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In March 2004, the Los Angeles County Department of Health Services
(LACDHS) was notified that a large nonprofit clinic serving the gay and lesbian
community in Los Angeles used a nonrecommended preparation of penicillin to
treat syphilis patients during January 1999–March 2004. The clinic had
inadvertently used Bicillin® C-R, a mixture of 1.2 million
units (MU) benzathine penicillin G (BPG) and 1.2 MU procaine penicillin G,
rather than Bicillin® L-A, a preparation that contains the
2.4 MU BPG per dose recommended by CDC.1 Bicillin
L-A is recommended for treating syphilis and upper respiratory tract infections
caused by susceptible streptococci.2 Bicillin
C-R is indicated for streptococcal infections of the skin and respiratory
tract; however, its efficacy in treating syphilis is unknown. The inadvertent
use of Bicillin C-R, which contains only half the recommended dose of BPG
for syphilis, was discovered after a patient treated for syphilis read the
product insert, which stated that the medication was not indicated for treatment
of syphilis. Review of clinic pharmacy records revealed that it received a
shipment of Bicillin C-R in lieu of an unfilled order for Bicillin L-A in
late 1998 and that the pharmacy subsequently ordered Bicillin C-R until March
2004. The clinic used Bicillin C-R as its exclusive formulation of injectable
penicillin during January 1999–March 2004. This report summarizes the
investigation of the misuse of Bicillin C-R at the Los Angeles clinic, which
represents the largest occurrence of inadvertent treatment with Bicillin C-R
to date. The investigation led to discussions among CDC, the Food and Drug
Administration (FDA), and King Pharmaceuticals, Inc. (Bristol, Tennessee),
whose Monarch Pharmaceuticals subsidiary markets Bicillin products. As a result,
King Pharmaceuticals agreed to institute packaging and labeling changes to
Bicillin products to prevent inadvertent treatment of syphilis with Bicillin
Five BPG-containing products are marketed by Monarch: Bicillin L-A,
Bicillin® L-A Pediatric (0.6 MU BPG), Bicillin C-R, Bicillin® C-R Pediatric (a mixture of 0.3 MU BPG and 0.3 MU procaine penicillin
G), and Bicillin® C-R 900/300 (a mixture of 0.9 MU BPG and
0.3 MU procaine penicillin G). Despite a change in package color in 2002 to
distinguish Bicillin C-R from Bicillin L-A,3 the
proprietary names and package appearances remained similar for the two formulations.
The product insert sheet included a warning against the use of Bicillin C-R
for treatment of syphilis.
Investigators reviewed databases from the clinic and from the LACDHS
Sexually Transmitted Disease (STD) Program to identify patients who were treated
during January 1999–March 2004 for confirmed syphilis infection or because
of contact with a person known or suspected to have syphilis. All available
data on treatment were evaluated.
During January 1999–March 2004, a total of 429 patients were treated
with Bicillin C-R for confirmed syphilis infection at the clinic. An additional
234 patients were treated with Bicillin C-R at the clinic for reported sexual
contact with someone who was known or suspected to be infected with syphilis
(contacts). Of persons with confirmed syphilis, none were female, and 215
(50%) were known to be infected with human immunodeficiency virus (HIV). Five
(2%) contacts were female, and 10 (4%) contacts were known to be infected
with HIV. No female patients were pregnant during or after treatment with
Clinic staff attempted to reach syphilis patients and contacts treated
with Bicillin C-R by letter, up to three telephone calls, and, if necessary,
telephone calls to emergency contacts listed on medical records. In addition,
the clinic and LACDHS issued press releases to inform potentially affected
patients and local health-care providers. LACDHS public health investigators
attempted to reach patients whom the clinic was unable to locate or contact.
A standard protocol was developed to retest and retreat all patients
and contacts who had been treated with Bicillin C-R for syphilis. All patients
were offered retreatment regardless of retesting results. Patients with a
confirmed syphilis diagnosis were evaluated by clinic medical staff, retested
with quantitative rapid plasma reagin (RPR) tests, and advised to undergo
lumbar puncture for cerebrospinal fluid analysis if they had either clinical
manifestations suggestive of neurosyphilis or evidence of treatment failure
(e.g., less than a fourfold decline in RPR titer since initial treatment).
