High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.

INTRODUCTION: Intramuscular benzathine penicillin G (BPG) injections are a cornerstone of secondary prophylaxis to prevent acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Uncertainties regarding inter-ethnic and preparation variability, and target exposure profiles of BPG injection are key knowledge gaps for RHD control. METHODS: To evaluate BPG pharmacokinetics (PK) in patients receiving 4-weekly doses in Ethiopia, we conducted a prospective cohort study of ARF/RHD patients attending cardiology outpatient clinics. Serum samples were collected weekly for one month after injection and assayed with a liquid chromatography-mass spectroscopy assay. Concentration-time datasets for BPG were analyzed by nonlinear mixed effects modelling using NONMEM. RESULTS: A total of 190 penicillin concentration samples from 74 patients were included in the final PK model. The median age, weight, BMI was 21 years, 47 kg and 18 kg/m2, respectively. When compared with estimates derived from Indigenous Australian patients, the estimate for median (95% confidence interval) volume of distribution (V/F) was lower (54.8 [43.9-66.3] l.70kg-1) whilst the absorption half-life (t1/2-abs2) was longer (12.0 [8.75-17.7] days). The median (IQR) percentage of time where the concentrations remained above 20 ng/mL and 10 ng/mL within the 28-day treatment cycle was 42.5% (27.5-60) and 73% (58.5-99), respectively. CONCLUSIONS: The majority of Ethiopian patients receiving BPG as secondary prophylaxis to prevent RHD do not attain target concentrations for more than two weeks during each 4-weekly injection cycle, highlighting the limitations of current BPG strategies. Between-population variation, together with PK differences between different preparations may be important considerations for ARF/RHD control programs.

A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease: new insights for improved secondary prophylaxis strategies.

BACKGROUND: Benzathine benzylpenicillin G (BPG) is recommended as secondary prophylaxis to prevent recurrence of acute rheumatic fever and subsequent rheumatic heart disease (RHD). Following intramuscular injection, BPG is hydrolysed to benzylpenicillin. Little is known of the pharmacokinetics of benzylpenicillin following BPG in populations at risk of RHD. METHODS: We conducted a longitudinal pharmacokinetic study of children and adolescents receiving secondary prophylaxis throughout six monthly cycles of BPG. Dried blood spot samples were assayed with LC-MS/MS. Benzylpenicillin concentrations were analysed using non-linear mixed-effects modelling with subsequent simulations based on published BMI-for-age and weight-for-age data. RESULTS: Eighteen participants contributed 256 concentrations for analysis. None had benzylpenicillin concentrations >0.02 mg/L for the full time between doses. The median duration above this target was 9.8 days for those with a lower BMI (<25 kg/m2), who also had lower weights, and 0 days for those with a higher BMI (≥25 kg/m2). Although fat-free mass was a key determinant of benzylpenicillin exposure after a standard dose of BPG, having a higher BMI influenced absorption and almost doubled (increase of 86%) the observed t½. CONCLUSIONS: Few children and adolescents receiving BPG as secondary prophylaxis will achieve concentrations >0.02 mg/L for the majority of the time between injections. The discordance of this observation with reported efficacy of BPG to prevent rheumatic fever implies a major knowledge gap relating to pharmacokinetic/pharmacodynamic relationships between benzylpenicillin exposure and clinical outcomes.

Immuno-nephelometric determination of group streptococcal anti-streptolysin O titres (ASOT) from dried blood spots: Method for validating a new assay.

This study was designed to determine the sensitivity and reproducibility of recovering anti-streptolysin O titres (ASOT) from dried blood spot (DBS) samples, a methodologic subcomponent of the penicillin pharmacokinetic studies in children receiving secondary prophylaxis with intramuscular benzathine penicillin for acute rheumatic fever.

A population pharmacokinetic modeling approach shows that serum penicillin G concentrations are below inhibitory concentrations by two weeks after benzathine penicillin G injection in the majority of young adults.

Serum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group A Streptococcus pyogenes (GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.

