Penicillin Dried Blood Spot Assay for Use in Patients Receiving Intramuscular Benzathine Penicillin G and Other Penicillin Preparations To Prevent Rheumatic Fever.

Rheumatic heart disease (RHD) remains an important global health challenge. Administration of benzathine penicillin (BPG) every 3 to 4 weeks is recommended as a secondary prophylaxis to prevent recurrent episodes of acute rheumatic fever and subsequent RHD. Following intramuscular injection, BPG is hydrolyzed to penicillin G (benzylpenicillin). However, little is known of the pharmacokinetics (PK) of BPG in pediatric populations at high risk of RHD or of the pharmacokinetic-pharmacodynamic relationship between penicillin exposure and clinically relevant outcomes. Dried blood spot (DBS) assays can facilitate PK studies in situations where frequent venous blood sampling is logistically difficult. A liquid chromatography-mass spectroscopy assay for penicillin G in plasma and DBS was developed and validated. Application of the DBS assay for PK studies was confirmed using samples from adult patients receiving penicillin as part of an infection management plan. The limit of quantification for penicillin G in DBS was 0.005 mg/liter. Penicillin G is stable in DBS for approximately 12 h at room temperature (22°C), 6 days at 4°C, and >1 month at -20°C. Plasma and DBS penicillin G concentrations for patients receiving BPG and penicillin G given via bolus doses correlated well and had comparable time-concentration profiles. There was poor correlation for patients receiving penicillin via continuous infusions, perhaps as a result of the presence of residual penicillin in the peripherally inserted central catheter, from which the plasma samples were collected. The present DBS penicillin G assay can be used as a surrogate for plasma concentrations to provide valid PK data for studies of BPG and other penicillin preparations developed to prevent rheumatic fever and RHD.

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.

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.

[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.

[Blood determination of benzathine-penicillin used in acute joint rheumatism prophylaxis]. / Le dosage sérique de la benzathine-pénicilline utilisée dans la prophylaxie du rhumatisme articulaire aigu.

Our actual work studies the effectiveness in vivo of the Benzathin penicillin that is realized on 88 subjects suffering from a stable rheumatic fever. It has shown that: The first hours after an intramuscular injection, the benzathin penicillin is found at an efficient concentration superior to 0.02 ug/ml at the level of the blood. The highest dose in the blood is obtained the first 24 hours. The amount of antibiotic at the level of the blood is very efficient during 4 weeks.

Persistence of penicillin G benzathine in pregnant group B streptococcus carriers.

OBJECTIVE: To determine if streptococcicidal levels of penicillin G benzathine can be detected in maternal serum 4 weeks after treatment with 4.8 million units. METHODS: Thirty-seven pregnant women with positive group B streptococcus vaginal or urine cultures were each given 4.8 million units of penicillin G benzathine. Maternal blood samples were collected after injection and at delivery. Serum penicillin levels were measured by high-pressure liquid chromatography. Follow-up cultures were done when possible. RESULTS: None of the patients had serum penicillin levels below 0.20 microgram/mL 30 days after treatment. Cord blood levels were approximately 50% lower than maternal levels. In all but three subjects, cord blood levels exceeded 0.06 microgram/mL, the minimal inhibitory concentration for group B streptococcus. The three exceptions were patients who delivered more than 100 days after treatment. Group B streptococcus cultures were negative at the time of delivery in 72% of cases. None of the patients with positive cultures were moderately or heavily colonized. CONCLUSION: In pregnant women, penicillin G benzathine levels are high enough to inhibit the growth of group B streptococcus for more than 4 weeks after injection with 4.8 million units. Further studies are needed to evaluate whether this regimen can prevent neonatal colonization and invasive group B streptococcus disease.

Long-term outcome of patients with rheumatic fever receiving benzathine penicillin G prophylaxis every three weeks versus every four weeks.

OBJECTIVE: To compare the efficacy of injections of 1.2 million units of benzathine penicillin G given every 3 weeks versus every 4 weeks for secondary prevention of rheumatic fever, based on the long-term outcome of patients receiving such prophylaxis. METHODS: A total of 249 consecutive patients with rheumatic fever, randomly assigned to either a 3-week or a 4-week regimen, were examined every 3 to 6 months, and followed for 794 and 775 patient-years, respectively. RESULTS: Compliance with each regimen was comparable: 83 (66.9%) of 124 patients in the 3-week group versus 92 (73.6%) of 125 patients in the 4-week group stayed in the program (p > 0.05). Streptococcal infections occurred less frequently in those receiving the 3-week regimen: 7.5 versus 12.6 per 100 patient-years (p < 0.01). Prophylaxis failed in 2 patients receiving the 3-week regimen and in 10 receiving the 4-week regimen (0.25 and 1.29 per 100 patient-years respectively; p = 0.015). Serum penicillin levels were adequate (> or = 0.02 micrograms/ml) in 100 (56%) of 179 samples obtained 21 days after penicillin injection in the 3-week regimen, and in 51 (33%) of 155 samples obtained 28 days after injection in the 4-week regimen (p < 0.01). Of 71 patients with mitral regurgitation in the 3-week regimen, 47 (66%) no longer had the murmur; of 87 patients in the 4-week regimen, 40 (46%) no longer had the murmur (p < 0.05). CONCLUSIONS: This 12-year controlled study indicates that the outcome of patients with rheumatic fever is better with a 3-week than with a 4-week penicillin prophylaxis regimen. Greater emphasis and more widespread use of the 3-week regimen should be recommended.

