Bioequivalence study in calves of three commercial penicillin/ dihydrostreptomycin fixed combination products for intramuscular injection

A bioequivalence study with three penicillin/dihydrostreptomycin fixed combination products for intramuscular administration was performed in dairy calves. In addition to plasma concentrations of penicillin and dihydrostreptomycin, creatine phosphokinase concentrations were determined during a period of 72 h after administration of the drug products. Considerable differences were observed in the pharmacokinetics of penicillin from the three products. Although the extent of absorption was similar for all products, one product showed a significantly slower release from the site of injection. Except for the AUC , the 90% confidence intervals for these parameters exceeded the acceptable range of 0.80-1.20. Therefore, these products are not bioequivalent with respect to the rate of absorption of penicillin. Concerning the pharmacokinetics of dihydrostreptomycin in calves, it could not be concluded that the products were bioequivalent, since the 90% confidence intervals of the ratios for C _max, t _max and MRT exceeded the range of 0.80-1.20. From this study in calves, it was also found that the product with the slowest release of penicillin from the injection site caused the most severe tissue damage, based on plasma creatine phosphokinase concentrations. Comparing the results from this study in calves with those from a previous study in rabbits, it can be concluded that the rabbit is a good animal model that could substitute for large animals, at least calves, in bioequivalence studies for penicillin/dihydrostreptomycin fixed combination products.     

'Pink eye' or 'zere oogjes' or keratoconjunctivitis infectiosa ovis (KIO). Clinical efficacy of a number of antimicrobial therapies

In a comparative study the clinical efficacy of five different treatments of keratoconjunctivitis infectiosa ovis (KIO) were tested, namely an intramuscular injection of chloramphenicol base (dosage 15 mg/kg), spiramycin base (Suanovil dosages 10 to 25 mg/kg), oxytetracycline (Engemycine Forte, Terramycin LA, dosages respectively 5 and 10 mg/kg), tiamulin (Dynamutulin, dosage 10 mg/kg) and subcutaneous injection of procaine penicillin G, benzathine penicillin G. and dihydrostreptomycin in the lower eyelid. It appeared from these field trials that spiramycin base, oxytetracycline and tiamulin had a clearly positive effect on the clinical course of 'pink eye', although with tiamulin there was only a temporary effect (high percentage of relapses). In view of the field data the following dosage schemes are, for the time being, advised: spiramycin base (Suanovil), and oxytetracycline (formulation with a good biological availability) both 20 to 30 mg/kg and, if necessary, to be repeated on days 5 and 10 after the first intramuscular injection. The dosage scheme advised for tiamulin is 20-30 mg/kg to be repeated on day 3 and if necessary on days 6 and 9 after the intramuscular injection. In mild cases it is sufficient to rub the eyes with for example oxytetracycline eye-ointment, a few times a day.     

Susceptibility of bacterial pathogens against lincomycin/spectinomycin (1/2), penicillin G/neomycin (1/1), and penicillin G/dihydrostreptomycin (1/1) as determined in the BfT-GermVet monitoring program 2004-2006

A total of 368 bacterial pathogens, including 72 coagulase-positive and coagulase-variable staphylococci, 97 beta-haemolytic streptococci, 51 Escherichia coli, 75 Pasteurella multocida, 25 Mannheimia haemolytica, 25 Pseudomonas aeruginosa, and 23 Arcanobacterium pyogenes, were investigated for their susceptibility to the three combinations of antimicrobial agents lincomycin/spectinomycin (1/2), penicillin G/neomycin (1/1), and penicillin G/dihydrostreptomycin (1/1) in comparison to their susceptibility to the corresponding single substances. When comparing the minimum inhibitory concentrations (MICs) determined for any of the three combinations with those for the single substances, the lowest MIC of one of the two substances usually determined the MIC of the combination.This observation was made for all three combinations and all bacterial pathogens tested.Thus, it is assumed that the combination of lincomycin with spectinomycin as well as that of penicillin with either neomycin or dihydrostreptomycin resulted in an extended spectrum of target bacterial pathogens rather than in an increase in antimicrobial efficacy.     

‘Pink eye’ or ‘zere oogjes’ or Keratoconjunctivitis Infectiosa Ovis (KIO)

In a comparative study the clinical efficacy of five different treatments of keratoconjunctivitis infectiosa ovis (KIO) were tested, namely an intramuscular injection of chloramphenicol base (dosage 15 mg/kg), spiramycin base (Suanovil^® dosages 10 to 25 mg/kg), oxytetracycline (Engemycine^® Forte, Terramycin^® LA, dosages respectively 5 and 10 mg/kg), tiamulin (Dynamutulin^®, dosage 10 mg/kg) and subcutaneous injection of procaine penicillin G, benzathine penicillin G, and dihydrostreptomycin in the lower eyelid.

