Azithromycin versus Penicillin for Early Syphilis
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In their study on the treatment of early syphilis, Riedner et al. (Sept. 22 issue)1 concluded that the wider use of oral azithromycin should be encouraged as part of syphilis-control programs in developing countries. Whereas this conclusion would appear to be rational on the basis of the authors' results, we believe that there are other factors that should be considered before opting for such a strategy.
Although the authors acknowledged the potential for the emergence of azithromycin-resistant Treponema pallidum, ongoing monitoring for such resistance, as they suggested, requires molecular-sequencing techniques,2 which are unavailable in most developing countries. More important, the inability of azithromycin to cross the placenta3 limits its use in the prevention of congenital disease. Treatment of seropositive mothers with oral azithromycin, after routine antenatal screening, could result in declining maternal titers on the rapid plasma reagin test without affecting the potential for fetal infection.
Since the prevention of congenital syphilis remains a major objective of control programs and is a current focus for global elimination activities,4 we believe that azithromycin has only a limited role in the management of syphilis in resource-constrained settings.
Ronald C. Ballard, Ph.D.
Stuart M. Berman, M.D., Sc.M.
Kevin A. Fenton, M.D., Ph.D., M.F.P.H.
Centers for Disease Control and Prevention
Atlanta, GA 30333
rballard@cdc.gov
References
Riedner G, Rusizoka M, Todd J, et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med 2005;353:1236-1244.
Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 2004;351:154-158.
Heikkinen T, Laine K, Neuvonen PJ, Ekblad U. The transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin. BJOG 2000;107:770-775.
Maternal and congenital syphilis. Bull World Health Organ 2004;82:399-478.
To the Editor: Riedner and colleagues report that azithromycin is equivalent to penicillin G benzathine in treating early syphilis and may be useful in developing countries in which use of penicillin G benzathine is problematic, and they alert us about the cases of azithromycin-resistant T. pallidum. In Brazil, we struggle even with inexpensive drugs, such as penicillin G benzathine; azithromycin is not widely available and can be 10 times as expensive as penicillin G benzathine. We believe that it is not wise to change from a known, inexpensive drug with few cases of resistance after a half century of use1 to a more expensive, unfamiliar drug that has already shown resistance after a few years of use.2 Thus, the implementation of azithromycin in developing countries remains prohibitive because of the cost and because of the possibility of resistance, and this drug should not be used as a first choice yet.
Ricardo F. Savaris, M.D.
Alberto M. Abeche, M.D.
Universidade Federal do Rio Grande do Sul
90035-003 Porto Alegre, Brazil
rsavaris@hcpa.ufrgs.br
References
Stapleton JT, Stamm LV, Bassford PJ Jr. Potential for development of antibiotic resistance in pathogenic treponemes. Rev Infect Dis 1985;7:Suppl 2:S314-S317.
Azithromycin treatment failures in syphilis infections -- San Francisco, California, 2002-2003. MMWR Morb Mortal Wkly Rep 2004;53:197-198.
To the Editor: Riedner and colleagues demonstrated the successful treatment of early syphilis with azithromycin. Holmes's accompanying editorial laments the absence of prospective data on patients treated for early syphilis with azithromycin and the influence of molecularly defined azithromycin-resistant T. pallidum on treatment outcomes.1
In San Francisco, where an estimated 56 percent of circulating strains of T. pallidum were resistant to azithromycin in 2004,2 we conducted a randomized, controlled trial of azithromycin (1 g given orally as a single dose) as compared with penicillin G benzathine (2.4 million units intramuscularly) in sexual contacts of persons with infectious syphilis; our aim was to compare the efficacy of the two drugs for the treatment of incubating syphilis. A data safety monitoring board (DSMB) supervised the study.
After two treatment failures in the 12 patients receiving azithromycin as compared with none in 13 patients receiving penicillin, the DSMB terminated the study (P=0.18, by Fisher's exact test). Although it was a small study sample (n=25), our data suggest that azithromycin was inferior to penicillin in the presence of high community levels of azithromycin-resistant T. pallidum. Although we have feasible methods to monitor macrolide resistance in T. pallidum, routine surveillance is not currently supported by federal agencies.
Jeffrey D. Klausner, M.D., M.P.H.