Rheumatic fever prophylaxis in South Africa--is bicillin 1,2 million units every 4 weeks appropriate?

Rheumatic fever is a major health problem in South Africa. Although intramuscular benzathine penicillin (bicillin) 1.2 million units (MU) every 4 weeks is widely used for secondary prophylaxis, studies in other countries have shown a recurrence rate of 3-8% over 5-6 years in patients on this regimen. It has been recommended that serum penicillin concentrations should be maintained above 0.02 mg/ml to prevent such recurrences. The World Health Organisation (WHO) and the American Heart Association have recommended since 1988 that patients in high-risk areas for the development of rheumatic fever should receive benzathine penicillin 1.2 MU every 3 weeks rather than every 4. The aims of this study were, firstly, to determine the prevalence of serum penicillin concentrations below 0.02 micrograms/ml in rheumatic fever patients on benzathine penicillin 1.2 MU 4-weekly and, secondly, to study the effect of increasing the dose of 1.8 MU 4-weekly in patients with subtherapeutic concentrations. Forty-five of 51 rheumatic fever patients (88%) in this study on benzathine penicillin 1.2 MU 4-weekly had low serum penicillin concentrations (< 0.02 micrograms/ml) at the end of the 4th week after the injection. Penicillin was detected in the urine of 30 of the 45 patients (67%) with low concentrations, suggesting that such patients have tissue-bound penicillin which might be important in preventing rheumatic fever. The 15 patients (33%) with subtherapeutic serum penicillin concentrations and no detectable penicillin in the urine could be at very high risk for recurrent attacks of rheumatic fever. Fourteen of 29 patients (48%) given the higher dose of benzathine penicillin (1.8 MU 4-weekly) had subtherapeutic serum penicillin concentrations at the end of the 4th week after the injection, but in all 29 penicillin was detected in the urine. Review of our present policy of secondary prophylaxis for rheumatic fever is necessary. Concentrated preparations of benzathine penicillin (600,000 U/ml) are not available in South Africa; administration of a higher dose (1.8 MU) 4-weekly would therefore require a double injection, which could affect compliance adversely. We recommend that rheumatic fever patients in our area should receive benzathine penicillin 1.2 MU 3-weekly as recommended by the WHO until strategies for secondary prophylaxis have been evaluated further.

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)

Evaluation of secondary prophylactic schemes, based on benzathine penicillin G, for rheumatic fever in children.

Serum concentrations of penicillin were measured in children with rheumatic fever. The adequacy of the values after administration of 1.2 million units of benzathine penicillin G every 2 or 3 weeks was confirmed; the adequacy of a 4-week regimen was questionable. The administration of 0.6 million units every 3 weeks was found to be inadequate to maintain serum levels high enough for the secondary prophylaxis of rheumatic fever.

Serum penicillin concentrations after intramuscular administration of benzathine penicillin G in children with rheumatic fever and controls.

Serum and urine penicillin levels were determined in 11 children with rheumatic fever (RF) who were receiving benzathine penicillin G (BPG) prophylactically every 3 weeks and in 10 children without RF who received the drug for the treatment of other infections. The dose given was 600,000 units for children weighing less than 25 kg and 1,200,000 units for those with a weight above 25 kg. Blood and urine samples were collected from both groups before and on days 7, 14 and 21 after BPG administration. Our results showed that: minimum inhibitory concentrations (MICs) of BPG for group A beta-hemolytic streptococci were 0.02 IU/ml or 0.0125 microgram/ml; intramuscular BPG did not give adequate serum levels to block the growth of group A beta-hemolytic streptococci in approximately 24 and 62% of children included in the study on days 14 and 21 after its administration, respectively; BPG metabolism was similar in both groups and did not depend on the underlying disease; serum and urine levels did not vary according to sex and weight; and there was a small correlation between serum and urine levels.

Evaluating the minimum active concentrations of penicillin G and V and of retard forms in clinical conditions.

