observed when patients had cultures taken 2 or more weeks after completion of therapy. Norfloxacin is ineffective in the treatment of chlamydiaI infections. 25 Ofloxacin demonstrated in vitro activity comparable with that of ciprofloxacin; however, therapy with a 7-day course of this drug resulted in a 99% cure rate, which is comparable with that of a full course of doxycycline." Because of the prolonged chlamydiallife cycle of 48 to 72 hours, effective antibiotic treatment requires therapeutic levels of a drug at the intracellular site of infection for sustained periods of time. Standard treatment regimens entail multiple daily doses of antibiotic for at least 7 days. Compliance is often poor and recurrence remains a problem. Achieving medical compliance in the sexual partner of the index patient is an additional challenge to eradicating the chlamydial infection. Azithromycin concentrates extensively within cells and has a tissue half-life of approximately 60 hours.'2 Azithromycin levels in human tissues after a single 500 mg dose may exceed the minimum inhibitory concentration of C. trachomatis by threefold to lO-fold for as long as 5 days. Clinical trials are examining the efficacy of twice that dose, I gm, for the treatment ofchlamydia I urethritis and cervicitis. If effective, a single-dose regimen with azithromycin would ensure adequate therapy and eliminate the compliance problem. In two published studies, one conducted in Iceland" and the other in Finland," a single 1 gm dose of oral azithromycin was as effective as 100 mg of doxycycline given twice a day for 7 days in eradicating urogenital C. trachomatis infections in both men and women. Side effects, primarily gastrointestinal, were mild and of similar incidence in the doxycycline and azithromycin groups. Additional data from two multicenter European studies seem to confirm these observations." In summary, new approaches to the treatment of chlamydial cervicitis and urethritis include compounds from the azalide and fluoroquinolone classes. Azithromycin, the first of the azalide antibiotics, offers the promise of efficacious single-dose therapy, an advance that should significantly improve control of this pathogen and help in the prevention of its serious sequelae.
June 1991 Am J Obstet Gynecol
of the same chlamydial serovar in patients with gonococcal infections also suggests that the original infection may not have been cured. A new azalide antibiotic, azithromycin, has been undergoing intensive clinical investigation as single-dose therapy for chlamydial urethritis and cervicitis. A single I gm dose has shown efficacy comparable with a standard 7-day course of doxycycline. The side effect profile has been mild, with an incidence similar to that of doxycycline. Effective single-dose therapy of chlamydial infections with azithromycin will significantly reduce compliance problems and enable greater control of chlamydia in the general population. It is hoped that this will ultimately reduce the serious sequelae caused by the pathogen.
1. 2.
3.
4. 5. 6.
7. 8. 9. 10. 11.
Summary Standard tetracycline, doxycycline, or erythromycin therapy appears to be effective against C. trachomatis infection under most circumstances. Doxycycline has been the preferred treatment because less frequent administration is required. Nevertheless, test-of-cure cultures obtained 4 to 7 days after completion of standard therapy indicate a failure rate of approximately 5%. Frequent recurrence
12. 13. 14.
