Potassium penicillin and gentamicin pharmacokinetics in healthy conscious and anesthetized horses.

OBJECTIVE: To determine the effects of general anesthesia on the safety and efficacy of co-administered potassium penicillin G (PEN) and gentamicin (GENT) in horses. STUDY DESIGN: Nonrandomized crossover. ANIMALS: Six adult, Thoroughbred horses. METHODS: Horses were administered PEN (22 000 IU/kg IV) and GENT (6.6 mg/kg IV). Plasma samples were collected over a 6 h period and synovial fluid was collected at 30 min and 6 h respectively. Drug administration and sample collection protocols were repeated after at least a 48 hour washout period and induction of anesthesia using xylazine/ketamine and maintenance with isoflurane gas. Drug concentrations were determined using ultrapressure liquid chromatography with mass spectrometry. A 2-compartment model was used to determine pharmacokinetics and differences were determined between conscious and anesthetized horses using paired t-tests (significance P < .05). RESULTS: Potassium penicillin g and GENT had higher minimum plasma concentrations (PEN 0.44 vs. 0.11 µg/mL, P = .002; GENT 3.0 vs. 1.9 µg/mL, P = .009), longer half lives (PEN 71 vs. 59 min, P = .018; GENT 149 vs. 109 min, P = .038), and slower clearances (PEN 3.41 vs. 5.1 mL/kg/min, P = .005; GENT 1.18 vs. 1.48 mL/kg/min, P = .028) in anesthetized horses vs. conscious horses. The PEN concentrations remained above the breakpoint minimum inhibitory concentration (MIC, 0.5 µg/mL) for 332 min in anesthetized vs. 199 min in conscious horses. The GENT concentrations reached 10 times higher than the breakpoint MIC (2 µg/mL) in all horses and were maintained for 58 vs. 59 min in anesthetized and conscious states, respectively. Synovial fluid concentrations were higher in conscious horses vs. anesthetized horses at 30 min for PEN (7.0 vs. 0.93 µg/mL, P < .001) and 30 (5.3 µg/mL vs. 0.79 µg/mL, P < .001) and 360 min (3.4 vs. 1.82 µg/mL, P < .003) for GENT. CONCLUSION: General anesthesia resulted in lower intrasynovial concentrations and delayed clearance of PEN/GENT in horses. CLINICAL SIGNIFICANCE: Redosing healthy anesthetized horses with PEN prior to 4-5 h is not necessary. When administered to anesthetized horses, intravenous PEN/GENT may not reach adequate intrasynovial concentrations to treat or prevent common pathogens. The doses or dosing intervals of antimicrobials administered to horses undergoing anesthesia may need to be adjusted to ensure maintenance of safe and effective plasma concentrations.

An Interactive Generic Physiologically Based Pharmacokinetic (igPBPK) Modeling Platform to Predict Drug Withdrawal Intervals in Cattle and Swine: A Case Study on Flunixin, Florfenicol, and Penicillin G.

Violative chemical residues in edible tissues from food-producing animals are of global public health concern. Great efforts have been made to develop physiologically based pharmacokinetic (PBPK) models for estimating withdrawal intervals (WDIs) for extralabel prescribed drugs in food animals. Existing models are insufficient to address the food safety concern as these models are either limited to 1 specific drug or difficult to be used by non-modelers. This study aimed to develop a user-friendly generic PBPK platform that can predict tissue residues and estimate WDIs for multiple drugs including flunixin, florfenicol, and penicillin G in cattle and swine. Mechanism-based in silico methods were used to predict tissue/plasma partition coefficients and the models were calibrated and evaluated with pharmacokinetic data from Food Animal Residue Avoidance Databank (FARAD). Results showed that model predictions were, in general, within a 2-fold factor of experimental data for all 3 drugs in both species. Following extralabel administration and respective U.S. FDA-approved tolerances, predicted WDIs for both cattle and swine were close to or slightly longer than FDA-approved label withdrawal times (eg, predicted 8, 28, and 7 days vs labeled 4, 28, and 4 days for flunixin, florfenicol, and penicillin G in cattle, respectively). The final model was converted to a web-based interactive generic PBPK platform. This PBPK platform serves as a user-friendly quantitative tool for real-time predictions of WDIs for flunixin, florfenicol, and penicillin G following FDA-approved label or extralabel use in both cattle and swine, and provides a basis for extrapolating to other drugs and species.

Exposure to benzylpenicillin after different dosage regimens in growing pigs.

