Treatment of Late Syphilis With 2.4 Million Units Benzathine Penicillin G (BPG): Tolerance of Single Versus Divided Doses

Janier, Michel PhD, MD*; Libar, Eliane NP*; Bonnet, Annie NP*; Meunier, Patrick NP*; Tabet, Magda NP*; Mathourais, Monique NP*; Paterour, Christine NP*; Porcher, Raphael MD, PhD

Sexually Transmitted Diseases:
doi: 10.1097/OLQ.0b013e318249968c
Case Report

Although there is no data in the literature, some textbooks recommend fractioning the injection of benzathine penicillin G (BPG) for alleviating the pain. In a monocentric study done in 50 consecutive patients with late syphilis. Patients were assigned to receive 1 dose of 2.4 million units BPG intramuscularly the first week and 2 doses of 1.2 million units BPG in each buttock the second week. In the third week, patients were asked to choose between the 2 options. It was demonstrated that the 2 techniques were equally well tolerated and equally preferred by patients.

Author Information

From the *Centre des MST, Hôpital St-Louis, AP-HP, Paris, France; Département de Biostatistiques, Hôpital St-Louis, AP-HP, Paris, France

Correspondence: Michel Janier, PhD, MD, STD Clinic, Centre des MST, Hôpital St-Louis, AP-HP, 42 rue Bichat, Paris 75010, France. E-mail:

Received for publication August 22, 2011, and accepted December 20, 2011.

Article Outline

Benzathine penicillin G (BPG) was synthesized by J. Lester Szabo in 1951 as an insoluble salt of penicillin (N-N′ dibenzyl ethylene diamine),1 conferring the enormous benefit of a very long half-life and action after a single intramuscular (intramuscularly) injection. It was subsequently used for treating syphilis and various conditions such as prevention of erysipela and rheumatic fever.

The use of BPG is somewhat hampered by the volume and insolubility of the penicillin salt with 2 closely related consequences: the injection is painful, and it is impossible to administer the product in another way than intramuscular.

An international consensus has at last been reached for recommending BPG as the first-choice treatment of both early syphilis (1 dose of 2.4 million units intramuscularly) and late syphilis (3 weekly doses of 2.4 million units intramuscularly), both in the French,2 European,3 US,4 and WHO5 guidelines.

In some textbooks and guidelines, such as in the European guidelines3 and WHO guidelines,5 therapy options are 1 single dose of 2.4 million units BPG or 2 doses of 1.2 million units BPG in each buttock, but we could not find any data on the subject favoring one or the other. In the Centers for Disease Control guidelines,4 there is no comment on the possibility of administering divided doses. In the WHO guidelines, it is stated that because of the volume, the dose of 2.4 mol/L is usually given as 2 injections at separate sites.5 Reconstitution of BPG in 1% lidocaine is recommended in the French2 and International Union against Sexually Transmitted Infections (IUSTI)-Europe guidelines3 because the injection is painful, the same volume of solvent, that is, 1 cc being replaced by lidocaine 1% solution (without epinephrine). This option is not possible in countries (such as, United States and Canada) where BPG is available only in prefilled syringes of 1.2 and 2.4 million units without lidocaine. Moreover, the dexterity of the nurse may be very important, the injection being difficult because of the thickness of the salt. Many other factors may also influence tolerance, such as the position of the patient (standing as it has for long being the preference in Hôpital Saint-Louis or lying), the site of injection in the buttock, the temperature of the penicillin salt, and so forth.

There are theoretical arguments for one or the other, dividing the volume by 2 could also divide the pain but needs 2 injections and a possible bilateral buttock discomfort.

Therefore, we decided to launch a pilot study aiming to compare the possible advantage of administering twice half dose or once full dose of BPG.

Fifty consecutive patients treated for late syphilis or syphilis of unknown duration with the classic scheme of 3 weekly intramuscular doses of 2.4 million units BPG were included in the study between September 2007 and June 2010, after informed consent. Patients with a history of allergy to penicillin or haemostasis anomalies were excluded. The first injection (day 0) was made in 1 buttock, 2.4 million units BPG in 7-cc saline serum and 1 cc 1% lidocaine. Second injection (day 7) was made in each buttock 1 dose of 1.2 million units BPG in 3.5-cc saline serum and 0.5 cc 1% lidocaine. Pain evaluation was made at day 7 and day 14 with the Senscale model (1 to 10).6 For the last injection at day 14, patients were asked to choose between the 2 methods, the choice being the study end point.

There were 40 men and 10 women, median age of 34 years (21 to 64 years). Twenty-five men were men who have sex with men. None had symptoms of tertiary syphilis. Median venereal diseases research laboratory (VDRL) was 1:4 (nonreactive to 1:256), median treponema pallidum haemagglutination (TPHA) was 1:2560 (1:80–1:10,240). Three patients refused to have 2 injections at day 7. Three were lost for follow-up after the first injection. And 3 other attended the day 7, but not the day 14. Mean pain was 3.1 (0–8) after the first shoot and 2.7 (0–7) after the divided dose. The difference was not significant (P = 0.28, paired Student test). Finally, among the 44 patients who made a choice at day 14, 22 chose the classic scheme and 22, the divided scheme.

Although many factors may interfere with the production of the pain after injection of BPG and particularly the dexterity of the nurse, this study argues for the equivalence of the 2 schemes and does not encourage to launch a more ambitious study.

The issue of this study may not be relevant all over the world. Many countries have difficulties in BPG supply, although the product is very cheap. In other countries, BPG may be supplied primarily only in 1.2 million units or only in 2.4 million units, encouraging the use of one or the other. In the United States and Canada, BPG is supplied only in prefilled syringes, hampering the reconstitution in lidocaine, and thus the results with lidocaine cannot be extrapolated to injections without lidocaine. One injection of 2.4 million units in 1 single shot has the advantage of simplicity and had the preference of a majority of nurses in our Hospital. We propose it as a first choice. If the pain has been strong after the first injection, one can propose the divided scheme at day 7. At day 14, the patient will choose the best personal option. These data may help the professionals to choose the best option in their own country.

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1. Szabo JL, Edwards CD, Bruce WF. N-N′-dibenzylethylenediamine penicillin: Preparation and properties. Antibiot Chemother 1951; 1:499–503.
2. Janier M, Dupin N, Gerhardt P, et al.. Syphilis in Maladies sexuellement transmissibles, Recommandations diagnostiques et thérapeutiques. Ann Dermatol Venereol 2006; 133:2S19–2S27.
3. French P, Gomberg M, Janier M, et al.. IUSTI 2008 European Guidelines on the management of syphilis. Int J STD AIDS 2009; 20:300–309.
4. Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines 2010. Morb Mortal Wkly Rep 2010; 59(RR-12):26–40.
5. WHO. Guidelines for the management of sexually transmitted infections. 2003:40–44.
6. Bowel A. The Mc Gill Pain questionnaire in measuring disease. Open University Press, 1994:31–32.
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