REFERENCES Alexander ER, Harrison HR. Role of Chlamydia trachomatis in perinatal infection. Rev Infect Dis 1983;5:713-9. Stamm WE, Holmes KK. Chlamydia trachomatis infections of the adult. In: Holmes KK, Mardh P-A, Sparling PF, et aI., eds. Sexually transmitted diseases. 2nd ed. New York: McGraw-Hill, 1990:181-93. Nettleman MD, Jones RB, Roberts SD, et al. Costeffectiveness of culturing for Chlamydia trachomatis. A study in a clinic for sexually transmitted diseases. Ann Intern Med 1986;105:189-96. Sanders LL, Harrison HR, Washington AE. Treatment of sexually transmitted chlamydial infections. JAMA 1986; 255: 1750-6. Centers for Disease Control. 1989 sexually transmitted diseases treatment guidelines. MMWR 1989;38(S-8 suppl): 1-43. WasserheitJN, Bell TA, Kiviat NB, et al. Microbial causes of proven pelvic inflammatory disease and efficacy of c1indamycin and tobramycin. Ann Intern Med 1986;104: 18793. Bowie WR, Yu JS, Jones HD. Partial efficacy of c1indamycin against Chlamydta trachomatis in men with nongonococcal urethritis. Sex Transm Dis 1986;13:76-80. Pearlman MD, Faro S, Riddle GD, Tortolero G. In vitro synergy of c1indamycin and aminoglycosides against Chlamydia trachomatlS. J Clin Microbiol 1990;34: 1399-401. Batteiger BE, Fraiz J, Newhall WJ, Katz BP, Jones RB. Association of recurrent chlamydial infection with gonorrhea. J Infect Dis 1989; 159:661-9. Blythe MJ, Katz BP, Batteiger BE, et al. Recurrent genitourinary C. trachomatis infection in adolescent females. Pediatr Res 1990;27:3A. Bell TA, Stamm WE, Kuo C-C, Holmes KK, GraystonJT. Chronic Chlamydia trachomatis infections in infants. In: Oriel D, Ridgway G, Schachter J, Taylor-Robinson D, Ward M, eds. Chlamydial infections. Proceedings of the Sixth International Symposium on Human Chlamydial Infections, Sanderstead, Surrey, June 15-21, 1986. Cambridge, England: Cambridge University Press, 1986:305-8. Dan M, Rotmensch HH, Eyland E, Rubinstein A, Ginsberg R, Liron M. A case of lymphogranuloma venereum of 20 years' duration. Br J Vener Dis 1980;56:344-6. Ozanne G, Pearce JH. Inapparent chlamydial infection in the urogenital tract of guinea pigs. J Gen Microbiol 1980;119:351-59. Shepard MK,Jones RB. Recovery of Chlamydia trachomatlS from endometrial and fallopian tube biopsies in women with infertility of tubal origin. Fertil Steril 1989;52: 232-8.
Volume ](;4 Number fl, Part 2
15. Jones RB, Van Der Pol B. Chlam}dw /rachoma/I.I isolates re~istant to multIple antibiotics. In: Bowie WR, Caldwell HD, Jones RB. et al., eds Chlamydial Infections. Proceedings of the Seventh International Svmposium on Human Chlamydial Infections, Harrison Hot Spnngs, BritIsh Columbia, Canada, June 24-29, 1990. Cambridge, England: Cambridge University Press, 1990:519-22. 16. Schachter .I, Sweet RL, Grossman M, Landers D, Robbie M, Bishop E. Experience with the routine use of erythromycin for chlamydial infections in pregnancy. N Engl .I Med 1986:314:276-9. 17. Crombleholme WR, Schachter .I, Grossman M, Landers DV, Sweet RY. AmoxlCIllin therapv for Chlam.vdw/rac/wma/I.I in pregnancy. Obstet Gynecol 1990:75:752-6. 18. Bell TA, Sandstrom IK, Eschenback DA, et al. Treatment of Chlam}dw/rrlchoma/1.1 in pregnancy with amoxlcillin In: Mardh PA, Holmes KK, OrielJD, Piot P, SchachterJ, eds. Chlamydial infections. Proceedings of the Fifth International Symposium on Human Chlamydial Infections, Lund, Sweden,June 15-19,1982. Anmerdam, The Netherlands: Elsevier Biomedical Press, 1982:221-4. 19. Cramers M, Kaspersen P, From E, Miller BR. Pivampicillin compared with erythromycin for treating women with genital Chlamvdw /mc/wma/II infection. Genitourin Med 1988;64:247-8. 20. Csango PA, Gunder~en T, Martinsen 1M. Effect of amoxiCllltn on simultaneous Chlamvdw /rachoma/II Infection In men with gonococcal urethrit;s: comparison of three dosage regimens. Sex Transm Dis 1985:12:93-6. 21. Bowie WR, Manzon LM, Borrie-Hume C.J, Fawcett A, Jones HD. Efficacy of treatment regimens for lower urogenital Chlamydw /rac/wma/iS infection in women. A~ .I OIlS rET GY:-.JE(.OL 1982;142:125-9. 22. Martin DH, Pastorek JC; II, Faro S. In vitro and in vivo activity of parenterally administered beta-Iactam antibiotIcs against Chlamvdw /rac/wma/II. Sex Transm Dis 1986;13:81-7. 23. Sweet RL, Schachter .I, Robbie MO. Failure of beta-lactam antibiotics to eradicate Chlamvdw /mc/wma/iS in the endometrium despite apparent cli~ical cure of acute ~alpingItis. .lAMA 1983:250:2641-5. 24. Black JR, Handsfield HH, Hook EW IlL Single-do~e oftoxacin vs. amoxicillin plus probeneCid for treatment of uncomplicated gonococcal infection. Rev Infect Dis 1989: Il(suppI5):SI3l3-4.