It appeared from these field trials that spiramycin base, oxytetracycline and tiamulin had a clearly positive effect on the clinical course of ‘pink eye’, although with tiamulin there was only a temporary effect (high percentage of relapses).

In view of the field data the following dosage schemes are, for the time being, advised: spiramycin. base (Suanovil^®), and oxytetracycline (formulation with a good biological availability) both 20 to 30 mg/kg and, if necessary, to be repeated on days 5 and 10 after the first intramuscular injection. The dosage scheme advised for tiamulin is 20–30 mg/kg to be repeated on day 3 and if necessary on days 6 and 9 after the intramuscular injection. In mild cases it is sufficient to rub the eyes with for example oxytetracycline eye‐ointment, a few times a day.     

Pharmacokinetics of an ampicillin/sulbactam (2:1) combination in rabbits

The pharmacokinetics of a 2:1 ampicillin-sulbactam combination in six rabbits, after intravenous and intramuscular injection at a single dosage of 20 mg/kg bodyweight (13.33 mg/kg of sodium ampicillin and 6.67 mg/kg of sodium sulbactam) were investigated by using a high performance liquid chromatographic method for determining plasma concentrations. The plasma concentration-time curves were analysed by compartmental pharmacokinetic and noncompartmental methods. The disposition curves for both drugs were best described by an open two-compartment model after intravenous administration and a one-compartment model with first order absorption after intramuscular administration. The apparent volumes of distribution calculated by the area method for ampicillin and sulbactam were 0.62 +/- 0.09 and 0.45 +/- 0.05 L/kg, respectively, and the total body clearances were 0.65 +/- 0.04 and 0.42 +/- 0.05 L/kg h, respectively. The elimination half-lives of ampicillin after intravenous and intramuscular administration were 0.64 +/- 0.11 and 0.63 +/- 0.16 h, respectively, whereas for sulbactam the half-lives were 0.74 +/- 0.12 and 0.77 +/- 0.17 h, respectively. The bioavailability after intramuscular injection was high and similar in both drugs (73.34 +/- 10.08% for ampicillin and 83.20 +/- 7.41% for sulbactam). The mean peak plasma concentrations of ampicillin and sulbactam were reached at similar times (0.20 +/- 0.09 and 0.34 +/- 0.15 h, respectively) and peak concentrations were also similar but nonproportional to the dose of both products administered (13.07 +/- 3.64 mg/L of ampicillin and 8.42 +/- 1.74 mg/L of sulbactam). Both drugs had similar pharmacokinetic behaviour after intramuscular administration in rabbits.     

Efficacy of intramammary treatment with procaine penicillin G vs. procaine penicillin G plus neomycin in bovine clinical mastitis caused by penicillin-susceptible,gram-positive bacteria--a double blind field study

The efficacy of intramammary treatments containing procaine penicillin G alone (treatment A) or a combination of procaine penicillin G and neomycin (treatment B) was compared in treating clinical bovine mastitis caused by gram-positive bacteria susceptible in vitro to penicillin G. Both treatments were supplemented with a single intramuscular injection of procaine penicillin G on the first day of treatment. The study was carried out using a double blind design on commercial dairy farms in Southern Finland. A total of 56 quarters were treated with treatment A and 61 with treatment B. The cure rates for both treatments were equal, which suggests that the use of the penicillin G-aminoglycoside combination does not increase the efficacy of the treatment over that achieved by using penicillin G alone in bovine clinical mastitis caused by penicillin-susceptible, gram-positive bacteria.     

Distribution of penicillin G in serum and tissue cage fluid in cattle

The penetration of penicillin into tissue cage fluid (TCF) in calves was studied after intravenous and intramuscular injection. The penicillin concentrations in TCF were lower than in serum and maximum was reached much later. Intravenous injection of benzyl-penicillin gave significantly higher levels in TCF than intramuscular injection. The penetration after procaine penicillin was very slow. The results showed that the serum peak rather than the area under curve determines the penetration of penicillin. Repeated intramuscular injections of benzylpenicillin and procaine penicillin caused an accumulation of penicillin in TCF. Similar levels were however reached by one single intravenous injection. The clinical counterparts to the used tissue cage model are abscesses. It was concluded that if high penicillin concentration are desireable in such foci, the drug must be given in a way that gives as high serum peaks as possible.     