Contacts were tested with a specific treponemal test, and those with a reactive
test were managed in the same way as those with a confirmed syphilis diagnosis.
Patients were offered retreatment with a CDC-recommended regimen appropriate
for their stage of infection.
As of January 26, 2005, of the 429 patients with confirmed syphilis,
282 (66%) were successfully contacted; 255 (59%) were retreated, 19 (4%) refused
retreatment, and eight (2%) are pending evaluation. Of those who were retreated,
19 (4%) underwent lumbar puncture for suspected treatment failure. One patient
treated for syphilis with Bicillin C-R subsequently had neurosyphilis diagnosed.
Of the 234 contacts, 116 (50%) were successfully contacted, 98 (42%) were
retested, and 15 (6%) are pending evaluation. Of the 98 contacts who were
retested, 22 (22%) had serologic evidence of previous syphilis infection,
and 19 (19%) were retreated; three (3%) refused retreatment.
Operations at the clinic were disrupted for approximately 6 months.
The clinic reassigned professional and clerical staff to the evaluation and
retreatment effort, and some clinic activities were postponed or canceled.
In addition, LACDHS dedicated two public health investigators to this effort
for nearly 4 months.
R Bolan, MD, P Amezola, MPH, Los Angeles Gay and Lesbian Center; P Kerndt,
MD, Los Angeles County Dept of Health Svcs, California. J Soreth, MD, Food
and Drug Admin. M Taylor, MD, J Heffelfinger, MD, H Weinstock, MD, Div of
STD Prevention, National Center for HIV, STD, and TB Prevention; M Greenberg,
MD, M Janowski, MD, EIS officers, CDC.
Inadvertent use of Bicillin C-R for treatment of syphilis was documented
in several STD programs during 1993-1998.4 However,
its misuse in treating approximately 660 persons in a Los Angeles clinic during
January 1999–March 2004 is the largest reported occurrence to date and
posed considerable clinical and programmatic challenges.
Compared with procaine penicillin G, use of BPG results in detectable
serum concentrations that are prolonged (up to 30 days for BPG, compared with
up to 7 days for procaine penicillin G). Prolonged serum concentration is
considered essential for treating syphilis effectively because sustained spirocheticidal
levels are required to treat the slowly reproducing agent of syphilis, Treponema pallidum. Treatment of syphilis with half the
recommended dose of BPG might have increased the risk for syphilis treatment
failure and neurosyphilis, particularly among those infected with HIV.5-7 However, treatment failure
and neurosyphilis can occur even with recommended penicillin regimens in persons
with and without HIV infection.8 Therefore,
whether treatment failures that occurred among those treated with Bicillin
C-R represent an excess over what would be expected had they been treated
with Bicillin L-A cannot be determined without additional data. An investigation
by CDC and state and local health departments is assessing whether treatment
failure was more common in patients treated with Bicillin C-R than in a similar
population treated with Bicillin L-A. Such inadvertent use entails discomfort
and inconvenience to patients because it requires retesting and possible retreatment
for syphilis. In addition, inadequate treatment of syphilis might have contributed
to an increase in the local transmission of the disease.
In May 2004, CDC contacted FDA about the inadvertent use of Bicillin
C-R. FDA worked with CDC and King Pharmaceuticals to design and implement
changes to the product labeling, including more easily visible carton-color
changes to distinguish L-A and C-R formulations, and the warning, “not
for the treatment of syphilis,” printed directly on syringes and cartons
of Bicillin C-R. In November 2004, King Pharmaceuticals distributed a letter
to clinicians, professional societies, and STD programs throughout the United
States, alerting them to the potential for confusing Bicillin C-R with Bicillin
L-A, the appropriate use of each formulation, changes in product labels, and
mechanisms for reporting inadvertent use of Bicillin C-R for treatment of
Education of clinic managers, pharmacists, and providers in the proper
use of different penicillin preparations might help reduce the inappropriate
use of Bicillin products. Providers, STD clinics, and pharmacies should review
their product records and tracking systems for ordering and delivering penicillin
treatments for syphilis.
Inadvertent Use of Bicillin. JAMA. 2005;293(16):1967–1968. doi:10.1001/jama.293.16.1967