New treatments for C. trachomatiS
1793
25. OrielJD. Use of quinolones in chlamydial infectulI1 Rev Infect Dis 1989; II (suppl 5):S 1273-6. 26. Ehret JM, Judson FN. Susceptibility te~ting of Chlamvdw /rac/wma/ls: from eggs to monoclonal antibodies. Antimicrob Agents Chemother 1988;32: 1295-99. 27. Jones RB. Antimicrobial susceptibility testing for some atypical microorganisms: M}coplawul.l, Chlmn.wlwe and Rlckel/.lw. In: Lonan V, ed. Antibiotics in laboratorv medicine. 2nd ed. Baltimore: Williams and Wilkins, 1986:34658. 28. Walsh M, Kappus EW, Qumn TC. In Vitro evaluation of CP-62,993, erythromycin, clindamycin, and tetracycline against Chlam.vdw /rac/wma/iS. AntImicrob Agents Chemother 1987;31:811-2. 29. Fong IW, Linton W, Simbul M, et al Treatment of nongonococcal urethritis with ciproftoxacin. AmJ Med 1987: 82:311-6. 30. van del' Willigen AH, Polak- Vogelzang AA, Habbema L, Wagenvoort JH. Clinical efficacy of ciproftoxacin versus doxycycline in the treatment of nongonococcal urethritis in males. EmJ Clin Microbiol Infect Dis 1988:7:658-61. 31. Batteiger BE, Jones RB, White A. Efficacv and safety of oftoxacin in the treatment of nongonococcal sexually transmitted disease. AmJ Med 1989:87(suppl 6C):75S7S. 32. Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in human serum and tissues. .I Antimicrob Chemother 1990;25(suppl A):73-82. 33. Stemgrimsson 0, Olafsson JH, Thorannsson H, Ryan RW, Johnson RB, Tilton RC. Azithromycinin the treatment of sexually transmitted disease. .I Antimtcrob Chemother 1990;25(suppl A)·'09-14. 34. Lassus A. Comparative studies of azIthromycin in skin and soft-tissue infection and sexually transmitted infections by Nel.I.lerw and Chlamydia species. .I AntImicrob Chemother 1990:25(suppl A).115-21. 35. Johnson RB, Azithromycin treatment of gemtal chlamydial infections In: BOWie WR, Caldwell HD, Jones RP, et aI., eds. Chlamydial infections. Proceedings of the Seventh International SymposIUm on Human Chlamydial Infections, Harnson Hot Spnngs, British Columbia, Canada, June 24-29, 1990. Cambridge, England: Cambridge U niversity Pre~s, 1990:534-6.
Volume 164 Number 6, Part 2
romycin for chlamydial infections in pregnancy. N Engl J Med 1986;314:276-9. 59. Black-Payne C, Ahrabi MM, Bocchini JA, Ridenour CR, Brouillette RM. Treatment of Chlamydia trachomatis identified with chlamydiazyme during pregnancy: impact on perinatal complications and infants. J Reprod Med 1990; 35:362-6. 60. McMillan JA, Weiner LB, Lamberson HV, et al. Efficacy of maternal screening and therapy in the prevention of chlamydial infection of the membranes. Infection 1985; 13:263-6.
61. Crombleholme WR, Schachter J, Grossman M, Landers DV, Sweet RL. Amoxicillin therapy for Chlamydia trachomatlS in pregnancy. Obstet Gynecol 1990;75:752-6. 62. Centers for Disease Control. 1989 Sexually transmitted diseases treatment guidelines. MMWR 1989;38(suppl 8):27-8. 63. McNeely SG, Ryan GM, Baselski V. Treatment of chlamydia infection of the cervix during pregnancy. Sex Transm Dis 1989;16:60-2.
New treatments for Chlamydia trachomatis Robert B. Jones, MD, PhD Indianapolis, Indiana Standard regimens of tetracycline, doxycycline, or erythromycin, if complied with, appear to be effective against Chlamydia trachomatis infections under most circumstances. However, the organism may sometimes persist despite what would seem to be adequate therapy. How often this occurs, to what extent noncompliance is the issue, and the role antibiotic resistance plays remain to be determined. Among newer antibiotics, azithromycin appears to be effective in the treatment of uncomplicated urogenital C. trachomatis infections. Single-dose therapy with azithromycin may be especially useful in overcoming compliance problems associated with the treatment of sexually transmitted disease. (AM J OSSTET GVNECOL 1991 ;164:1789-93.)