Distribution of penicillin G, dihydrostreptomycin, oxytetracycline, and chloramphenicol in serum and subcutaneous chamber fluid

Penetration of penicillin G, dihydrostreptomycin, oxytetracycline, and chloramphenicol into interstitial fluid of calves was estimated using subcutaneously implanted, multiple perforated spherical polypropylene capsules as a model. Antibiotic concentrations were determined in simultaneously withdrawn serum and capsular fluid (CF) samples at intervals after single and multiple intramuscular injections of antibiotics at recommended dose schedules. Peak concentrations of penicillin G in CF were 57% of those in serum, and the drug was eliminated from CF at a slower rate than from serum. Dihydrostreptomycin diffused into CF to a limited degree and was eliminated from CF much more slowly than from serum leading to gradual drug accumulation in CF upon repeated dosing. Multiple injections of oxytetracycline resulted in CF drug levels comparable with those in serum. Concentrations of chloramphenicol in CF were generally similar to free (non-protein bound) serum drug levels. CF concentrations of penicillin G were within the range of the minimal inhibitory concentrations of the drug for pathogenic gram positive micro-organisms and CF levels of dihydrostreptomycin, oxytetracycline, and chloramphenicol were apparently sufficient to inhibit the majority of gram negative pathogens involved in bovine injections. Advantages and limitations of the tissue cage model are briefly discussed.     

Rabbit model for estimating relative bioavailability, residues and tissue tolerance of intramuscular products: comparison of two ampicillin products

A rabbit model for simultaneous investigation of the bioavailability, tissue residues and tissue tolerance of intramuscularly administered veterinary medicines is described. The bioavailability of ampicillin from two intramuscular products, which had been found to be different in calves, were compared in a two-way crossover design. The ampicillin levels in plasma, ampicillin residues in tissues, the plasma creatine kinase activity and the tissue damage at the injection sites were studied. The absolute bioavailabilities for the products were 100% and 40%. Differences in pharmacokinetics of ampicillin between sexes were observed after intravenous and intramuscular administration. Only slight tissue damage could be detected at the injection sites after intramuscular administration of these products. The results were compared with those obtained previously in calves and were found to be similar. Further investigations with other intramuscular drug products to validate this model are under way.     

Clinical trial of three therapeutic regimens for bovine mastitis

An open, block randomised multi-centre clinical trial was performed in Norway during 1985 to 1987 to compare the therapeutic efficacy of three antibiotic regimens against clinical bovine mastitis caused by penicillin-sensitive bacteria. Two regimens consisted of procaine penicillin injected intramuscularly for either three or five days, and the third, the traditional Norwegian regimen, consisted of one intramuscular injection of a combination of procaine penicillin and dihydrostreptomycin followed by one intramammary treatment daily per infected quarter for four days. The study included 621 quarters with infectious mastitis from 439 cows. The most efficient regimen for all bacteria was five days systemic treatment (53.1 per cent cured), and the traditional regimen was second best (46.7 per cent cured). The least efficient regimen consisted of systemic therapy with procaine penicillin for three days (36.9 per cent cured). The difference between the therapeutic efficacies of the three regimens was reduced when the clinical mastitis was severe, and in severe mastitis caused by Staphylococcus aureus the difference was very small.     

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.     

Penetration of some antibiotics into the lacrimal fluid of sheep

Antibiotic concentrations were determined in the lacrimal fluid of sheep following subcutaneous application of penicillin/ dihydrostreptomycin into the lower eyelid, and intramuscular administration of spiramycin base, tiamulin, and oxytetracycline formulations. The penetration of penicillin and dihydrostreptomycin into the lacrimal fluid was poor. The spiramycin and tiamulin concentrations in the lacrimal fluid were 10‐ and 4‐fold higher than in the serum. The peak spiramycin concentration in the lacrimal fluid was 3.4 ±0.8 μg/ml at 8 h post injection (p.i.) and the drug could be detected at least 72 h p. i. For tiamulin and oxytetracycline (OTC) peak concentrations of 1.53 ±0.70 and 1.88 ±1.9 μg/ml, respectively, were achieved in the lacrimal fluid and these drugs could be detected 25 to 30 h p.i. The OTC and tiamulin concentration‐time curves for lacrimal fluid and serum were parallel, whereas for the spiramycin appearance in the lacrimal fluid was delayed.     