BACKGROUND: Penicillin is important for treatment of pigs, but data on its absorption and disposition in pigs are sparse. This is reflected by the variation in recommended dosages in the literature. Inadequate dosage may lead to treatment failure and selection of resistant bacteria. To optimize treatment regimens, plasma exposure to benzylpenicillin for two sustained release formulations of procaine benzylpenicillin for intramuscular administration was studied in growing pigs by means of tandem mass spectrometry (UPLC-MS/MS). One formulation was an aqueous suspension, Ethacilin® vet (ETH), and the other an oily suspension, Ultrapen vet (UPA). Benzylpenicillin exposure after intravenous administration of potassium benzylpenicillin was also explored. Exposure profiles were first studied after single administrations of the approved dosages in healthy pigs and then after repeated administration of different dosages in pigs inoculated intranasally with an Actinobacillus pleuropneumoniae serotype 2 strain. RESULTS: After intravenous administration of benzylpenicillin (n = 6), maximum plasma concentration (Cmax), 1860-9318 µg/L, was observed after 15 min. At four h, plasma concentrations decreased to 15-76 µg/L. After intramuscular administration of ETH (n = 6) Cmax, 1000-4270 µg/L, was observed within one h (tmax) in 5 pigs but at four h in one pig. Cmax for UPA (n = 6), 910-3220 µg/L, was observed within one h in three pigs, but at four or 24 h in three pigs. For both ETH and UPA, the terminal phase was characterized by slow decline compared with intravenous administration. Repeated administration of different dosages of ETH and UPA in pigs inoculated with A. pleuropneumoniae (n = 54) showed that the approved dose for UPA (30 mg/kg, qd) but not for ETH (20 mg/kg, qd) gave adequate plasma exposure for bacteria with a penicillin MIC of 500 µg/L. However, more frequent dosing of ETH (bid) or increased dosage gave an adequate exposure. CONCLUSIONS: The approved dosage of ETH provided insufficient plasma exposure for adequate therapy of infections caused by A. pleuropneumoniae or other bacteria with a penicillin MIC of 500 µg/L. More frequent ETH dosing (bid) or an increased dosage would improve exposure. The approved dosage of UPA however provided adequate exposure.

Effect of benzylpenicillin on intravenous pharmacokinetics of acyclovir in red-eared slider turtles (Trachemys scripta elegans).

The aim of this study was to determine the effect of benzylpenicillin on the pharmacokinetics of acyclovir in red-eared slider turtles (Trachemys scripta elegans). Six clinically healthy red-eared slider turtles weighing 400 and 580 g were used for the study. Acyclovir (40 mg/kg) and benzylpenicillin (30 mg/kg) were administered intravenously to turtles. In the study, the cross-pharmacokinetic design (2 × 2) with a 30-day washout period was performed in two periods. Plasma concentrations of acyclovir were assayed using the high-performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated by two-compartment open pharmacokinetic model. Following the administration of acyclovir alone, elimination half-life (t1/2 ß ), area under the plasma concentration-time curve (AUC), total clearance (ClT ), and volume of distribution at steady-state (Vdss ) were 20.12 hr, 1,372 hr * µg/mL, 0.03 L hr-1  kg-1 , and 0.84 L/kg, respectively. Benzylpenicillin administration increased t1/2 ß , AUC, and Vdss while decreased ClT of acyclovir. These results showed that benzylpenicillin changed the pharmacokinetics of acyclovir following simultaneous administration in turtles. However, further research is needed to determine molecular mechanism of interaction in turtle.

Pharmacokinetics of Benzylpenicillin (Penicillin G) during Prolonged Intermittent Renal Replacement Therapy.

Prolonged intermittent renal replacement therapy (PIRRT) is an increasingly adopted method of renal replacement in critically ill patients. Like continuous renal replacement therapy, PIRRT can alter the pharmacokinetics (PK) of many drugs. In this setting, dosing data for antibiotics like benzylpenicillin are lacking. In order to enable clinicians to prescribe benzylpenicillin safely and effectively, knowledge of the effects of PIRRT on the plasma PK of benzylpenicillin is required. Herein, we describe the PK of benzylpenicillin in 2 critically ill patients on PIRRT for the treatment of penicillin-susceptible Staphylococcus aureus bacteremia complicated by infective endocarditis. Blood samples were taken for each patient taken over dosing periods during PIRRT and off PIRRT. Two-compartment PK models described significant differences in the mean clearance of benzylpenicillin with and without PIRRT (6.61 vs. 3.04 L/h respectively). We would suggest a benzylpenicillin dose of 1,800 mg (3 million units) every 6-h during PIRRT therapy as sufficient to attain PK/pharmacodynamic target.