Key words: C. trachomatis, recurrent infection, antibiotics, azithromycin
Chlamydia trachomatis infections of the genital tract are prevalent among young, sexually active persons. They are associated with considerable morbidity, including infertility, ectopic pregnancy, infant pneumonia, and co~unctivitis.l.2 Efforts at controlling transmission and preventing complications have focused on the identification of infected persons and treatment with effective antibiotics. Selection of the antibiotic has been based primarily on demonstrated efficacy in clinical trials and on cost. 3.4 The treatment presently recommended for uncomplicated genital tract infection with C. trachomatis is doxycycline, 100 mg orally twice a day for 7 days, or tetracycline, 500 mg orally 4 times a day for 7 days.5 The essential therapeutic equivalency of tetracycline,
doxycycline, and minocycline has been established in several clinical trials.' Doxycycline has become the preferred agent, because less frequent dosing is required. 5 Minocycline has been used less often because of vestibular side effecs, particularly at higher doses. Of interest has been the observations that clindamycin in combination with an aminoglycoside has been effective in eradicating C. trachomatis in women with salpingitis,6 whereas clindamycin alone was ineffective in treating men with chlamydial urethritis. 7 A possible explanation may lie in the recent demonstration of in vitro synergy of clindamycin and gentamicin or tobramycin against C. trachomatis despite the fact that the aminoglycosides are inactive when used alone. s
From the Department ofMedIcine, IndIana UniversIty School ofMed-
Although the present treatment regimens appear effective in most patients who are compliant, there has been a failure rate of approximately 5% in most studies in which a test-of-cure culture is obtained 4 to 7 days
iCine. Reprint requests: Robert B. Jones, MD, PhD, Department of MedIcine, EM 435, 545 Barnhill Dr., Indianapolis, IN 46202-5124. 6/0/29339
Recurrent or persistent infections
1789
1790 Jones
June 1991 Am J Obstet Gyneco1
Table I. Time to recurrence of C. trachomatis infection in adolescent girls Recurrence rate Mo after initial infection 0-3
3-6 6-9
9-12 12-15 15-18 18-21 21-24 Cumulative
No. positive/No. tested
%
4/34* 20/79 13/34 13/34 4/20
12 25 38 38 20 54
7/l3 4/7
3/5
68/176
57 60 39
*Test of cure visits not included. Each subject counted only at the time of first recurrence, if she had more than one.
after completion of therapy" Furthermore, a high proportion of persons with chlamydial infections who come to a sexually transmitted diseases clinic have recurrent infections. 9 In a study performed in Indianapolis between Sept. 1, 1983, and April 15, 1986,5722 persons attending a sexually transmitted diseases clinic were identified by culture as having a chlamydial infection. Of these, 2224 (39%) returned at least once during the same period because of symptoms or concern about having a sexually transmitted disease, and 573 (26%) were again infected with C. trachomatis-some on as many as five separate occasions. 9 These observations led to a closer evaluation of recurrent chlamydial infection, particularly in the setting of concurrent gonococcal infection at the time of recurrence. It was observed that a high proportion of persons (47%) with concurrent gonococcal infection were again infected with the same serovar of C. trachomatis. 9 In patients with no gonococcal infection, recurrence of the same serovar was considerably less frequent (22%). This association between gonococcal infection and the same serovar recurrence persisted for more than a year. By contrast, in persons without gonococcal infection, same serovar recurrence was infrequent beyond 6 months. 9 The most likely explanation of these findings is that a number of patients had not been cured of the original chlamydia infection, which was somehow reactivated by the gonococcal infection. In patients without gonorrhea, the occurrence of same serovar reinfections at less than 6 months may represent either relapses or reinfections from untreated partners. In this group, however, most reinfections after more than 6 months involve a different serovar and presumably represent a new exogenous infection. If the original serovar was still present at the time of the second infection, it would