An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows

Penicillin G is widely used in food‐producing animals at extralabel doses and is one of the most frequently identified violative drug residues in animal‐derived food products. In this study, the plasma pharmacokinetics and tissue residue depletion of penicillin G in heavy sows after repeated intramuscular administrations at label (6.5 mg/kg) and 5 × label (32.5 mg/kg) doses were determined. Plasma, urine, and environmental samples were tested as potential antemortem markers for penicillin G residues. The collected new data and other available data from the literature were used to develop a population physiologically based pharmacokinetic (PBPK) model for penicillin G in heavy sows. The results showed that antemortem testing of urine provided potential correlation with tissue residue levels. Based on the United States Department of Agriculture Food Safety and Inspection Service action limit of 25 ng/g, the model estimated a withdrawal interval of 38 days for penicillin G in heavy sows after 3 repeated intramuscular injections at 5 × label dose. This study improves our understanding of penicillin G pharmacokinetics and tissue residue depletion in heavy sows and provides a tool to predict proper withdrawal intervals after extralabel use of penicillin G in heavy sows, thereby helping safety assessment of sow‐derived meat products.     

Pharmacokinetics of phenoxymethyl penicillin (penicillin V) in calves

Phenoxymethyl penicillin (penicillin V) was administered intravenously (i.v.) and orally to pre-ruminant calves and the distribution and elimination kinetics, as well as the oral bioavailability, were determined. After i.v. injection, the drug was distributed rapidly in the body, the elimination half-life (t1/2 beta) was 34 min and the apparent volume of distribution at steady-state (Vd ss) was 0.30 l/kg. Mean peak serum drug concentrations were directly related to the oral dose administered, i.e. 0.22 microgram/ml, 1.06 micrograms/ml and 2.14 micrograms/ml after dosing at 10, 20 and 40 mg/kg, respectively. The elimination t1/2 of the drug after oral dosing varied between 90 and 110 min, and the oral bioavailability was approximately 30% of the dose. The co-administration of phenoxymethyl penicillin and probenecid resulted in elevation and prolongation of serum drug concentration. The percentage of drug bound to serum proteins was 78.8% +/- 8.2%. Phenoxymethyl penicillin was probably inactivated and degraded in the gastrointestinal tract of 6-week-old calves fed exclusively hay, silage and concentrates as very low and erratic serum drug concentrations were measured after these calves were dosed orally with the drug at 40 mg/kg. In view of the narrow antibacterial spectrum of the drug and the relatively high dose required, it appears that phenoxymethyl penicillin can only be of limited practical value for the treatment of bacterial infections in preruminant calves.     

Concentrations of penicillin, streptomycin, and spiramycin in bovine udder tissue liquids

Concentrations of benzylpenicillin and spiramycin adipate were determined in bovine plasma and milk and in lymph draining the udder tissue after IM or IV administration. Combined benzylpenicillin and dihydrostreptomycin sulfate concentrations were also determined in the same fluids after intramammary injection. A superficial parenchymal lymph vessel, afferent to the supramammary lymph gland of the left quarters, was cannulated with a polythene catheter from which the lymph was allowed to drain freely. After injections of 9.5 mg of benzylpenicillin/kg of body weight IM, a mean peak concentration (PC) in lymph (3.7 micrograms/ml), constituting 77% of the PC in plasma (4.8 micrograms/ml), was obtained 0.5 to 1 hour after PC in the plasma. The benzylpenicillin lymph concentration was close to that in plasma for about 7 hours after injection. Thereafter, the benzylpenicillin lymph concentration continued to exceed that in plasma, but not that in milk. After IV administration of spiramycin adipate, the lymph concentration was almost identical to that in plasma. After intramammary injection of procaine benzylpenicillin (400 mg), in combination with the same amount of dihydrostreptomycin sulfate, into 2 udder quarters each, mean PC in the lymph of 3.5 micrograms/ml and 8.4 micrograms/ml, respectively, were obtained 6 hours after injection. In plasma, the mean PC of benzylpenicillin (0.07 micrograms/ml) and of dihydrostreptomycin sulfate (0.85 micrograms/ml) were obtained after 4 and 6 hours, respectively. In milk from the nontreated quarters, a mean concentration of 5 ng of benzylpenicillin/ml was obtained, whereas dihydrostreptomycin sulfate (greater than or equal to 0.3 microgram/ml) was not detected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of the injection site on the pharmacokinetics of procaine penicillin G in horses

