REVIEW gREVIEW j

Benzathine Penicillin G for the Management of RHD

Concerns About Quality and Access, and Opportunities
for Intervention and Improvement
Rosemary Wyber*, Kathryn Tauberty, Stephen Markoz, Edward L. Kaplanx
Perth, Western Australia, Australia; Geneva, Switzerland; Farmington, CT, USA; and Minneapolis, MN, USA

ABSTRACT
Benzathine penicillin G is an important antibiotic for the treatment and prevention of group A streptococcal
infections associated with rheumatic fever and rheumatic heart disease. However, as rheumatic heart disease
has receded as a public health priority in most high-income settings, attention to the supply, manufacture, and
accessibility of benzathine penicillin G has declined. Concerns about the quality, efficacy, and innovation of
the drug have emerged following plasma analysis and anecdotal reports from low-resource settings. This
review collates core issues in supply and delivery of benzathine penicillin G as a foundation for concerted
efforts to improve global quality and access. Opportunities for intervention and improvement are explored.

Rheumatic fever (RF) and rheumatic heart disease targeted searches of public records revealing patent infor-
(RHD) are an autoimmune sequel of group A streptococcal mation, commercial details, and correspondence.
(GAS) infections. Recurrences of RF accelerate progression
of cardiac valve damage, culminating in heart failure, ar- PHARMACOLOGY OF BPG
rhythmias, and often fatalities. The global burden of RF/ Benzathine penicillin G is a crystalline powder formed
RHD is significanteconservatively estimated at 471,000 through the fusion of 2 penicillin G molecules and charac-
cases of RF annually and 233,000 deaths per year. At least terized by very low solubility and in vivo hydrolysis
15.6 million people suffer from RF/RHD worldwide. RF/ [2,12e14]. These features are associated with slow absorp-
RHD is a neglected disease of poverty endemic in low- tion from IM injection, producing prolonged therapeutic
resource settings and some subpopulations in high- serum concentrations [12,15]. Prolonged concentration in
income countries [1]. serum provides excellent protection from GAS infection. No
Antibiotics are essential for prophylaxis to prevent GAS resistance to BPG has been documented in vitro [16].
recurrences of RF (secondary prophylaxis) and for treatment The mechanism for the apparent persistent susceptibility of
of symptomatic GAS infections (primary prevention). Since GAS to BPG is relatively poorly understood [15,17,18].
the 1950s, prophylaxis has been achieved via intramuscular
(IM) administration of benzathine penicillin G (BPG) [2].
Although other antibiotics have been used, BPG is a partic- DISEASES, DOSES, AND DEMANDS FOR BPG
From the *Telethon Insti-
ularly effective agent for primary and secondary prevention From the 1950s, BPG was widely used as the first list drug for tute for Child Health
because its long half-life provides prolonged bactericidal an array of conditions: syphilis, yaws, Lyme disease, and Research, Perth, Western
protection from GAS infection. With effective secondary pneumococcal prophylaxis in sickle cell disease [19e21]. Australia, Australia; yWorld
However, development of new antibiotics has narrowed the Heart Federation, Geneva,
prophylaxis recurrence, the progression of RF to RHD can be Switzerland; zUniversity of
prevented [3,4]. A small number of oral alternatives for RF clinical indications for BPG. Conditions requiring BPG
Connecticut School of
secondary prophylaxis have been used; these are all less treatment have also become less common in high-resource Medicine, Farmington, CT,
effective than IM BPG in preventing recurrences of RF settings, further shrinking demand. This section profiles USA; and xUniversity of
[3,5,6]. Alternative regimes for individuals with severe the existing indications for BPG, providing a foundation for Minnesota Medical School,
much-needed research work on the potential size of com- Minneapolis, MN, USA.
penicillin allergy or intolerance are addressed in most Correspondence: R. Wyber
RF/RHD treatment guidelines but are outside the scope of mercial markets. ([email protected]).
this review [5,7e11]. GLOBAL HEART
This review presents an overview of the current issues Secondary prophylaxis for RHD © 2013 World Heart
surrounding BPG for the management of RHD and RF. Federation (Geneva).
The World Health Organization (WHO) defines secondary
Published by Elsevier Ltd.
A systematic search of peer-reviewed literature identified a prophylaxis as “the continuous administration of specific Open access under
small number of basic science articles and commentaries antibiotics to patients with a previous attack of rheumatic CC BY-NC-ND license.
VOL. 8, NO. 3, 2013
on BPG. Expanding bibliographic review identified a range fever, or well-documented rheumatic heart disease. The ISSN 2211-8160
of other articles documenting concerns about supply, purpose is to prevent colonization or infection of the upper http://dx.doi.org/10.1016/
quality, and access. These issues were explored with respiratory tract with group A beta-hemolytic streptococci j.gheart.2013.08.011