have been replaced by the newly infecting serovar, perhaps by further stimulation of the immune response. Preliminary data from another study in adolescent girls also indicate a high rate of recurrence. lO Adolescent girls attending county health department clinics, primarily for contraception, pregnancy testing, and other gynecologic services, were cultured for C. trachomatis and followed up, respectively. One hundred seventy-six girls with positive cultures had a negative culture result within 3 months after treatment and had a second culture taken at a subsequent return visit, which was usually for contraceptive purposes (Table I). At each evaluation after the first 3 months, a recurrence rate greater than 20% was observed, with a cumulative rate of 39% for the entire 2-year follow-up period. Distinguishing relapse from same serovar reinfection is particularly difficult in this population. None of the women was abstinent during the interval between infections, and many resumed sexual activity with a former partner who had not been treated for a chlamydial infection. Nevertheless, these data suggest that little if any protection against reinfection results from a natural infection and that persistence may represent more of a problem than is generally recognized. Other evidence supporting such a concept includes the documentation of persistent C. trachomatis infection in infants for as long as 2 years, II as well as persistent infection with lymphogranuloma venereum strains for as long as 20 years in persons not likely to have been reinfected. 12 In addition, there is an animal model in which persistence of sexually transmitted chlamydia infection is observed. Guinea pigs infected intraurethrallY with low doses of the guinea pig inclusion conjunctivitis agent may have no evidence of infection and become culture negative. Yet they remain capable of transmitting the agent to other guinea pigs. 13 Infertility and antibiotic resistance
Persistent infection may also be a contributing factor to infertility in women. We recently reported the recovery of C. trachomatis from the fallopian tubes and endometrium of 8 of 52 women (15%) undergoing microtuboplasty for tubal infertility.l4 In two women who had received tetracycline before microtuboplasty, the organisms were relatively resistant to tetracycline in vitro.'5 These isolates were also resistant to erythromycin, clindamycin, and sulfamethoxazole but were sensitive to ciproftoxacin, oftoxacin, and rifampin. One of the patients was treated with minocycline after microtuboplasty. She had a culture negative result in the lower genital tract and conceived. The other patient was lost to follow-up.
New treatments for C. trachomatis
Volume 164 Number 6, Part 2
Table II. Eradication of C. trachomatis by
~-lactam
1791
antibiotics and erythromycin Bactenologzc cure rate
Szte mfected, reference
Urethra (F)/cervix
Urethra (M) Cervix Cervix (postpartum) Cervix (postpartum) Endometrium (Salpingitis)
I
Antzbzotzc
Day 7*
Pivampicillin, 700 mg 2 times a day for 7 days Erythromycin, 500 mg 2 times a day for 7 days Amoxicillin, 750 mg 3 times a day for 7 days Ampicillin, 3.5 gm loading dose, then 500 mg 4 times a day for 7 days Timentin (5), piperacillin (2) Cefoxitin (2), cefotetan (I) Cephalosporin
26/26
26/26
23/23
22/23
Day i4
I
% 19
11/11
20
10/12
21
6/7t 0/3
22
2/10t
23
*After initiation of therapy. tThree to 58 days after completion of therapy. tType of follow-up cultures not specified.
The clinical significance of the type of resistance observed in these isolates remains to be determined. It was heterotypic, because only a small proportion of organisms in each isolate showed high-level resistance to tetracycline after in vitro growth. I5 Consequently, both a high inoculum and immunofluorescent staining of inclusions were necessary to demonstrate resistance. In addition, the resistant isolates did not grow well in vitro and may have had limited in vivo viability.
Erythromycin and p-Iactam antibiotics Treatment of chlamydial infections in pregnancy has proved to be a particularly difficult problem. Tetracycline cannot be used, and many pregnant women cannot tolerate the gastrointestinal side effects associated with erythromycin. However, in one study in which oral erythromycin ethylsuccinate was given to infected pregnant women at a dose of 400 mg four times a day, cure rates of 92% were observed. Only 3% of subjects discontinued medication because of gastrointestinal intolerance. 16 In a subsequent study in pregnant women, oral amoxicillin, 500 mg three times a day for 7 days, was compared with an oral erythromycin base, four times a day for 7 days. There was a slightly higher cure rate in the amoxicillin-treated women, and the regimen was better tolerated. I? In a much smaller study nine infected, pregnant women were treated with comparable doses of amoxicillin for 10 days, and three were not cured. I8 Thus although further evaluation is in order, amoxicillin appears to be an acceptable alternative to erythromycin when erythromycin cannot be tolerated. Limited data indicate that when given for several days, penicillins or erythromycin may also be effective
Table III. In vitro activity of selected antimicrobial agents against C. trachomatis Antzmzcrobial agent
MiC range (pglml)
Tetracycline Doxycycline Erythromycin Clindamycin Azithromycin Ampicillin Sulfamethoxazole Rifampin Ofloxacin Ciprofloxacin Fleroxacin Lomefloxacin Perfloxacin Norfloxacin Enoxacin
0.02-0.5 0.03-0.05 0.05-0.5 0.25-2.0 0.26-1.02 0.2-50 4-50 0.005-0.25 0.5-2.0 1.0-4.0 1.5-2.5 2.0-4.0 2.0-8.0 8.0-16.0 8.0-16.0
- -I- -
See references 24 through 28. MIC, Minimum inhibitory concentration.