The plasma penicillin concentrations were determined in 5 horses given an IV injection of sodium penicillin G; plasma penicillin concentrations were also determined in a crossover experiment, where animals were given procaine penicillin G subcutaneously at 1 site and IM at 4 sites. The mean penicillin plasma peak concentration and bioavailability were highest after the drug was injected in the neck and biceps musculature. Injections in the gluteal muscle and in the subcutaneous sites resulted in similar, but lower, more persistent penicillin plasma concentrations and a lower bioavailability than were obtained with injection in the neck and biceps musculature. The pharmacokinetic data obtained after penicillin was administered via the pectoral muscle route exhibited an intermediate position. Therapeutic implications of the routes of administration with respect to hemolytic streptococcal infections are discussed.     

普鲁卡因青霉素-硫酸双氢链霉素混悬液在猪体内的药物动力学

健康长白猪7头,按拉丁方试验设计,进行单剂量静脉注射青霉素(20 000单位/kg体重)钠、硫酸双氢链霉素(20 000单位/kg体重)及肌肉注射普鲁卡因青霉素-硫酸双氢链霉素混悬剂(20 000单位/kg体重)的药物动力学研究。HPLC法和HPLC-MS/MS法分别测定血浆中的青霉素和双氢链霉素浓度,WinNonlin软件处理血药浓度-时间数据。静脉注射青霉素钠、硫酸双氢链霉素的药时数据最佳模型为三室开放模型。肌肉注射混悬剂后青霉素G的药时数据符合一级吸收一室模型。主要药物动力学参数:t1/2ka为0.66 h,t1/2β为5.80 h,t(max)为2.3 h,C(max)为1.66 mg/L,AUC为17.65,CL为0.69 L/h.kg,F为70.57%;肌肉注射混悬剂后双氢链霉素数据符合一级吸收二室开放模型,主要药动参数:t1/2ka为0.21 h;t1/2α为2.06 h;t1/2β为8.22 h,t(max)为0.8 h,C(max)为51.42 mg/L,AUC为280.74,F为101.96%。肌肉注射混悬液药物动力学特征为青霉素G吸收迅速,消除缓慢;双氢链霉素吸收迅速完全,消除缓慢,生物利用度高。     

Dihydrostreptomycin or streptomycin in combination with penicillin G in dairy cattle therapeutics: A review and re-analysis of published data Part 1: Clinical pharmacology

Combination formulations of penicillin G salts and dihydrostreptomycin were developed during the 1960s and are currently marketed in New Zealand for parenteral and intramammary use in dairy cattle. In this paper, the clinical indications and efficacy, pharmacokinetics and potential for antimicrobial synergy of penicillin and dihydrostreptomycin or streptomycin, when combined, are discussed.     

Dihydrostreptomycin or streptomycin in combination with penicillin G in dairy cattle therapeutics: a review and re-analysis of published data. Part 1: clinical pharmacology

Combination formulations of penicillin G salts and dihydrostreptomycin were developed during the 1960s and are currently marketed in New Zealand for parenteral and intramammary use in dairy cattle. In this paper, the clinical indications and efficacy, pharmacokinetics and potential for antimicrobial synergy of penicillin and dihydrostreptomycin or streptomycin, when combined, are discussed.     

Effects of experimentally induced Streptococcus suis infection on the pharmacokinetics of penicillin G in pigs

The pharmacokinetics of potassium penicillin G were studied in both healthy (n = 8) and experimentally Streptococcus-suis-infected (n = 6) pigs following intramuscular administration (15,000 iu/kg). Streptococcus-suis infection was induced artificially in young cross-bred pigs by subcutaneous inoculation with 9 x 10(8) to 10(9) colony-forming units of S. suis. The rectal temperature of infected pigs was significantly increased (P less than 0.01) before penicillin G injection and this was maintained for 8 h after the drug was given. Other clinical symptoms were also present. The serum concentration-time data for penicillin were found to fit a one-compartment open model with first-order absorption in the two groups of pigs. Significant changes were not observed between healthy and diseased pigs in following parameters: A, Ka, Ke and Tmax. However, in diseased pigs, significant increases (P less than 0.01) were found in Vd and ClB, and significant decreases (P less than 0.01) in Cmax and AUC occurred. The increased body clearance (ClB) and greater apparent volume of distribution (Vd) of penicillin G could partly explain why the serum values of the drug were much lower in diseased pigs than in healthy pigs.