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j gREVIEW

and the development of recurrent attacks of rheumatic treating pregnant women to prevent transmission to the
fever” [9]. The internationally accepted dose for secondary fetus and avert congenital syphilis in neonates [30,31].
prophylaxis with BPG in adults is 900 mg (1.2 million IU)
intramuscularly. There is some uncertainly over the opti-
Yaws
mum frequency of administration; some papers suggest
Yaws is a skin infection caused by the spirochete bacterium
2-weekly administration [22], others report very good
Treponema pallidum subspecies pertenue, which is related to
outcomes on a 3-weekly regime [23,24]. Most guidelines
the causative organism of syphilis. The disease is estimated
recommend 4-weekly administration as a pragmatic
to affect approximately half a million people, predomi-
choice, with an option to escalate to 3-weekly adminis-
nantly children in low-resource rural areas [33]. The
tration if there are unexplained recurrences or very high
burden of yaws in Africa, South East Asia, and the Pacific
risk [3,5,9,10,25]. The recommended BPG dose for chil-
Islands parallels the particular persistence of RF/RHD in
dren varies between guidelines: 450 mg (0.6 million IU) up
resource-limited settings. Treatment of yaws has tradi-
to 20 kg in Australia; 450 mg up to 27 kg in American
tionally been with 1.2 MU of IM BPG for adults and 0.6
Heart Association guidelines; and 450 mg up to 30 kg in
MU IM BPG for children [34]. Evidence for the role of oral
WHO guidelines [5,9,10].
azithromycin as a treatment of choice for yaws is emerging,
The optimal duration of secondary prophylaxis is
potentially reducing demand in the BPG market [35]
controversial. In most guidelines, duration depends on the
initial presentation of RF and location within a high-risk
population [5,10]. An array of anecdotal factors have PAST AND PRESENT BPG SUPPLIES
been distilled into consensus guidelines for local imple- BPG was developed by J. Lester Szabo in 1951, and the first
mentation [7,10]. Exploring the indications for prolonged BPG patent appears to have been held in the United States
prophylaxis is outside the scope of this review. However, it in 1953 by Bruce [2,36,37]. Advances in stabilizing this
is noteworthy that the minimum duration of secondary original powdered formulation were patented in subsequent
prophylaxis in most guidelines is 10 years [5,7,9e11]. In years [37]. Initial clinical application was for the treatment of
severe cases, lifelong regular BPG administration may be syphilitic infections, spurring considerable demand, com-
recommended [5,10]. Missing even a single dose of BPG mercial interest, and a variety of branded products throughout
raises the risk of recurrent RF and can undermine entire the 1950s [36,38]. The patents, production, and formulation
secondary prophylaxis programs. Stability of supply is a of powdered BPG over the last 60 years is difficult to track
critical issue for programmatic success. amid a crowded manufacturing market, frequent stock out-
ages, and changes in suppliers [39e43].
A pre-mixed liquid formulation of BPG has been
Primary treatment of group A streptococcal developed, eliminating the need for a dilutant, but requiring
pharyngitis refrigeration. The initial patent on this new product was first
Antibiotic treatment of symptomatic GAS pharyngitis is held by Wyeth under the brand name Bicillin L-A, a 2-ml
widely recommended [5,7,9,10]. However, access to culture formulation distributed in a Bicillin Tubex injector [15].
or rapid antigen tests is limited in low-resource settings, and Wyeth’s Bicillin L-A, distributed by Aspen Pharmaceuticals,
may delay treatment. Evidence for empiric treatment of was introduced into the Australia market in 1995 and
childhood sore throats according to a clinical decision rule in became the sole source of BPG to the country [44]. Industry
high-risk populations has recently been published [26]. A statements suggest that global rights to Bicillin L-A were
single dose of BPG (between 225 g and 900 g depending on transferred to U.S.-based King Pharmaceuticals (reportedly
weight) is recommended in high-risk settings or where oral owned by Monarch at this time) in August 2005 [39,45,46].
compliance is challenging [7,10]. Treatment of asymptom- Some conflicting reports suggest that the patent rights had
atic GAS carriers is not routine but may be considered in rare been transferred years earlier, but that Wyeth had continued
circumstances, such as disease outbreaks in closed com- to produce for King under contract [47]. In 2007, the U.S.
munities [5,27,28]. Food and Drug Administration approved King Pharmaceu-
tical to produce Bicillin L-A at a new manufacturing and
production facility in Michigan, USA [48]. A company press
Syphilis release from that time records King Pharmaceuticals as the
An estimated 12 million people are infected with the only manufacturer of Bicillin L-A in the United States [48].
spirochete Treponema pallidum [29]. T. pallidum is partic- Pfizer acquired King/Monarch Pharmaceuticals in 2010 and
ularly responsive to penicillin in the form of BPG [30]. The Wyeth in 2009 and now appears to be the sole provider
recommended dose is double the RF/RHD prophylaxis of the suspension formulation of BPG in high-resource set-
dose at 1.44 g (2.4 million IU) as a single immediate dose tings [49].
for primary syphilis or 3 doses for late syphilis [31]. There In this complicated patent and manufacturing land-
is some evidence that use of oral azithromycin is compa- scape, shortages of BPG have occurred. Details of stock
rable to a single dose of BPG for treatment of early syphilis outages have been best documented in high-resource set-
[32]. However, BPG remains the only agent suitable for tings with pockets of endemic RF/RHD in vulnerable