for the treatment of chlamydial infections in other situations (Table 11).19.23 However, to date, single-dose or short-course therapy has been ineffective,20 and cephalosporins have not been effective treatment when tried in patients. 23
New antimicrobials Some of the fluoroquinolones and the azalide antibiotic, azithromycin, demonstrate significant promise for the treatment of chlamydial infections. Table III outlines the in vitro susceptibility of C. trachomatis to several of these agents. 24 •28 Ciprofloxacin was one of the first fluoroquinolones to undergo clinical trials for the treatment of chlamy-
1792 Jones
dial infections. 29 • '0 Despite excellent in vitro activity, a substantial incidence of late failures was observed when patients had cultures taken 2 or more weeks after completion of therapy. Norfloxacin is ineffective in the treatment of chlamydiaI infections. 25 Ofloxacin demonstrated in vitro activity comparable with that of ciprofloxacin; however, therapy with a 7-day course of this drug resulted in a 99% cure rate, which is comparable with that of a full course of doxycycline." Because of the prolonged chlamydiallife cycle of 48 to 72 hours, effective antibiotic treatment requires therapeutic levels of a drug at the intracellular site of infection for sustained periods of time. Standard treatment regimens entail multiple daily doses of antibiotic for at least 7 days. Compliance is often poor and recurrence remains a problem. Achieving medical compliance in the sexual partner of the index patient is an additional challenge to eradicating the chlamydial infection. Azithromycin concentrates extensively within cells and has a tissue half-life of approximately 60 hours.'2 Azithromycin levels in human tissues after a single 500 mg dose may exceed the minimum inhibitory concentration of C. trachomatis by threefold to lO-fold for as long as 5 days. Clinical trials are examining the efficacy of twice that dose, I gm, for the treatment ofchlamydia I urethritis and cervicitis. If effective, a single-dose regimen with azithromycin would ensure adequate therapy and eliminate the compliance problem. In two published studies, one conducted in Iceland" and the other in Finland," a single 1 gm dose of oral azithromycin was as effective as 100 mg of doxycycline given twice a day for 7 days in eradicating urogenital C. trachomatis infections in both men and women. Side effects, primarily gastrointestinal, were mild and of similar incidence in the doxycycline and azithromycin groups. Additional data from two multicenter European studies seem to confirm these observations." In summary, new approaches to the treatment of chlamydial cervicitis and urethritis include compounds from the azalide and fluoroquinolone classes. Azithromycin, the first of the azalide antibiotics, offers the promise of efficacious single-dose therapy, an advance that should significantly improve control of this pathogen and help in the prevention of its serious sequelae.
June 1991 Am J Obstet Gynecol
of the same chlamydial serovar in patients with gonococcal infections also suggests that the original infection may not have been cured. A new azalide antibiotic, azithromycin, has been undergoing intensive clinical investigation as single-dose therapy for chlamydial urethritis and cervicitis. A single I gm dose has shown efficacy comparable with a standard 7-day course of doxycycline. The side effect profile has been mild, with an incidence similar to that of doxycycline. Effective single-dose therapy of chlamydial infections with azithromycin will significantly reduce compliance problems and enable greater control of chlamydia in the general population. It is hoped that this will ultimately reduce the serious sequelae caused by the pathogen.
1. 2.
3.
4. 5. 6.
7. 8. 9. 10. 11.