Following several signals indicating the inefficiency of the clinical treatment with various penicillin preparations in some cases, we decided to study the seric penicillin concentrations in the patients hospitalized in the "V. Babes" Hospital of Infectious Diseases, after administration of the various Romanian made forms of penicillin currently used in the therapy of streptococcal infections and in the prophylaxis of the sequelae of these infections. The data obtained on groups exceeding 30 persons by using two methods of determining the penicillin concentrations the dilutions and the diffusimetric methods revealed protective penicillin seric levels satisfactory for penicillin G and Efitard, according to the present treatment schemes. After 5 days from Moldamin administration only 45.4% of children and 43.3% of adults were found to have satisfactory penicillin concentrations. The administration of penicillin V reaches active penicillin concentrations in terms of the dose administered. The paper points out only one of the causes which together with others (such as beta-lactamase production and tolerance), contribute to the unsuccessful treatment with various forms of penicillin.

Pharmacokinetics of rheumatic fever prophylaxis regimens.

The pharmacokinetics of benzathine penicillin G (1,200,000 IU given intramuscularly), penicillin V (250 mg given orally twice daily), erythromycin stearate (250 mg given orally twice daily) and roxithromycin (150 mg given orally once daily) were investigated. The drugs were given prophylactically to prevent the recurrence of rheumatic fever to 20 patients attending a rheumatic fever clinic in a study of crossover design. Serum antibiotic concentrations were determined by microbiological assay at intervals of up to 28 days after intramuscular injection and immediately before and 1-2 h after the fifth oral dose. The concentrations of penicillin G in all serum samples obtained on day 28 after parenteral benzathine penicillin G administration were greater than 0.01 mg/dl. Most patients had no detectable penicillin V or erythromycin in blood samples drawn immediately before the fifth dose. The concentration of roxithromycin at 24 h after the dose was greater than 1.2 mg/dl in all patients. Based on the pharmacokinetic profiles, it is suggested that 1,200,000 IU benzathine penicillin G given every 4 weeks is an appropriate regimen for preventing the recurrence of rheumatic fever in Thai adults. Roxithromycin had much better pharmacokinetics than penicillin V and erythromycin stearate, and is probably the best alternative regimen to intramuscular penicillin G.

Pharmacokinetics of benzathine penicillin G: serum levels during the 28 days after intramuscular injection of 1,200,000 units.

Because of published data suggesting the inadequacy of once-every-4-weeks intramuscular injections of benzathine penicillin G for secondary rheumatic fever prevention, serum penicillin levels were determined at 1, 3, 10, 21, and 28 days after administration of 1,200,000 units of this repository penicillin. A total of 193 samples were studied. Mean serum penicillin levels remained greater than or equal to 0.02 micrograms/ml for 21 days, but by 28 days only 44% of the serum samples had detectable levels of penicillin and only 36% had levels greater than or equal to 0.02 micrograms/ml. Patients weighing more than 45 kg had significantly lower serum penicillin levels than did those who weighed less. There were similar correlations with body surface area and with age. These data indicate that a significant percentage of patients receiving benzathine penicillin G prophylaxis for prevention of recurrent attacks of rheumatic fever are not protected during the fourth week. More frequent administration of benzathine penicillin G should be considered in instances of high risk of recurrence of rheumatic fever.

[In vivo study of the sensitivity of Treponema pallidum to ofloxacin]. / Etude in vivo de la sensibilité de Treponema pallidum à l'ofloxacine.

Treponema pallidum has not been yet cultivated. Hence any in vitro investigation is excluded, and it is owing to the experimental animal model, the rabbit, that we have studied the susceptibility of that germ to ofloxacin. This quinolone, owing to its pharmacokinetic and therapeutic properties, can specially be indicated in the treatment of Sexually Transmitted Diseases. Thus, its appeared to be of the utmost importance to know if the suggested schedule of treatment for STD, might not be susceptible to modify the course of a co-existing incubating syphilis by either delaying or inhibiting the apparition of the clinical features of primary syphilis. This study was undertaken at the incubation period, in syphilitic rabbits, using kinetic data obtained in man, after a given dosage of ofloxacin. Results were appraised upon converging data: lesions, bacteriology, and serology of the tested lot compared with two control batches of infected rabbits, the first one being untreated, the other having received the reference antibiotic treatment. From the data obtained and in the experimental settled conditions where this study was done, it results that ofloxacin has no effect on the course of the experimental syphilitic infection.

Penicillin concentrations in serum following weekly injections of benzathine penicillin G.

Twelve patients with syphilis were treated weekly with injections of 1.44 g (2.4 X 10(6) IU) of benzathine penicillin G for up to 3 weeks. Almost daily, serum penicillin concentrations were measured by a sensitive microbiological agar cup method. An individual and interindividual variation was found. Concentrations below the recommended 0.018 micrograms/ml were found 7 days after the first or second injection in 5 samples. Shorter intervals between injections are recommended.