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populations. Supply of BPG for secondary prophylaxis was the RHD community for some years [46,64,65]. Attempts
limited in countries of the former Yugoslavia in the early to obtain process information from manufacturers have
1990s [50]. Shortages have occurred in North America been unsuccessful despite a number of concerted efforts
from 2002 when Wyeth-Ayerst stopped producing BPG [46,66]. In Canada, 2 “notice of compliance” documents
from a Canadian plant [51,52]. Liquid Bicillin-LA stock have been issued for branded, liquid formulation Bicillin L-
outages occurred in Australia and New Zealand between A (Pfizer and King); those documents represent compliance
2001 and 2008 [15,53]. In the United States, shortages with local Food and Drug Regulations [67]. The need for
were notified to the Center for Disease Control in 2005; by continuous quality improvement activities to address
2010, 15% of 353 surveyed directors of pharmacy were different preparations of BPG has also been identified by
still dealing with shortages in America [54,55]. A World WHO with little effect [68].
Heart Federation survey of healthcare providers who treat
patients with RF/RHD prophylaxis collected data from 24
Efficacy
countries in Africa, the Asia-Pacific region, and Central and
In the absence of readily available manufacturing standards
South America in 2011 [56]. Minimal access to BPG was
or chemical composition assays, the efficacy of BPG for-
reported in almost all settings, with some respondents
mulations must be determined from clinical testing. Anal-
indicating no access to BPG at all [56]. Of 39 respondents,
ysis of BPG is complicated by its prolonged half-life,
35% indicated that their BPG supply is inadequate to treat
necessitating lengthy and potentially expensive follow-up
all of their patients using recommended prophylaxis
[69]. This is important for U.S. Food and Drug Adminis-
schedules [56].
tration licensing of generic medications, which evaluates
bioequivalence via a plasma concentration-time curve from
COST OF BPG zero to complete drug excretion [69,70].
Reliable data on the purchase price of BPG is difficult to Secondary prophylaxis for RF/RHD is thought to
secure. Powdered BPG is available to some providers through require a minimum serum concentration of 0.02 mg/ml
the support of the United Nations Children’s Fund pooled BGP to prevent GAS infection, based on a reported mini-
procurement [57]. A 2010 report from the United Nations mum inhibitory concentration 90 of 0.0016 [66,71]. The
Children’s Fund records 2.4 million IU vials of powdered oft-recommended 28-day dosing interval of BPG is calcu-
benzathine benzylpenicillin at a median of US$0.31 per dose. lated to keep serum concentrations above this therapeutic
A 2010 human immunodeficiency virus guide for Zambia threshold in order to prevent GAS infection. However,
documents Monarch-branded 1.2 million IU of pre-mixed there are well-founded concerns about the variability of
BPG priced at $57.60 [58]. South African researchers used a penicillin serum concentration from an array of manufac-
value of US $1 in 2010 (sensitivity range 0 to 13), for a single turers over a period of some years [46,65,66]. In a recent
vial of powdered BPG in a recent cost-effectiveness analysis trial, young American military recruits received a single stat
guided by local pharmacy data [26]. A recent newspaper dose of 1.2 MU of BPG; mean serum concentrations were
report from Kenya suggests the cost of a single dose of less than the minimum serum concentration of 0.02 mg/ml
BPG costs Sh250, approximately US$2.90 [59]. In Australia, by day 9 after administration in one-half of the subjects.
a 900-mg dose of Pfizer-branded Bicillin L-A is listed in the Generalizing these results to the RHD secondary prophy-
Pharmaceutical Benefits Scheme at a cost of AU$29.32 laxis population suggests that patients may be unprotected
(US$29.85) per dose [60]. This is comparable with the same from GAS infection for up to 19 days prior to the next dose
product in the New Zealand Pharmaceutical Schedule, which administration [66]. A meta-analysis of 37 similar studies
indicates a price of NZ $31.50 (US$25.03) (http://www. evaluated trends in therapeutic penicillin serum concen-
pharmac.health.nz/ckeditor_assets/attachments/15/sched.pdf). trations; investigators have reported that the duration of
Finally, understanding the uses and supply of BPG has therapeutic serum concentrations is significantly shorter in
been confused by a number of similarly named products. studies since 1990 than it is in data from earlier decades
In particular, Bicillin C-R (controlled release) and Bicillin [71]. This raises significant concerns about the effective-
A-P (all purpose) [15,61,62]. These formulations contain ness of contemporary secondary prophylaxis programs.
procaine penicillin G and/or aqueous penicillin, which
achieve higher and shorter serum concentration levels after
Safety
IM administration. Combinations of BPG and procaine
Generally accepted international data suggests that the
penicillin G have been proposed for the treatment of res-
incidence of allergic reactions to monthly BPG injection is
piratory tract infections, scarlet fever, and skin infections,
3.2% and anaphylactic reactions is 0.2% [9,72]. However,
but they are not suitable for RF secondary prophylaxis
anecdotal reports of adverse reactions appear to have
[63].
increased in recent years, in conjunction with concerns
about medication quality. Three deaths documented in
BPG QUALITY Zimbabwe in 2000 were associated with BPG from 3
The paucity of readily accessible quality control guidelines different manufacturers [73]. A high frequency of
in BPG manufacturing has been a source of concern within anaphylaxis events has also been reported in World Heart

