Evaluation of plasma concentration after intravenous and intramuscular penicillin administration over 24 hr in healthy adult horses.

Penicillin is administered intravenously (IV) or intramuscularly (IM) to horses for the prevention and treatment of infections, and both routes have disadvantages. To minimize these shortcomings, a 24-hr hybrid administration protocol (HPP) was developed. Our objective was to determine penicillin plasma concentrations in horses administered via HPP. Venous blood was collected from seven healthy horses administered IV potassium penicillin G at 0 and 6 hr and IM procaine penicillin G at 12 hr. Blood was collected at 2-hr intervals from 0 to 20 hr and at 24 hr. Plasma penicillin concentrations were measured using liquid chromatography and mass spectrometry. Penicillin susceptibility from equine isolates was examined to determine pharmacodynamic targets. The MIC90 of penicillin for 264 isolates of Streptococcus sp. was ≤0.06 µg/ml. For the 24-hr dosing interval, the mean plasma penicillin concentration was >0.07 µg/ml. Five horses (72%) exceeded 0.06 µg/ml for 98% of the dosing interval, and two horses exceeded this value for 52%-65% of the dosing interval. The HPP achieved mean plasma penicillin concentrations in healthy adult horses above 0.07 µg/ml for a 24-hr dosing interval. However, individual variations in plasma concentrations were apparent and deserve future clinical study.

Intramuscular administration of sodium benzylpenicillin in horses as an alternative to procaine benzylpenicillin.

The aim was to supply information about the possibility of replacing the procaine salt with the sodium salt for benzylpenicillin IM treatment in horse in order to diminish the risk for procaine adverse effects. In a crossover study eight horses were given 15 mg/kg sodium benzylpenicillin (Na-pc) twice daily or procaine benzylpenicillin (control) once daily IM for four days. The half-life of Na-pc was 1.9h, peak concentration was 14,600 ng/mL reached after about 23 min. Trough plasma concentration was 281 ng/mL and protein binding 62.8%. The fT>MIC for Staphylococcus aureus was 63% and 100% for Streptococcus equi subsp. equi and Streptococcus zooepidemicus, indicating an adequate antimicrobial therapy. However, Na-pc cannot be recommended from a welfare point of view since the horses showed more pain related behaviour and more pain and swelling compared to the control treatment.

Kinetics and residues after intraperitoneal procaine penicillin G administration in lactating dairy cows.

This paper describes the pharmacokinetic profile of procaine penicillin G after intraperitoneal (IP) administration in eight lactating dairy cows. Procaine pencillin G (PPG, 21 000 IU/kg) was deposited into the abdominal cavity of each cow following an incision in the right paralumbar fossa. Blood and milk samples were taken over the following 10 days, at which point the cows were euthanized. Plasma, milk, muscle, liver, and kidney penicillin concentrations were determined by HPLC, with a limit of quantification of 5 ng/mL for plasma and milk and 40 ng/g for tissue samples. A noncompartmental method was used to analyze plasma kinetics. The mean pharmacokinetic parameters (+/-SD) were: C(max), 5.5 +/- 2.6 microg/mL; T(max), 0.75 +/- 0.27 h; AUC(0-infinity), 10.8 +/- 4.9 microg x h/mL; MRT, 2.2 +/- 0.9 h. All milk from treated cows contained detectable penicillin residues for a minimum of three milkings (31 h) and maximum of five milkings (52 h) after administration. Concentrations of penicillin in all muscle, liver, and kidney samples taken 10 days postadministration were below the limit of quantification. Necropsy examinations revealed foci of hemorrhage on the rumenal omentum of most cows but peritonitis was not observed. Systemic inflammation as determined by change in leukogram or plasma fibrinogen was noted in one cow. The results of this study demonstrate that IP PPG is absorbed and eliminated rapidly in lactating dairy cows.

Meta-analysis of pharmacokinetic data of veterinary drugs using the Food Animal Residue Avoidance Databank: oxytetracycline and procaine penicillin G.