Summary Standard tetracycline, doxycycline, or erythromycin therapy appears to be effective against C. trachomatis infection under most circumstances. Doxycycline has been the preferred treatment because less frequent administration is required. Nevertheless, test-of-cure cultures obtained 4 to 7 days after completion of standard therapy indicate a failure rate of approximately 5%. Frequent recurrence
12. 13. 14.
REFERENCES Alexander ER, Harrison HR. Role of Chlamydia trachomatis in perinatal infection. Rev Infect Dis 1983;5:713-9. Stamm WE, Holmes KK. Chlamydia trachomatis infections of the adult. In: Holmes KK, Mardh P-A, Sparling PF, et aI., eds. Sexually transmitted diseases. 2nd ed. New York: McGraw-Hill, 1990:181-93. Nettleman MD, Jones RB, Roberts SD, et al. Costeffectiveness of culturing for Chlamydia trachomatis. A study in a clinic for sexually transmitted diseases. Ann Intern Med 1986;105:189-96. Sanders LL, Harrison HR, Washington AE. Treatment of sexually transmitted chlamydial infections. JAMA 1986; 255: 1750-6. Centers for Disease Control. 1989 sexually transmitted diseases treatment guidelines. MMWR 1989;38(S-8 suppl): 1-43. WasserheitJN, Bell TA, Kiviat NB, et al. Microbial causes of proven pelvic inflammatory disease and efficacy of c1indamycin and tobramycin. Ann Intern Med 1986;104: 18793. Bowie WR, Yu JS, Jones HD. Partial efficacy of c1indamycin against Chlamydta trachomatis in men with nongonococcal urethritis. Sex Transm Dis 1986;13:76-80. Pearlman MD, Faro S, Riddle GD, Tortolero G. In vitro synergy of c1indamycin and aminoglycosides against Chlamydia trachomatlS. J Clin Microbiol 1990;34: 1399-401. Batteiger BE, Fraiz J, Newhall WJ, Katz BP, Jones RB. Association of recurrent chlamydial infection with gonorrhea. J Infect Dis 1989; 159:661-9. Blythe MJ, Katz BP, Batteiger BE, et al. Recurrent genitourinary C. trachomatis infection in adolescent females. Pediatr Res 1990;27:3A. Bell TA, Stamm WE, Kuo C-C, Holmes KK, GraystonJT. Chronic Chlamydia trachomatis infections in infants. In: Oriel D, Ridgway G, Schachter J, Taylor-Robinson D, Ward M, eds. Chlamydial infections. Proceedings of the Sixth International Symposium on Human Chlamydial Infections, Sanderstead, Surrey, June 15-21, 1986. Cambridge, England: Cambridge University Press, 1986:305-8. Dan M, Rotmensch HH, Eyland E, Rubinstein A, Ginsberg R, Liron M. A case of lymphogranuloma venereum of 20 years' duration. Br J Vener Dis 1980;56:344-6. Ozanne G, Pearce JH. Inapparent chlamydial infection in the urogenital tract of guinea pigs. J Gen Microbiol 1980;119:351-59. Shepard MK,Jones RB. Recovery of Chlamydia trachomatlS from endometrial and fallopian tube biopsies in women with infertility of tubal origin. Fertil Steril 1989;52: 232-8.