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Federation’s BPG survey; 26% of 39 clinicians reported at DELIVERY MECHANISMS

least 1 anaphylactic reaction, and 21% of all providers Delivering each injection in secondary prophylaxis regimes
reported that they have had a patient die due to anaphy- is a global challenge. In many settings, far fewer than 80%
laxis after BPG injection [56]. At present, it is impossible to of scheduled injections are delivered, significantly
determine whether adverse drug reactions are caused by increasing the risk of rheumatic fever [83e87]. Although
penicillin, reactions to other components of the medica- the link between the pain of BPG administration and
tion/dilatant, unrelated to BPG administration, or mis- compliance has little published support, it is reasonable to
classified reactions. The role of vasovagal reactions to IM assume that discomfort is a factor for young people
injection, particularly in diverse cultural settings, may also [10,88,89]. Adherence with secondary prophylaxis is crit-
be an important area for further research. A system for ically low in many settings; any attempt to improve
reporting adverse drug events is important for BPG as a acceptability of BPG warrants vigorous investigation.
way of monitoring both penicillin safety and perhaps a Some centers employ techniques to reduce the pain of
proxy guide to BPG quality [74]. IM injections, such as use of smaller gauge needles, direct
pressure, slow injections, and distractions [10]. In some
Administration challenges programs, local anesthetic is routinely used as a dilutant for
Powdered BPG forms a suspension when reconstituted prior powdered BPG to reduce injection pain [90]. There is good
to administration. This incomplete dissolution predisposes evidence that the practice is effective at relieving pain,
to precipitation and needle blockage during administration without reducing absorption or serum concentration of
[75]. Worldwide anecdotal reports suggest this precipitation BPG [10,91,92]. However, pain could be further mini-
is a common problem. For example, when Australia used mized by alternative delivery mechanisms, potentially an
powdered Pan Benz during the 2006 stock outage of Bicillin implantable device.
L-A, up to 40% of injections of Pan Benz were affected by An implantable or longer acting BPG delivery device
needle blockages. Concerns were reportedly raised to the would be a more appropriate and acceptable mechanism
Therapeutic Goods Administration via the Centers for Dis- for delivering secondary prophylaxis [64,93,94]. Although
ease Control, though no record of subsequent regulatory this is a conceptually promising approach, there has been
intervention can be found [76]. Many countries are depen- little reported innovation in this field.
dent on powdered BPG for the near future, and effective
administration remains an unmet challenge. IMPROVING BPG ACCESS
Control of RF and RHD depends on supply, procurement,
BPG AS AN ESSENTIAL MEDICINE and delivery of BPG. Vaccine prospects remain years from
clinical implementation, forcing primary and secondary pre-
WHO has biennially produced a list of essential drugs since
vention activities to the fore [95]. Improved global burden of
1977, forming the foundation for 156 national Essential
disease data and echocardiographic screening programs are
Medicines Lists (EML) [77,78]. The success of EML spur-