Investigators frequently face the quandary of how to interpret the often times disparate pharmacokinetic parameter values reported in the literature. Combining of data from multiple studies (meta-analysis) is a useful tool in pharmacokinetics. Few studies have explored the use of meta-analysis for veterinary species. Even fewer studies have explored the potential strengths and weaknesses of the various methods of performing a meta-analysis. Therefore, in this study we performed a meta-analysis for oxytetracycline (OTC) and procaine penicillin G (PPG) given intramuscularly to cattle. The analysis included 28 individual data sets from 18 published papers for PPG (288 data points), and 41 individual data sets from 25 published papers for OTC (489 data points). Three methods were used to calculate the parameters. The first was a simple statistical analysis of the parameter values reported in each paper. The second method was a standard Two-Stage Method (TSM) using the mean concentration vs. time data extracted from each paper. The third method was the use of nonlinear mixed effect modeling (NMEM) of the concentration vs. time data reported in the various papers, treating the mean data as if each set came from an individual animal. The results of this evaluation indicate that all three methods generate comparable mean parameter estimates for OTC and PPG. The only significant difference noted was for OTC absorption half-lives taken from the published literature, a difference attributable to the use of an alternative method of parameter calculation. The NMEM procedure offers the possibility of including covariates such as dose, age, and weight. In this study the covariates did not influence the derived parameters. A combination approach to meta-analysis of published mean data is recommended, where the TSM is the first step, followed by the NMEM approach.

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.

Bioavailability and disposition of sodium and procaine penicillin G (benzylpenicillin) administered orally with milk to calves.

Eighteen 1-week-old Holstein calves were randomly assigned to one of three groups: (a) sodium penicillin G administered intravenously, (b) sodium penicillin G administered orally, or (c) procaine penicillin G administered orally. All calves were dosed with penicillin G at 4.0 mg/kg BW. At 5 weeks of age, the calves were dosed again. Blood samples were taken serially for 24 h after both dosings. Plasma was assayed for penicillin G by high performance liquid chromatography (HPLC). For i.v. administration, the area under the concentration-time curve (AUC), 7456 and 5508 ng/mL h, and systemic clearance, 0.54 and 0.73 L/kg h, were significantly different (P < 0.05) at 1 and 5 weeks of age, respectively. There were no significant differences between orally administered sodium and procaine penicillin G within the same age groups. Following oral (p.o.) administration, there were significant differences (P < 0.01) at 1 and 5 weeks of age in the AUC, 760 and 409 ng/mL h, terminal half-life, 2.1 and 1.6 h, time of maximum concentration (TMAX), 3.0 and 2.3 h, and maximum plasma concentration (CMAX), 85 and 58 ng/mL, respectively. Bioavailability was 10.2 and 7.4% at 1 and 5 weeks, respectively.

Pharmacokinetics of penicillin G procaine versus penicillin G potassium and procaine hydrochloride in horses.

OBJECTIVE: To compare the pharmacokinetics of penicillin G and procaine in racehorses following i.m. administration of penicillin G procaine (PGP) with pharmacokinetics following i.m. administration of penicillin G potassium and procaine hydrochloride (PH). ANIMALS: 6 healthy adult mares. PROCEDURE: Horses were treated with PGP (22,000 units of penicillin G/kg of body weight, i.m.) and with penicillin G potassium (22,000 U/kg, i.m.) and PH (1.55 mg/kg, i.m.). A minimum of 3 weeks was allowed to elapse between drug treatments. Plasma and urine penicillin G and procaine concentrations were measured by use of high-pressure liquid chromatography. RESULTS: Median elimination phase half-lives of penicillin G were 24.7 and 12.9 hours, respectively, after administration of PGP and penicillin G potassium. Plasma penicillin G concentration 24 hours after administration of penicillin G potassium and PH was not significantly different from concentration 24 hours after administration of PGP. Median elimination phase half-life of procaine following administration of PGP (15.6 hours) was significantly longer than value obtained after administration of penicillin G potassium and PH (1 hour). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that i.m. administration of penicillin G potassium will result in plasma penicillin G concentrations for 24 hours after drug administration comparable to those obtained with administration of PGP Clearance of procaine from plasma following administration of penicillin G potassium and PH was rapid, compared with clearance following administration of PGP.