Tratamiento de la sífilis temprana en pacientes infectados con VIH: una dosis de penicilina benzatínica es suficiente / The outcome of treatment of early syphilis in HIV-infected patients: a single dose of benzathine penicillin seems sufficient

Comparar la respuesta clínica y serológica de pacientes infectados con VIH y sífilis temprana según hubieran recibido 1 ó más dosis de penicilina benzatínica, y evaluar factores asociados a fallo del tratamiento. Métodos: estudio retrospectivo, observacional, descriptivo en pacientes infectados con VIH tratados con penicilina benzatínica por sífilis temprana entre 1999-2009. Se consideró régimen corto de enicilina benzatínica 2.400.000 unidades cuando se administró 1 dosis, y régimen largo cuando se administraron más de 1 dosis. Se definió respuesta serológica adecuada al descenso de 4 títulos de la VDRL tras 6-12 meses del tratamiento. Se compraron las frcuencias de las respuestas serológicas mediante tablas de contingencia de 2x2; se determinó la significación estadística mediante la prueba de Chi2 corregida por Yates; las variables continuas se analizaron mediante Mann-Whitney; las proporciones se compararon mediante la prueba de las proporciones para dos muestras (Statistix 7.0). Las diferencias fueron consideradas significativas cuando p fue< 0,05. Resultados: evaluamos 237 eventos de sífilis temprana. Todos los pacientes con sífilis primaria y secundaria resolvieron los signos o síntomas de la enfermedad. Hubo respuesta serológica adecuada en 92,9 % y 90,99 % de quienes recibieron régimen corto versus largo respectivamente (p=0,59). No observamos diferencias significativas en los porcentajes de pacientes con respuesta serológica adecuada entre quienes recibieron el régimen corto o largo en ninguno de los subgrupos conformados: estratos de CD4, pacientes con o sin sida, con o sin TARGA, presentación clínica de la sífilis temprana y título de VDRL. Conclusiones: en nuestra experiencia, para tratar la sífilis temprana en pacientes con VIH, una dosis de penicilina benzatínica fue suficiente. No se halló ningún factor asociado a fallo serológico...

To compare the serological and clinical response to treatment of early syphilis in HIV-infected patients who received a single-dose versus more than 1 dose of benzathine penicillin 2.4 millon U associated with treatment failure. Methods: retrospective, observational, descriptive study (1999-2009). Adequate serological response was defined as at least a four-fold decrease in VDRL titers at 6-12 months of treatment. We compared the rate of response with contingency tables; the statistic significance was determined by Yate's corrected x 2 test; for continuous variables analysis Mann-Whitney was applied; to compare proportions, the proportion test was applied (Statistix 7.0). Differences were considered significant if p< 0,05. Results: 237 HIV-infected patients with early syphilis were evaluated. Every patient with primary or secondary syphilis resolved the signs or sympthoms of the disease. We found an adequate serological response in 92.9 % versus 90.99% of whom received a single-dose versus >1 doses of benzathine penicillin 2.4 million U, respectively (p=0.59). The difference between groups was not statistically significant regardless of their CD4 cell count, antiretroviral tretment, AIDS status or VDRL titer. Conclusions: in our experience, a single dose of benzathine penicillin 2.4 million U for the treatment of early syphilis in HIV-infected patients was sufficient to achieve an adequate serological response. None factor was found to be associated wth serological failure...

Late latent syphilis in a patient with end-stage renal disease and presumptive penicillin allergy.

PURPOSE: Pharmacotherapy challenges in a case of late latent syphilis complicated by end-stage renal disease and presumptive penicillin allergy are described. SUMMARY: A 58-year-old white woman was admitted to the hospital for symptoms including altered mental status, shortness of breath, and chest pain. The initial workup isolated syphilis immunoglobulin G antibody. A treponemal test was reactive, and a nontreponemal test was nonreactive; analysis of cerebrospinal fluid did not indicate neurosyphilis. The patient was diagnosed as having late latent syphilis of unknown duration, for which the standard treatment is intramuscular penicillin G benzathine 2.4 million units once weekly for three weeks. Given the patient's advanced renal disease and other serious comorbidities, there were concerns about the potential need for renal dosage adjustment and repeated desensitization. However, given the slow absorption and long half-life of penicillin G and published data indicating its safe use in the context of hemodialysis, the treating clinicians decided to proceed with penicillin G therapy at the usual dose after an oral penicillin desensitization protocol; repeat desensitization before two subsequent injections was not performed. The patient completed the full course of penicillin G without incident. Notably, skin testing was not performed to definitively establish penicillin allergy. Microbiological testing to determine a cure of syphilis was not performed. CONCLUSION: After the completion of an oral desensitization protocol, the standard three-dose regimen of intramuscular penicillin G for late latent syphilis was safely administered to a hemodialysis patient without dosage adjustment or repeated desensitization.