Robert P. Kohn, M.P.H.
Charlotte K. Kent, M.P.H.
San Francisco Department of Public Health
San Francisco, CA 94103
jeff.klausner@sfdph.org
Dr. Klausner reports having received honoraria from King Pharmaceuticals and a research grant from Pfizer.
References
Holmes KK. Azithromycin versus penicillin G benzathine for early syphilis. N Engl J Med 2005;353:1291-1293.
Klausner JD, Mitchell SJ, Lukehart SA, Gordones C, Engelman J. Rapid and large increase in azithromycin resistance in syphilis whilst low steady resistance in gonorrhea 2000-2004. In: Program and abstracts of the 16th Biennial Meeting of the International Society for Sexually Transmitted Diseases Research, Amsterdam, July 10–13, 2005.
The authors reply: We agree with Ballard et al. that further studies are needed before azithromycin can be recommended for the treatment of syphilis in pregnancy, although studies in women undergoing cesarean section have shown that azithromycin does cross the placenta.1
Resistance is clearly a concern in view of the high proportion of strains of T. pallidum found among men who have sex with men in the United States and Ireland that contain mutations that may confer resistance to macrolides. The clinical significance of this mutation has not been definitively established, although the small study by Klausner et al.2 provides some support for such a link. The results of our trial suggest that azithromycin resistance is not currently a clinically significant problem among heterosexual patients in Tanzania. We recognize that most laboratories in Africa do not have the facilities to identify mutations in local strains of T. pallidum. In view of the considerable advantages that would be conferred by a single-dose oral treatment for syphilis, however, we believe further studies are warranted to study the geographic distribution and clinical significance of strains bearing this mutation.
We do not agree with Savaris and Abeche that azithromycin is too expensive to be used for the treatment of syphilis in developing countries. Generic supplies of the drug, made in India, have been available for some years at a cost of approximately $1.20 for a 2-g dose.3 Azithromycin came off patent in the United States in November 2005. Although penicillin G benzathine is an inexpensive drug, the cost of administering it has to include the cost of the needle and syringe.
Despite the issues raised by the correspondents, we consider that single-dose azithromycin may have a place in the treatment of early syphilis and in the management of genital-ulcer disease at the primary health care level in developing countries.
Gabriele Riedner, M.D., Ph.D.
London School of Hygiene and Tropical Medicine
London WC1E 7HT, United Kingdom
riednerg@emro.who.int
Heiner Grosskurth, M.D., Ph.D.
Uganda Virus Research Institute
Entebbe, Uganda
Richard Hayes, D.Sc.
London School of Hygiene and Tropical Medicine
London WC1E 7HT, United Kingdom
References
Ramsey PS, Vaules MB, Vasdev GM, Andrews WW, Ramin KD. Maternal and transplacental pharmacokinetics of azithromycin. Am J Obstet Gynecol 2003;188:714-718.
Klausner JD, Mitchell SJ, Lukehart SA, Gordones C, Engelman J. Rapid and large increase in azithromycin resistance in syphilis whilst low steady resistance in gonorrhea 2000-2004. In: Program and abstracts of the 16th Biennial Meeting of the International Society for Sexually Transmitted Diseases Research, Amsterdam, July 10–13, 2005.
Pepin J, Mabey D. Sexually transmitted infections in Africa: single dose treatment is now affordable. Sex Transm Infect 2003;79:432-434.
The editorialist replies: It is striking that the first randomized trial demonstrating azithromycin's efficacy for early syphilis in Africa was conducted virtually simultaneously with the emergence of azithromycin-resistance mutations in T. pallidum in all five cities where such mutations were sought in the United States and Ireland. This may represent a world record for the adaptation of a pathogen to an antimicrobial agent newly proved effective to treat it — and this by an organism not previously known for its propensity to develop resistance to other antimicrobial agents. Reservations about the use of azithromycin for the treatment of early syphilis are clearly warranted.
Fortunately, T. pallidum remains fully susceptible to penicillin G benzathine worldwide, and the forthcoming 2006 Sexually Transmitted Disease Guidelines from the Centers for Disease Control and Prevention will correctly recommend that "penicillin G, administered parenterally, is the preferred drug for treatment of all stages of syphilis" and that the recommended regimen for adults with primary, secondary, or early latent syphilis is "benzathine penicillin G 2.4 million units IM in a single intramuscular dose."