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)

Influence of the pre-treatment duration of infection on the efficacies of various antibiotic regimens in experimental streptococcal endocarditis.

The influence of the pre-treatment duration of infection on the efficacies of three different antibiotic regimens was investigated in a rabbit model of subacute endocarditis caused by a novel, nutritionally-variant species, Streptococcus adjacens strain GaDT. Treatment was initiated either 6 or 10 days after bacterial inoculation (days 7 and 11 respectively) and comprised procaine penicillin (150,000 IU/kg bd), alone or combined with tobramycin (12 mg/kg od), teicoplanin (10 mg/kg bd), all administered by the intramuscular route for 4 days. The MICs and MBCs of penicillin, tobramycin and teicoplanin were 0.015 and 1 mg/L, 8 and 16 mg/L and 0.25 and 256 mg/L respectively. In the control rabbits, the mean (+/- S.D.) weights of the vegetations were 25 +/- 16 mg on day 7 and 45 +/- 34 mg on day 11 (P = 0.06). The mean (+/- S.D.) reductions in the number of cfu in the vegetations of the treated groups of animals after completion of therapy which had been started on days 7 and 11, compared with the mean numbers of cfu in the vegetations of the untreated controls on days 7 and 11 (delta log10 cfu/g), were 4.0 +/- 1.3 and 2.1 +/- 1.5 respectively for penicillin (P < 0.05), 3.2 +/- 1.8 and 2.4 +/- 1.8 respectively for teicoplanin and 5.4 +/- 1.2 and 5.2 +/- 1.2 respectively for the combination of penicillin and tobramycin. The increase in the size of the vegetations and changes in the metabolism of the bacteria within the vegetations between days 7 and 11, as demonstrated by electron microscopy, might explain why penicillin was more effective earlier in the course of the disease and why the influence of the duration of infection before treatment was initiated, varied according to the antibiotic regimen. These results suggest that the use of bactericidal regimens, such as the combination of penicillin and tobramycin, which are equally effective in reducing the bacterial counts in vegetations which have been infected for both long and short periods could minimize the risk of relapse in patients with endocarditis in whom there have been long delays before initiating treatment and/or who have large vegetations.

Depletion of intramuscularly and subcutaneously injected procaine penicillin G from tissues and plasma of yearling beef steers.

Withdrawal periods required when doses of 24,000 IU and 66,000 IU of procaine penicillin G/kg body weight were administered to yearling beef steers by intramuscular injection daily for five consecutive days were investigated. These dosages are in excess of product label recommendations, but are in the range of procaine penicillin G dosages that have been administered for the treatment of some feedlot bacterial diseases. The approved dose in Canada is 7,500 IU/kg body weight intramuscularly, once daily, with a withdrawal period of five days. Based on the tissue residue data from this study, the appropriate withdrawal period is ten days for the 24,000 IU/kg body weight dose and 21 days for the 66,000 IU/kg body weight dose when administered intramuscularly to yearling beef steers. In a related study, 18 yearling beef steers received 66,000 IU of procaine penicillin G/kg body weight administered by subcutaneous injection, an extra-label treatment in terms of both dose and route of administration, typical of current practice in some circumstances. Deposits of the drug were visible at subcutaneous injection sites up to ten days after injection, with more inflammation and hemorrhage observed than for intramuscular injections of the same dose. These results suggest that procaine penicillin G should not be administered subcutaneously at high doses; and therefore a withdrawal period was not established for subcutaneous injection.

Optimal aminoglycoside dosing regimen for penicillin-tobramycin synergism in experimental Streptococcus adjacens endocarditis.