Urticaria recurrente asociada a infección por Streptococcus pyogenes / Recurrent urticaria associated with group Streptococcus pyogenes infection

La mayoría de las urticarias crónicas o agudas recidivantes son idiopáticas. Presentamos un caso de urticaria aguda recidivante en una niña de tres años, en la que, tras el estudio realizado, solo se objetivó un valor elevado de anticuerpos antiestreptolisina O (ASLO). La desaparición de la urticaria tras el tratamiento con penicilina G-benzatina intramuscular, junto con la normalización de los ASLO, sugiere que la etiología de esta podría ser las infecciones recurrentes por el Streptococcus pyogenes. Destacar la importancia de incluir en el protocolo diagnóstico de la urticaria la determinación de los ASLO, lo cual permite el diagnóstico y tratamiento precoces de las infecciones por S. pyogenes (AU)

We present a case of relapsing acute urticaria in a three years old girl who after the study only showed a high value of ASLO (antistreptolysin O titer). The disappearance of urticaria after intramuscular penicillin G benzathine treatment, together with the ASLO normalization, suggested that the etiology of this could be recurrent Streptococcal infections. We conclude the importance of including ASLO determination in the diagnostic protocol of urticaria, allowing early diagnosis and treatment of Group A Streptococcus infections (AU)

Benzathine penicillin G: a model for long-term pharmacokinetic comparison of parenteral long-acting formulations.

WHAT IS KNOWN AND OBJECTIVE:   Long-acting intramuscular penicillin G injection is an important product for the management of some severe infections. However, testing the bioequivalence of such long-acting formulations is difficult. Our aim was to undertake such a test using a generic formulation containing 1 200 000 IU of benzathine penicillin G powder and an innovator's product (Retarpen(®) 1·2 million units; Sandoz, Switzerland). METHODS:   In an open, double-blind, randomized, two-periods, two-group crossover study, 12 healthy male volunteers received both formulations of benzathine penicillin G on two different days with a 5-month washout period between the doses and a sampling period of over 500 h. A simple, sensitive and rapid high-performance liquid chromatography (HPLC)-UV method was developed and validated for determination of penicillin G plasma concentrations and other pharmacokinetic (PK) parameters. RESULTS AND DISCUSSION:   The analytical method used produced linear responses within a wide analyte concentration range with average within-run and between-run variations of below 15% with acceptable recovery, accuracy and sensitivity. The primary PK parameters we used were maximum plasma concentration (Cmax ), time to reach the maximal concentration (Tmax ) and the area under the plasma concentration vs. time curve from time zero to the last sampling time (AUC0→t ) using a standard non-compartmental approach. Based on these parameters, the two formulations were bioequivalent. WHAT IS NEW AND CONCLUSION:   We illustrate the bioequivalence testing of a very long-acting product. The data indicate that the generic test formulation and the branded reference formulation were bioequivalent in fasting healthy Iranian male volunteers.

Factors associated with loss of penicillin G concentrations in serum after intramuscular benzathine penicillin G injection: a meta-analysis.

BACKGROUND: An interval of 3-4 weeks between intramuscular injections of 1.2 million units of benzathine penicillin G as prophylaxis against group A streptococcal infection is recommended by health organizations for patients with pediatric rheumatic fever and heart disease. METHODS: We reviewed the literature for evidence of the persistence of serum penicillin G during the first 4 weeks after the recommended dose of benzathine penicillin G. RESULTS: The weighted-mean concentration was <0.02 µg/mL by 3 weeks after the initial dose. Weighted means were lower in studies done after 1990 than before (P<0.01), in studies dealing with secondary versus primary prophylaxis (P<0.01) and in studies in children versus those in adults (P<0.02). CONCLUSIONS: Recommendations for benzathine penicillin G prophylaxis may need reevaluation.

Penicillin concentrations in sera and tonsils after intramuscular administration of benzathine penicillin G to children.

BACKGROUND: The optimal regimen of benzathine penicillin G for secondary prevention of rheumatic fever is controversial. Data from serum pharmacokinetic studies do not fully agree on the period of protection after drug administration. Data from concentration of penicillin in tonsils may provide additional information. METHODS: To evaluate penicillin concentrations in palatine tonsils and in sera 1, 10, 14 and 21 days after intramuscular injection of benzathine penicillin G 40,000 IU/kg, 58 children between 4 and 12 years of age with chronic tonsillitis and indication for tonsillectomy were given the study drug 1, 10, 14 or 21 days before surgery. Blood and tonsil samples were obtained during surgery, and penicillin concentrations were determined microbiologically by the agar well diffusion technique. RESULTS: Mean serum penicillin concentrations 1, 10, 14 and 21 days after drug administration were, respectively, 0.080, 0.031, 0.023 and 0.014 microg/ml. Mean penicillin concentrations in tonsils at 1, 10, 14 and 21 days were 0.023, 0.010, 0.007 and 0.002 microg/g, respectively. Detectable penicillin concentration in tonsils (method sensitivity, 0.006 microg/g) was obtained in all patients on Day 1 and in 91% and 83.3% of patients on Days 10 and 14, respectively. By Day 21 this proportion was reduced to 30%. CONCLUSIONS: The results of this study suggest that penicillin values may be inadequate for prevention of rheumatic fever by Week 3 of administration in a majority of children.