likely to expand demand for BPG, particular if echocardiog-
red the development of further specific lists, including the
raphy moves from a descriptive to an interventional phase
Interagency List of Essential Medicines for Reproductive
[95,96]. Thus, improving access to BPG and supporting
Health in 2006 and the Essential Medicines List for Chil-
compliance should be a key priority for the RHD community
dren (EMLc) in 2007 [79,80]. These lists were supple-
[64,95]. Three domains of intervention are required.
mented by a WHO publication on model prescribing
information for RF/RHD in 1999 [68].
The adult 1.2 million MU dose of BPG appears in the Technical and clinical research interventions
(current) 17th edition 2011 EML of WHO [81]. The pe- Technical manufacturing standards or specifications for
diatric EML also includes BPG but only at the standard BPG have not been located during this review, nor in
adult dose. Theoretically, this could be problematic for earlier attempts by other investigators [64]. Some specifi-
countries with a high burden of RF/RHD in young children cations may reside with patent holders for pre-mixed BPG.
or with widespread growth stunting. The inclusion of pe- Older standards for powdered formulations may be held by
diatric doses for RHD prophylaxis received specific atten- regulatory agencies that are inaccessible to electronic re-
tion during the drafting of the EMLc, including in a view. Locating and distributing of nonproprietary stan-
detailed report [80,82]. Similarly, BPG appears on the dards is needed in order to evaluate generic formulations
Interagency List of Essential Medicines for Reproductive and ensure standardization. Simple assays for establishing
Health in a 1.44 g (2.4 million IU) form for treatment of the quality and purity of BPG may also need to be devel-
syphilis [79]. It is unclear whether the recommended for- oped to assist procurement agencies in purchasing
mulations of BPG, which appear on the WHO EML, are decisions.
translated to national level EMLs. This requires a targeted Updated data for anaphylaxis and adverse drug reactions
investigation to evaluate which countries with a high is essential, particular if use of BPG is to be expanded. Adverse
burden of RHD have adopted the EML recommendations drug reaction data may be accessible by interrogating existing
to national formularies. national level databases or supporting the development of

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pharmaco-vigilance programs [97]. In settings without any required to move forward on priority issues for improving
mechanism for reporting drug events, a BGP-specific register access [95].
may be needed as an interim measure.

ACKNOWLEDGMENTS
Market interventions and research partnerships The authors are grateful for the feedback and additional
interventions references provided by Professors Bongani Mayosi, Diana
Increasing attention to the market dynamics of pharma- Lennon, and Stanford T. Shulman. Participants in the World
ceutical products in low- and middle-income countries has Heart Federation’s survey on access to BPG are warmly
emerged in recent years. Organizations such as the United acknowledged.
Nations Children’s Fund, UNITAID, Drugs for Neglected
Diseases Initiative, and the Medicines Patent Pool illustrate
new ways of tackling access to medicines barriers REFERENCES
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