The combination of penicillin and aminoglycoside is the recommended therapy for endocarditis caused by nutritionally variant streptococci (NVS). However, the optimal aminoglycoside dosing regimen remains controversial. We compared the efficacies of four regimens of tobramycin alone or combined with procaine penicillin in the therapy of rabbits with endocarditis caused by Streptococcus adjacens, a new species of NVS. Animals were injected intramuscularly for 4 days with procaine penicillin (150,000 U/kg of body weight twice daily) or tobramycin at a low dose (3 mg/kg every 24 h) or a high dose (12 mg/kg every 24 h) either once or three times daily (t.i.d.) alone or in combination with procaine penicillin. Additional groups of animals were treated with the combination regimens for a shorter period of time (2 days) in order to demonstrate a possible difference in the rapidity of efficacy between the regimens. The MICs and MBCs were 0.015 and 1 micrograms/ml and 8 and 16 micrograms/ml for penicillin and tobramycin, respectively. The mean peak tobramycin levels in plasma were 2.4 +/- 1.3 (1 mg/kg t.i.d.), 5.4 +/- 3.7 (4 mg/kg t.i.d.), and 25 +/- 9.3 (12 mg/kg once daily). The mean penicillin levels in serum were always above the MIC. In vitro kill curves plotted at the time that peak concentrations were reached in plasma showed a concentration-dependent killing effect of tobramycin alone but not in combination with penicillin. In vivo, low-dose tobramycin was significantly less effective than the high dose. Results for the combinations of the different dosing regimens of tobramycin with procaine penicillin were not significantly different. Our results suggest that (i) against susceptible strains of streptococci, aminoglycoside alone exhibits a concentration-dependent killing effect both in vitro and in vivo; (ii) against NVS strains, combinations of penicillin and high- or low-dose tobramycin are equally effective; and (iii) aminoglycoside given once daily or at a low dose t.i.d. with penicillin could be a cost-effective alternative with reduced toxic risk for patients with NVS endocarditis when the bacteria are susceptible to the killing activities of both compounds.

Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys.

Concentrations of penicillin, doxycycline, and ciprofloxacin were measured by bioassay in sera of rhesus monkeys treated with these drugs for inhalation anthrax. Antibiotic doses were determined on the basis of published serum concentration data from humans and comparative body surface area calculations for humans and rhesus monkeys. The antibiotics were well tolerated. Serum peak and trough concentrations of penicillin, doxycycline, and ciprofloxacin, respectively, averaged 2.7 and 0.8, 1.31 and 0.26, and 1.22 and 0.14 microgram/mL. These were within the range usually observed with standard oral doses in humans, and peak concentrations in all monkeys exceeded the MICs for 90% of Bacillus anthracis strains.

Bovine platelets retain functional activity in the presence of penicillin G.

It has been reported that antibiotics of the penicillin family impair the functional response of human, canine and lapine platelets to a broad range of agonists. In contrast, we have shown that the bovine platelet retained full functional responses to stimulation by adenosine diphosphate (ADP) or platelet activating factor (PAF) following administration of penicillin G to clinically normal cattle at 20,000 IU/kg for three days. The aggregation response to collagen was transiently reduced to approximately 50% of pretreatment values, but only while the drug was detectable in the circulation. When penicillin was added to platelet rich plasma suspensions, ADP-induced aggregation was similar to that of the control untreated platelets, while the PAF-induced aggregation response was reduced by not more than 25%. Only collagen-induced aggregation exhibited a modest dose-dependent inhibitory response in the presence of penicillin. It is postulated that the relative insensitivity of the bovine platelet to penicillin may be related to differences in postreceptor biochemical events compared to the human platelet.

Efficacy of temafloxacin in experimental Streptococcus adjacens endocarditis and autoradiographic diffusion pattern of [14C]temafloxacin in cardiac vegetations.