Benzathine penicillin G and procaine penicillin G in piglets: comparison of intramuscular and subcutaneous injection.

The disposition of penicillin G in piglets is described after intramuscular or subcutaneous injection of depot preparations. The piglets were injected with 33,000 IU/kg or 100,000 IU/kg benzathine + procaine penicillin G intramuscularly or subcutaneously, or 100,000 IU/kg procaine penicillin G intramuscularly or subcutaneously. Intramuscular injection of benzathine + procaine penicillin resulted in higher maximum concentrations in plasma (Cmax) than did subcutaneous injection. The mean residence time (MRT) of penicillin G was longer when the drugs were injected subcutaneously rather than intramuscularly. The plasma concentration versus time profiles of the subcutaneous injections of benzathine + procaine penicillin revealed secondary peaks, possibly reflecting a certain degree of inflammation at the injection site.

Inflammatory response to intramuscular implantation of polyacrylonitrile ultrafiltration probes in sheep.

Polyacrylonitrile is used in the manufacture of dialysis membranes. These membranes are fundamental to the functioning of implantable probes for microdialysis and ultrafiltration sampling of tissue fluids. Although in vivo experimentation using polyacrylonitrile has been reported to cause little inflammatory response when implanted subcutaneously, such information is not available for intramuscular implantation in sheep. The procaine and benzathine salts of penicillin are formulated for intramuscular injection. These salts of penicillin or the formulation excipients may cause inflammatory reactions. Use of polyacrylonitrile probes to draw samples from sites at which these formulations have been injected may be compromised by inflammation or direct interaction between formulation excipients and the dialysis membrane. The aim of this project was to describe tissue responses to intramuscular implantation of polyacrylonitrile in the presence and absence of either procaine or procaine plus benzathine salts of penicillin G. Each of 20 normal sheep was implanted with two ultrafiltration probes, one at the site of an injection of procaine or benzathine plus procaine penicillin G. Similar injections were also made at remote intramuscular sites. After 8, 9, and 11 days of the experiment, sheep were killed and the injection and implantation site muscle were excised and prepared for histopathological examination. The implantation of the probe alone caused greater inflammatory response than the injection of procaine or procaine plus benzathine penicillin G at remote intramuscular sites. The histopathological lesions were greatest where the implantation site was coupled with the injection of either formulation of penicillin G. Polyacrylonitrile may not be a suitable dialysis membrane material for intramuscular implantation in sheep.

Colloidal carriers for benzathine penicillin G: nanoemulsions and nanocapsules.

The main purpose of this work is to formulate benzathine penicillin G nanoemulsion and nanocapsules, to evaluate their physicochemical and stabilising characteristics, and to determine their antimicrobial activity and penicillin in vitro release kinetics. Nanoemulsions were produced by the spontaneous emulsification approach and nanocapsules of poly (D,L-lactic acid-co-glycolic acid) polymer (PLGA) were prepared by the method of interfacial deposition of a pre-formed polymer. A 207+/-8 nm mean diameter nanoemulsion formulation maintained stability for more than 5 months at 4 degrees C. Stable nanocapsules with 224+/-58 nm mean diameter were obtained, which remained stabilised over 120 days at 4 degrees C. The penicillin encapsulation ratio in the nanocapsules was 85%. The in vitro release profiles indicated that penicillin released from the nanoemulsion was similar to the one observed from nanocapsules. However it can be clearly deduced from the in vitro kinetic analysis that the antibiotic cannot be protected in colloidal delivery systems. Nevertheless, stable formulations obtained in this investigation supply a potential dosage form to encapsulate more easily soluble drugs.

[A comparative evaluation of the pharmacokinetics of different forms of benzathine benzylpenicillin]. / Sravnitel'naia otsenka farmakokinetiki razlichnykh lekarstvennykh form benzatin benzilpenitsillina.