Volume ](;4 Number fl, Part 2
15. Jones RB, Van Der Pol B. Chlam}dw /rachoma/I.I isolates re~istant to multIple antibiotics. In: Bowie WR, Caldwell HD, Jones RB. et al., eds Chlamydial Infections. Proceedings of the Seventh International Svmposium on Human Chlamydial Infections, Harrison Hot Spnngs, BritIsh Columbia, Canada, June 24-29, 1990. Cambridge, England: Cambridge University Press, 1990:519-22. 16. Schachter .I, Sweet RL, Grossman M, Landers D, Robbie M, Bishop E. Experience with the routine use of erythromycin for chlamydial infections in pregnancy. N Engl .I Med 1986:314:276-9. 17. Crombleholme WR, Schachter .I, Grossman M, Landers DV, Sweet RY. AmoxlCIllin therapv for Chlam.vdw/rac/wma/I.I in pregnancy. Obstet Gynecol 1990:75:752-6. 18. Bell TA, Sandstrom IK, Eschenback DA, et al. Treatment of Chlam}dw/rrlchoma/1.1 in pregnancy with amoxlcillin In: Mardh PA, Holmes KK, OrielJD, Piot P, SchachterJ, eds. Chlamydial infections. Proceedings of the Fifth International Symposium on Human Chlamydial Infections, Lund, Sweden,June 15-19,1982. Anmerdam, The Netherlands: Elsevier Biomedical Press, 1982:221-4. 19. Cramers M, Kaspersen P, From E, Miller BR. Pivampicillin compared with erythromycin for treating women with genital Chlamvdw /mc/wma/II infection. Genitourin Med 1988;64:247-8. 20. Csango PA, Gunder~en T, Martinsen 1M. Effect of amoxiCllltn on simultaneous Chlamvdw /rachoma/II Infection In men with gonococcal urethrit;s: comparison of three dosage regimens. Sex Transm Dis 1985:12:93-6. 21. Bowie WR, Manzon LM, Borrie-Hume C.J, Fawcett A, Jones HD. Efficacy of treatment regimens for lower urogenital Chlamydw /rac/wma/iS infection in women. A~ .I OIlS rET GY:-.JE(.OL 1982;142:125-9. 22. Martin DH, Pastorek JC; II, Faro S. In vitro and in vivo activity of parenterally administered beta-Iactam antibiotIcs against Chlamvdw /rac/wma/II. Sex Transm Dis 1986;13:81-7. 23. Sweet RL, Schachter .I, Robbie MO. Failure of beta-lactam antibiotics to eradicate Chlamvdw /mc/wma/iS in the endometrium despite apparent cli~ical cure of acute ~alpingItis. .lAMA 1983:250:2641-5. 24. Black JR, Handsfield HH, Hook EW IlL Single-do~e oftoxacin vs. amoxicillin plus probeneCid for treatment of uncomplicated gonococcal infection. Rev Infect Dis 1989: Il(suppI5):SI3l3-4.
New treatments for C. trachomatiS
1793
25. OrielJD. Use of quinolones in chlamydial infectulI1 Rev Infect Dis 1989; II (suppl 5):S 1273-6. 26. Ehret JM, Judson FN. Susceptibility te~ting of Chlamvdw /rac/wma/ls: from eggs to monoclonal antibodies. Antimicrob Agents Chemother 1988;32: 1295-99. 27. Jones RB. Antimicrobial susceptibility testing for some atypical microorganisms: M}coplawul.l, Chlmn.wlwe and Rlckel/.lw. In: Lonan V, ed. Antibiotics in laboratorv medicine. 2nd ed. Baltimore: Williams and Wilkins, 1986:34658. 28. Walsh M, Kappus EW, Qumn TC. In Vitro evaluation of CP-62,993, erythromycin, clindamycin, and tetracycline against Chlam.vdw /rac/wma/iS. AntImicrob Agents Chemother 1987;31:811-2. 29. Fong IW, Linton W, Simbul M, et al Treatment of nongonococcal urethritis with ciproftoxacin. AmJ Med 1987: 82:311-6. 30. van del' Willigen AH, Polak- Vogelzang AA, Habbema L, Wagenvoort JH. Clinical efficacy of ciproftoxacin versus doxycycline in the treatment of nongonococcal urethritis in males. EmJ Clin Microbiol Infect Dis 1988:7:658-61. 31. Batteiger BE, Jones RB, White A. Efficacv and safety of oftoxacin in the treatment of nongonococcal sexually transmitted disease. AmJ Med 1989:87(suppl 6C):75S7S. 32. Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in human serum and tissues. .I Antimicrob Chemother 1990;25(suppl A):73-82. 33. Stemgrimsson 0, Olafsson JH, Thorannsson H, Ryan RW, Johnson RB, Tilton RC. Azithromycinin the treatment of sexually transmitted disease. .I Antimtcrob Chemother 1990;25(suppl A)·'09-14. 34. Lassus A. Comparative studies of azIthromycin in skin and soft-tissue infection and sexually transmitted infections by Nel.I.lerw and Chlamydia species. .I AntImicrob Chemother 1990:25(suppl A).115-21. 35. Johnson RB, Azithromycin treatment of gemtal chlamydial infections In: BOWie WR, Caldwell HD, Jones RP, et aI., eds. Chlamydial infections. Proceedings of the Seventh International SymposIUm on Human Chlamydial Infections, Harnson Hot Spnngs, British Columbia, Canada, June 24-29, 1990. Cambridge, England: Cambridge U niversity Pre~s, 1990:534-6.