Temafloxacin, a new fluoroquinolone, alone or in combination with tobramycin, was compared with penicillin, tobramycin, and their combination in the therapy of rabbits with endocarditis caused by Streptococcus adjacens GaDT, a new species of nutritionally variant streptococci. Animals were injected intramuscularly for 4 days with temafloxacin (50 mg/kg of body weight twice daily [b.i.d.]) alone or combined with tobramycin (12 mg/kg once daily), with procaine penicillin (150,000 U/kg b.i.d.) alone or combined with tobramycin (12 mg/kg once daily), or with tobramycin (12 mg/kg once daily) alone. Another group of animals was treated with a higher dose of temafloxacin (100 mg/kg b.i.d.). Temafloxacin, penicillin, and tobramycin MICs and MBCs were 1 and 2, 0.015 and 1, and 8 and 16 micrograms/ml, respectively. Time-kill curves showed that the addition of tobramycin to penicillin or temafloxacin increased the killing rate. In vivo, treatment with temafloxacin (50 and 100 mg/kg b.i.d.) alone reduced the bacterial counts in vegetations (3.9 +/- 0.9 and 3.1 +/- 0.8 log10 CFU/g of vegetation) compared with those in the vegetations of control animals (7.5 +/- 0.9 log10 CFU/g of vegetation). This result was similar to that obtained with penicillin alone (4.5 +/- 0.8 log10 CFU/g of vegetation). The combination of temafloxacin (50 mg/kg) and tobramycin was as effective as penicillin plus tobramycin (2.5 +/- 0.3 versus 2.3 +/- 0.4 log10 CFU/g of vegetation, respectively). The autoradiographic pattern of [14C]temafloxacin diffusion into infected cardiac vegetations was studied. Thirty minutes after the end of infusion of 250 microCi of [14C]temafloxacin, the [14C]temafloxacin was homogeneously distributed throughout the vegetations. These data support further evaluation of quinolones in experimental endocarditis.

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.

Mathematical description of the concentration of oxytetracycline and penicillin-G in tissue cages in calves as related to the serum concentration.

A mathematical model based on Fick's laws of diffusion describing the concentration of drug in tissue cage models was elaborated. The model takes into account differences in protein binding, tissue cage geometry and serum pharmacokinetics. The validity of the model was tested against experimental data obtained from a tissue cage model in calves by simultaneous fitting to serum and tissue cage fluid (TCF) data in a non-linear least-squares regression computer program. Concentrations of penicillin-G (pen-G) in serum and TCF following intravenous (i.v.) administration of potassium pen-G were adequately described by the mathematical model. Concentrations in TCF after intramuscular (i.m.) administration of the same drug and of procaine pen-G could be predicted by the mathematical model. Concentrations of oxytetracycline (OTC) in serum and TCF following i.v. administration and continuous i.v. infusions were also adequately described by the model, and TCF concentrations after i.m. administration of the same drug could be roughly predicted. The results indicate that pen-G and OTC have the same permeability coefficient for transport from serum to TCF.

Concentrations of sulphadimidine, oxytetracycline and penicillin G in serum, synovial fluid and tissue cage fluid after parenteral administration to calves.

Drug concentrations in serum, synovial fluid and tissue cage fluid (TCF) in calves were measured after single i.m. doses of oxytetracycline hydrochloride (OTC), procaine penicillin G (PPG) and potassium penicillin G (KPG) and single i.v. doses of sulphadimidine (SDM) and OTC. For all drugs, concentration-time curves in serum and synovial fluid were not identical but they had similar profiles, with peak levels occurring at about the same time. Concurrent concentrations were lower in synovial fluid than in serum. For each drug, elimination half-lives from synovial fluid and from serum were similar, except for penicillin G after KPG administration which had a significantly longer half-life from synovial fluid than from serum (P less than 0.05). Of the two penicillin G preparations, PPG gave a significantly higher synovial fluid:serum area under curve (AUC) ratio than did KPG; 0.76 +/- 0.10 and 0.54 +/- 0.12, respectively (P less than 0.05). For OTC, the synovial fluid:serum AUC-ratio was 0.33 +/- 0.12 after i.m. and 0.34 +/- 0.08 after i.v. administration. Drug concentration-time curves of TCF had different profiles compared with serum, with relatively low and delayed peak levels and slow elimination from TCF. TCF:serum AUC-ratios did not differ significantly for i.m. and i.v. administration of OTC; 0.10 +/- 0.10 and 0.19 +/- 0.03 respectively (P greater than 0.05). Potassium penicillin G (KPG), however, gave a significantly higher TCF:serum AUC-ratio than PPG; 0.55 +/- 0.21 and 0.19 +/- 0.07, respectively (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

[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.