Comparative randomized opened pharmacokinetic evaluation of benzathine benzylpenicillin in three dosage forms was performed. Benzathine benzylpenicillin was used as extencilline (2.4 million U or 1.2 million U, "Rhône-Poulenc Rorer", France) and as bicillin-5 (1.5 million U, "Synthesis" Russia). 33 patients were included in investigation (23 women and 10 men aged 16-60 years). 25 persons had verified rheumatism without blood circulation failure signs, 4--had chronic tonsillitis and 4 were healthy volunteers. Benzylpenicillin concentration was estimated by microbiology test in blood samples taken at 1, 3, 24 hours and 7, 14 and 21 days after intramuscular drug injection. After 2.4 million U extencilline injection (12 patients) its concentration, was at the inhibition level for beta-hemolytic streptococcus group A (25 ng/ml) for 3 weeks-period in 83.3 per cent of patients. After 1.2 million U extencilline injection (10 patients) or 1.5 million U bicillin-5 injection (12 patients) the above mentioned concentration was achieved on the 21st day in 30 and 0 per cent of patients respectively. Thus the treatment with benzathine benzylpenicillin at the 1.2 million U dose in the form of extencilline or bicillin-5 doesn't provide adequate antistreptococcal concentration in blood in prolonged period and is not suitable for correct rheumatism prophylaxis in adult patients.

Lidocaine as a diluent for administration of benzathine penicillin G.

OBJECTIVE: Benzathine penicillin G is recommended for secondary prophylaxis of rheumatic fever. Its main disadvantage is local pain and discomfort associated with the injection. Lidocaine as a diluent may reduce this discomfort. We compared the administration of benzathine penicillin G with two diluents; sterile water and lidocaine hydrochloride 1% for penicillin concentrations and pain of injection. DESIGN: In a randomized double blind, crossover trial, 18 children ages 11 to 19 years who required prophylactic treatment for rheumatic fever were randomly divided into two groups. One received an injection of benzathine penicillin G diluted with 3.2 ml of sterile water, followed 1 month later by an injection of benzathine penicillin G diluted in lidocaine hydrochloride 1%; the second group received the same regimen in the reverse order. Serum penicillin concentrations and subjective pain sensation were determined after each injection. RESULTS: Peak serum penicillin concentrations at 24 h after injection were similar for both preparations (0.100 microg/ml for water, 0.102 microg/ml for lidocaine), as were the other serum values measured throughout the month. After 28 days detectable concentrations (> or =0.020 microg/ml) were found in 44 and 291% of the subjects, respectively (P = 0.4). Urine penicillin concentrations on Day 28 were 1.81 +/- 0.25 and 2.31 +/- 0.25 microg/ml, respectively. The pain score immediately after the injection was significantly lower with the lidocaine than with the sterile water dilution. CONCLUSION: Use of lidocaine hydrochloride as a diluent for benzathine penicillin G does not change the penicillin concentration in body fluids and significantly reduces the pain of injection. We suggest the use of lidocaine hydrochloride 1% as a diluent for benzathine penicillin G.

Disposition of penicillin G after administration of benzathine penicillin G, or a combination of benzathine penicillin G and procaine penicillin G in cattle.

Plasma concentration of penicillin G was evaluated in beef steers after administration of either a combination of benzathine penicillin G and procaine penicillin G in a 1:1 mixture at a dosage of 9,000 U/kg of body weight, IM (n = 5), 24,000 U/kg, IM (n = 5), or 8,800 U/kg, SC (n = 5), or benzathine penicillin G alone at a dosage of 12,000 U/kg, IM (n = 7). Plasma concentration of penicillin G was measured by use of a high-performance liquid chromatography assay that had a limit of determination of 0.005 microgram/ml. At a dosage for this combination of 9,000 U/kg IM, and 8,800 U/kg, SC, which are approved label recommendations in Canada, and the United States, respectively, mean (+/- SEM) peak plasma concentration was 0.58 (+/- 0.15) and 0.44 (+/- 0.02) microgram/ml, respectively. Although plasma penicillin concentration was quantifiable for 7 days in the steers that received 9,000 U/kg, IM, and for 4 days in the steers that received 8,800 U/kg, SC, the concentration was < 0.1 microgram/ml in both groups after the first 12 hours. After administration of the combination at dosage of 24,000 U/kg, IM, there was an initial peak plasma concentration at approximately 2 hours; thereafter, plasma concentration decreased slowly, with half-life of 58 hours. Although plasma penicillin G concentration was quantifiable for 12 days at this dosage, concentration was < 0.1 microgram/ml after the first 48 hours. After the initial 48 hours, plasma concentration of penicillin was of similar magnitude and decreased at similar rate for the combination at dosage of 24,000 U/kg and for 12,000 U/kg of benzathine penicillin G alone.(ABSTRACT TRUNCATED AT 250 WORDS)