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.

Probabilistic Physiologically Based Pharmacokinetic Model for Penicillin G in Milk From Dairy Cows Following Intramammary or Intramuscular Administrations.

Penicillin remains one of the most frequently identified violative drug residues in food-producing animals. The predominant violations of penicillin were found in cull dairy cows. In the United States, procaine penicillin G is approved to be used in dairy cows through intramuscular (IM) and intramammary (IMM) administrations. Physiologically based pharmacokinetic (PBPK) models are useful tools to predict withdrawal intervals and tissue residues of drugs in food animals to ensure food safety, especially for extralabel drug use due to the scarcity of experimental data after extralabel administrations. Currently, no PBPK model is available to predict penicillin concentrations in milk. A population PBPK model with a physiologically based compartment for the mammary gland was established for penicillin G in dairy cows. The model predicted the tissue and milk residues well based on comparison with data from previous pharmacokinetic studies. The predicted milk discard interval of procaine penicillin G administered at 10 times the label dose for 3 repeated IM administrations was 182 h, and 122 h at 4 times the label dose after 3 repeated IMM infusions. Predicted results showed that even 4 times label dose did not lead to violative tissue residues in healthy dairy cows with IMM infusions. The predominant violations found in cull dairy cows may be caused by altered pharmacokinetics due to mastitis, other diseases, and/or interactions with other drugs, which have impacts on penicillin distribution and elimination. The current PBPK model can help predict milk discard interval for penicillin following extralabel use through IM and IMM administrations.

Pharmacokinetics of Penicillin G in Preterm and Term Neonates.

Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but have been poorly described for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We describe the PK of penicillin G in neonates with a gestational age (GA) of ≥32 weeks and a postnatal age of <72 h. Penicillin G was administered intravenously at a dose of 25,000 or 50,000 IU/kg of body weight every 12 h (q12h). At steady state, PK blood samples were collected prior to and at 5 min, 1 h, 3 h, 8 h, and 12 h after injection. Noncompartmental PK analysis was performed with WinNonlin software. With those data in combination with data from neonates with a GA of ≤28 weeks, we developed a population PK model using NONMEM software and performed probability of target attainment (PTA) simulations. In total, 16 neonates with a GA of ≥32 weeks were included in noncompartmental analysis. The median volume of distribution (V) was 0.50 liters/kg (interquartile range, 0.42 to 0.57 liters/kg), the median clearance (CL) was 0.21 liters/h (interquartile range, 0.16 to 0.29 liters/kg), and the median half-life was 3.6 h (interquartile range, 3.2 to 4.3 h). In the population PK analysis that included 35 neonates, a two-compartment model best described the data. The final parameter estimates were 10.3 liters/70 kg and 29.8 liters/70 kg for V of the central and peripheral compartments, respectively, and 13.2 liters/h/70 kg for CL. Considering the fraction of unbound penicillin G to be 40%, the PTA of an unbound drug concentration that exceeds the MIC for 40% of the dosing interval was >90% for MICs of ≤2 mg/liter with doses of 25,000 IU/kg q12h. In neonates, regardless of GA, the PK parameters of penicillin G were similar. The dose of 25,000 IU/kg q12h is suggested for treatment of group B streptococcal EOS diagnosed within the first 72 h of life. (This study was registered with the EU Clinical Trials Register under EudraCT number 2012-002836-97.).

Evaluation of a System-Specific Function To Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia.

The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with a priori birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The system-specific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3,000 g, PNA of 2 days (TEMP, 33.5°C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU/kg/day every 8 h (q8h), 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and ≥42 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development.

Translational studies on a ready-to-use intramuscular injection of penethamate for bovine mastitis.