King K. Holmes, M.D., Ph.D.
University of Washington
Seattle, WA 98195
Although the authors acknowledged the potential for the emergence of azithromycin-resistant Treponema pallidum, ongoing monitoring for such resistance, as they suggested, requires molecular-sequencing techniques,2 which are unavailable in most developing countries. More important, the inability of azithromycin to cross the placenta3 limits its use in the prevention of congenital disease. Treatment of seropositive mothers with oral azithromycin, after routine antenatal screening, could result in declining maternal titers on the rapid plasma reagin test without affecting the potential for fetal infection.
Since the prevention of congenital syphilis remains a major objective of control programs and is a current focus for global elimination activities,4 we believe that azithromycin has only a limited role in the management of syphilis in resource-constrained settings.
Ronald C. Ballard, Ph.D.
Stuart M. Berman, M.D., Sc.M.
Kevin A. Fenton, M.D., Ph.D., M.F.P.H.
Centers for Disease Control and Prevention
Atlanta, GA 30333
rballard@cdc.gov
References
Riedner G, Rusizoka M, Todd J, et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med 2005;353:1236-1244.
Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 2004;351:154-158.
Heikkinen T, Laine K, Neuvonen PJ, Ekblad U. The transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin. BJOG 2000;107:770-775.
Maternal and congenital syphilis. Bull World Health Organ 2004;82:399-478.
To the Editor: Riedner and colleagues report that azithromycin is equivalent to penicillin G benzathine in treating early syphilis and may be useful in developing countries in which use of penicillin G benzathine is problematic, and they alert us about the cases of azithromycin-resistant T. pallidum. In Brazil, we struggle even with inexpensive drugs, such as penicillin G benzathine; azithromycin is not widely available and can be 10 times as expensive as penicillin G benzathine. We believe that it is not wise to change from a known, inexpensive drug with few cases of resistance after a half century of use1 to a more expensive, unfamiliar drug that has already shown resistance after a few years of use.2 Thus, the implementation of azithromycin in developing countries remains prohibitive because of the cost and because of the possibility of resistance, and this drug should not be used as a first choice yet.
Ricardo F. Savaris, M.D.
Alberto M. Abeche, M.D.
Universidade Federal do Rio Grande do Sul
90035-003 Porto Alegre, Brazil
rsavaris@hcpa.ufrgs.br
References
Stapleton JT, Stamm LV, Bassford PJ Jr. Potential for development of antibiotic resistance in pathogenic treponemes. Rev Infect Dis 1985;7:Suppl 2:S314-S317.
Azithromycin treatment failures in syphilis infections -- San Francisco, California, 2002-2003. MMWR Morb Mortal Wkly Rep 2004;53:197-198.
To the Editor: Riedner and colleagues demonstrated the successful treatment of early syphilis with azithromycin. Holmes's accompanying editorial laments the absence of prospective data on patients treated for early syphilis with azithromycin and the influence of molecularly defined azithromycin-resistant T. pallidum on treatment outcomes.1
In San Francisco, where an estimated 56 percent of circulating strains of T. pallidum were resistant to azithromycin in 2004,2 we conducted a randomized, controlled trial of azithromycin (1 g given orally as a single dose) as compared with penicillin G benzathine (2.4 million units intramuscularly) in sexual contacts of persons with infectious syphilis; our aim was to compare the efficacy of the two drugs for the treatment of incubating syphilis. A data safety monitoring board (DSMB) supervised the study.
After two treatment failures in the 12 patients receiving azithromycin as compared with none in 13 patients receiving penicillin, the DSMB terminated the study (P=0.18, by Fisher's exact test). Although it was a small study sample (n=25), our data suggest that azithromycin was inferior to penicillin in the presence of high community levels of azithromycin-resistant T. pallidum. Although we have feasible methods to monitor macrolide resistance in T. pallidum, routine surveillance is not currently supported by federal agencies.
Jeffrey D. Klausner, M.D., M.P.H.
Robert P. Kohn, M.P.H.
Charlotte K. Kent, M.P.H.
San Francisco Department of Public Health
San Francisco, CA 94103
jeff.klausner@sfdph.org
Dr. Klausner reports having received honoraria from King Pharmaceuticals and a research grant from Pfizer.