Bovine mastitis caused by bacterial infections of the mammary gland (udder) of dairy cows is a costly pathology for the dairy industry due to direct and indirect losses in production. Penethamate, a pro-drug of benzylpenicillin, is used by intramuscular injection (IM). The existing products are powders which must be reconstituted in water-for-injection and this presents difficulties in the field. Penethamate is too unstable to be formulated as an aqueous formulation but a chemically stable suspension formulation was possible in certain oils; however, some literature suggests that such formulations would have unacceptable prolonged release. The translational research proceeded iteratively from lab to the target species, rather than via laboratory animal trials. Pilot studies in cows suggested that some oily suspensions would give concentrations of benzylpenicillin, (in both blood and milk) comparable with those of the reconstituted product. A physicochemical screen and a low level in vitro-in vivo correlation (IVIVC) was cautiously used to guide selection of formulations for subsequent animal trials which have resulted in a lead formulation for good laboratory practices (GLP), good clinical practices (GCP) studies.

Pharmacokinetics and Pharmacodynamic Target Attainment of Benzylpenicillin in an Adult Severely Ill Sub-Saharan African Patient Population.

Background: In intensive care (ICU) patients, systemic exposure of ß-lactam antibiotics can be altered, and positive clinical outcome is associated with increasing fT > MIC ratios. In sub-Saharan African hospitals, benzylpenicillin (PEN) is frequently used for the empiric treatment of severe pneumococcal infections. Pharmacokinetic data for non-ICU hospitalized populations are lacking. Methods: We performed a population pharmacokinetic (PPK) study in an adult Mozambican hospital population treated intravenously with PEN from October 2014 through November 2015. Four blood samples/patient were collected for total PEN (PENt) and unbound PEN (PENu) concentration measurement. We developed a PPK model through nonlinear mixed-effects analysis and performed simulations for different patient variable, dosing, and pharmacodynamic target scenarios. Results: One hundred twelve participants yielded 387 PENt and 53 PENu concentrations. The median body mass index was 18.3 (range, 10.5-31.3) kg/m2 and the median albumin concentration and creatinine clearance (CrCl) were 29 (range, 12-44) g/L and 80 (range, 3-195) mL/minute, respectively. In a 1-compartment model, CrCl was positively correlated with PENt clearance. For infections with a microorganism with a minimum inhibitory concentration (MIC) of 1 mg/L, simulations demonstrated that with 3 million IU (1.8 g) every 6 hours, 74.1% would have a PENu concentration greater than the MIC during half of the dosing interval (fT > MIC = 50%), whereas this was 24.8% for the fT > MIC = 100% target. For pathogens with an MIC of 0.06 mg/L, these percentages were 98.2% and 72.3%, respectively. Conclusions: Severely ill adult sub-Saharan African patients may be at high risk for underexposure to PENu during routine intermittent bolus dosing, especially when their renal function is intact and when infected with pathogens with intermediate susceptibility.

Radiolabeling of benzylpenicillin with lutetium-177: Quality control and biodistribution study to develop theranostic infection imaging agent.

Benzylpenicillin acts through binding with beta-lactamase enzyme and inhibiting the bacterial cell wall biosynthesis. Therefore, the radiolabeling of benzylpenicillin with lutetium-177 is expected to serve as a theranostic agent for deep-seated bacterial infections. The radiolabeling of benzylpenicillin resulted ~93% radiochemical yield at optimized reaction conditions. Radiochemical purity analysis was tested with the help of Whatman No. 2 paper and instant thin layer chromatography. Biodistribution study with healthy New Zeeland white rabbit revealed moderate accumulation in different organs. Kidneys are the major organs, showed not more than 4.57±0.89% injected dose per gram organ (ID/gm organ) at 1 h time point and 3.48±1.11% ID/gm organ at 6 h time point. The accumulation of tracer agent in liver was found in the range of 7.42±2.42% to 9.09±2.76 ID/gm organ. The glomerular filtration rate studies revealed rapid clearance - omitting the chance of nephrotoxicity. The radiolabeling yield, biodistribution and glomerular filtration rate results revealed 177Lu-benzylpencillin could be a potential candidate to diagnose the deep-seated bacterial infection.

Development and application of a population physiologically based pharmacokinetic model for penicillin G in swine and cattle for food safety assessment.

Penicillin G is a widely used antimicrobial in food-producing animals, and one of the most predominant drug residues in animal-derived food products. Due to reduced sensitivity of bacteria to penicillin, extralabel use of penicillin G is common, which may lead to violative residues in edible tissues and cause adverse reactions in consumers. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict drug residues in edible tissues and estimate extended withdrawal intervals for penicillin G in swine and cattle. A flow-limited PBPK model was developed with data from Food Animal Residue Avoidance Databank using Berkeley Madonna. The model predicted observed drug concentrations in edible tissues, including liver, muscle, and kidney for penicillin G both in swine and cattle well, including data not used in model calibration. For extralabel use (5× and 10× label dose) of penicillin G, Monte Carlo sampling technique was applied to predict times needed for tissue concentrations to fall below established tolerances for the 99th percentile of the population. This model provides a useful tool to predict tissue residues of penicillin G in swine and cattle to aid food safety assessment, and also provide a framework for extrapolation to other food animal species.

Quantitative Prediction of Human Renal Clearance and Drug-Drug Interactions of Organic Anion Transporter Substrates Using In Vitro Transport Data: A Relative Activity Factor Approach.

Organic anion transporters (OATs) are important in the renal secretion, and thus, the clearance, of many drugs; and their functional change can result in pharmacokinetic variability. In this study, we applied transport rates measured in vitro using OAT-transfected human embryonic kidney cells to predict human renal secretory and total renal clearance of 31 diverse drugs. Selective substrates to OAT1 (tenofovir), OAT2 (acyclovir and ganciclovir), and OAT3 (benzylpenicillin, oseltamivir acid) were used to obtain relative activity factors (RAFs) for these individual transporters by relating in vitro transport clearance (after physiologic scaling) to in vivo secretory clearance. Using the estimated RAFs (0.64, 7.3, and 4.1, respectively, for OAT1, OAT2, and OAT3, respectively) and the in vitro active clearances, renal secretory clearance and total renal clearance were predicted with average fold errors (AFEs) of 1.89 and 1.40, respectively. The results show that OAT3-mediated transport play a predominant role in renal secretion for 22 of the 31 drugs evaluated. This mechanistic static approach was further applied to quantitatively predict renal drug-drug interactions (AFE ∼1.6) of the substrate drugs with probenecid, a clinical probe OAT inhibitor. In conclusion, the proposed in vitro-in vivo extrapolation approach is the first comprehensive attempt toward mechanistic modeling of renal secretory clearance based on routinely employed in vitro cell models.

Penicillin G Treatment in Infective Endocarditis Patients - Does Standard Dosing Result in Therapeutic Plasma Concentrations?

Penicillin G is frequently used to treat infective endocarditis (IE) caused by streptococci, penicillin-susceptible staphylococci and enterococci. Appropriate antibiotic exposure is essential for survival and reduces the risk of complications and drug resistance development. We determined penicillin G plasma concentration [p-penicillin] once weekly in 46 IE patients. The aim was to evaluate whether penicillin G 3 g every 6 hr (q6 h) resulted in therapeutic concentrations and to analyse potential factors that influence inter- and intra-individual variability, using linear regression and a random coefficient model. [P-penicillin] at 3 hr and at 6 hr was compared with the minimal inhibitory concentration (MIC) of the bacteria isolated from blood cultures to evaluate the following PK/PD targets: 50% fT > MIC and 100% fT > MIC. [P-penicillin] varied notably between patients and was associated with age, weight, p-creatinine and estimated creatinine clearance (eCLcr). Additionally, an increase in [p-penicillin] during the treatment period showed strong correlation with age, a low eCLcr, a low weight and a low p-albumin. Of the 46 patients, 96% had [p-penicillin] that resulted in 50% fT > MIC, while 71% had [p-penicillin] resulting in 100% fT > MIC. The majority of patients not achieving the 100% fT > MIC target were infected with enterococci. Streptococci and staphylococci isolated from blood cultures were highly susceptible to penicillin G. Our results suggest that penicillin G 3 g q6 h is suitable to treat IE caused by streptococci and penicillin-susceptible staphylococci, but caution must be taken when the infection is caused by enterococci. When treating enterococci, therapeutic drug monitoring should be applied to optimize penicillin G dosing and exposure.

Pharmacokinetics of intravenous continuous rate infusions of sodium benzylpenicillin and ceftiofur sodium in adult horses.