References
Holmes KK. Azithromycin versus penicillin G benzathine for early syphilis. N Engl J Med 2005;353:1291-1293.
Klausner JD, Mitchell SJ, Lukehart SA, Gordones C, Engelman J. Rapid and large increase in azithromycin resistance in syphilis whilst low steady resistance in gonorrhea 2000-2004. In: Program and abstracts of the 16th Biennial Meeting of the International Society for Sexually Transmitted Diseases Research, Amsterdam, July 10–13, 2005.
The authors reply: We agree with Ballard et al. that further studies are needed before azithromycin can be recommended for the treatment of syphilis in pregnancy, although studies in women undergoing cesarean section have shown that azithromycin does cross the placenta.1
Resistance is clearly a concern in view of the high proportion of strains of T. pallidum found among men who have sex with men in the United States and Ireland that contain mutations that may confer resistance to macrolides. The clinical significance of this mutation has not been definitively established, although the small study by Klausner et al.2 provides some support for such a link. The results of our trial suggest that azithromycin resistance is not currently a clinically significant problem among heterosexual patients in Tanzania. We recognize that most laboratories in Africa do not have the facilities to identify mutations in local strains of T. pallidum. In view of the considerable advantages that would be conferred by a single-dose oral treatment for syphilis, however, we believe further studies are warranted to study the geographic distribution and clinical significance of strains bearing this mutation.
We do not agree with Savaris and Abeche that azithromycin is too expensive to be used for the treatment of syphilis in developing countries. Generic supplies of the drug, made in India, have been available for some years at a cost of approximately $1.20 for a 2-g dose.3 Azithromycin came off patent in the United States in November 2005. Although penicillin G benzathine is an inexpensive drug, the cost of administering it has to include the cost of the needle and syringe.
Despite the issues raised by the correspondents, we consider that single-dose azithromycin may have a place in the treatment of early syphilis and in the management of genital-ulcer disease at the primary health care level in developing countries.
Gabriele Riedner, M.D., Ph.D.
London School of Hygiene and Tropical Medicine
London WC1E 7HT, United Kingdom
riednerg@emro.who.int
Heiner Grosskurth, M.D., Ph.D.
Uganda Virus Research Institute
Entebbe, Uganda
Richard Hayes, D.Sc.
London School of Hygiene and Tropical Medicine
London WC1E 7HT, United Kingdom
References
Ramsey PS, Vaules MB, Vasdev GM, Andrews WW, Ramin KD. Maternal and transplacental pharmacokinetics of azithromycin. Am J Obstet Gynecol 2003;188:714-718.
Klausner JD, Mitchell SJ, Lukehart SA, Gordones C, Engelman J. Rapid and large increase in azithromycin resistance in syphilis whilst low steady resistance in gonorrhea 2000-2004. In: Program and abstracts of the 16th Biennial Meeting of the International Society for Sexually Transmitted Diseases Research, Amsterdam, July 10–13, 2005.
Pepin J, Mabey D. Sexually transmitted infections in Africa: single dose treatment is now affordable. Sex Transm Infect 2003;79:432-434.
The editorialist replies: It is striking that the first randomized trial demonstrating azithromycin's efficacy for early syphilis in Africa was conducted virtually simultaneously with the emergence of azithromycin-resistance mutations in T. pallidum in all five cities where such mutations were sought in the United States and Ireland. This may represent a world record for the adaptation of a pathogen to an antimicrobial agent newly proved effective to treat it — and this by an organism not previously known for its propensity to develop resistance to other antimicrobial agents. Reservations about the use of azithromycin for the treatment of early syphilis are clearly warranted.
Fortunately, T. pallidum remains fully susceptible to penicillin G benzathine worldwide, and the forthcoming 2006 Sexually Transmitted Disease Guidelines from the Centers for Disease Control and Prevention will correctly recommend that "penicillin G, administered parenterally, is the preferred drug for treatment of all stages of syphilis" and that the recommended regimen for adults with primary, secondary, or early latent syphilis is "benzathine penicillin G 2.4 million units IM in a single intramuscular dose."
King K. Holmes, M.D., Ph.D.
University of Washington
Seattle, WA 98195