OBJECTIVE To determine plasma drug concentrations after IV administration of a bolus followed by continuous rate infusion (CRI) of sodium benzylpenicillin and ceftiofur sodium to healthy adult horses. ANIMALS 6 Thoroughbred mares (3 to 9 years old; mean ± SD body weight, 544 ± 55 kg) with no history of recent antimicrobial treatment. PROCEDURES Horses were used in 2 experiments conducted 14 days apart. For each experiment, horses were housed individually in stables, and catheters were placed bilaterally in both jugular veins for drug administration by CRI (left catheter) and for intermittent collection of blood samples (right catheter). Synovial fluid samples were obtained from carpal joints following ceftiofur administration to evaluate drug diffusion into articular spaces. RESULTS Plasma concentrations above accepted minimum inhibitory concentrations for common pathogens of horses were achieved within 1 minute after bolus administration and remained above the minimum inhibitory concentration for 48 (ceftiofur) or 12 (benzylpenicillin) hours (ie, the duration of the CRI). Mean synovial fluid ceftiofur free acid equivalent concentrations were approximately 46% (range, 25.4% to 59.8%) of plasma concentrations at the end of infusion. CONCLUSIONS AND CLINICAL RELEVANCE Compared with intermittent bolus administration, the loading dose and CRI used less drug but maintained high plasma concentrations for the duration of infusion. By use of pharmacological parameters derived in this study, a loading dose of 2.5 mg/kg and CRI of 200 µg/kg/h should achieve plasma ceftiofur concentrations of 4 µg/mL; a loading dose and CRI of 1.3 mg/kg and 2.5 µg/kg/h, respectively, should achieve plasma benzylpenicillin concentrations of 2 µg/mL.

Time-kill curve analysis and pharmacodynamic modelling for in vitro evaluation of antimicrobials against Neisseria gonorrhoeae.

BACKGROUND: Gonorrhoea is a sexually transmitted infection caused by the Gram-negative bacterium Neisseria gonorrhoeae. Resistance to first-line empirical monotherapy has emerged, so robust methods are needed to evaluate the activity of existing and novel antimicrobials against the bacterium. Pharmacodynamic models describing the relationship between the concentration of antimicrobials and the minimum growth rate of the bacteria provide more detailed information than the MIC only. RESULTS: In this study, a novel standardised in vitro time-kill curve assay was developed. The assay was validated using five World Health Organization N. gonorrhoeae reference strains and a range of ciprofloxacin concentrations below and above the MIC. Then the activity of nine antimicrobials with different target mechanisms was examined against a highly antimicrobial susceptible clinical strain isolated in 1964. The experimental time-kill curves were analysed and quantified with a previously established pharmacodynamic model. First, the bacterial growth rates at each antimicrobial concentration were estimated with linear regression. Second, we fitted the model to the growth rates, resulting in four parameters that describe the pharmacodynamic properties of each antimicrobial. A gradual decrease of bactericidal effects from ciprofloxacin to spectinomycin and gentamicin was found. The beta-lactams ceftriaxone, cefixime and benzylpenicillin showed bactericidal and time-dependent properties. Chloramphenicol and tetracycline were purely bacteriostatic as they fully inhibited the growth but did not kill the bacteria. We also tested ciprofloxacin resistant strains and found higher pharmacodynamic MICs (zMIC) in the resistant strains and attenuated bactericidal effects at concentrations above the zMIC. CONCLUSIONS: N. gonorrhoeae time-kill curve experiments analysed with a pharmacodynamic model have potential for in vitro evaluation of new and existing antimicrobials. The pharmacodynamic parameters based on a wide range of concentrations below and above the MIC provide information that could support improving future dosing strategies to treat gonorrhoea.

Pharmacokinetics of a combination of amikacin sulfate and penicillin G sodium for intravenous regional limb perfusion in adult horses.

The aim of this study was to determine the pharmacokinetics of amikacin and penicillin G sodium when administered in combination as an intravenous regional limb perfusion (IVRLP) to horses. Seven healthy adult horses underwent an IVRLP in the cephalic vein with 2 g of amikacin sulfate and 10 mill IU of penicillin G sodium diluted to 60 mL in 0.9% saline. A pneumatic tourniquet set at 450 mmHg was left in place for 30 min. Synovial fluid was collected from the metacarpophalangeal joint 35 min and 2, 6, 12, and 24 h after infusion of the antimicrobials. Concentrations of amikacin and penicillin in synovial fluid were quantitated by liquid chromatography tandem-mass spectrometry analysis. Therapeutic concentrations of amikacin and penicillin for equine-susceptible pathogens were achieved in the synovial fluid. Maximum synovial concentrations (Cmax) (mean ± SE) for amikacin and penicillin were 132 ± 33 µg/mL and 8474 ± 5710 ng/mL, respectively. Only 3 horses had detectable levels of penicillin at 6 h and 1 at the 12 h sample. The combination of amikacin with penicillin G sodium via IVDLP resulted in reported therapeutic concentrations of both antibiotics in the synovial fluid. The Cmax:MIC (minimum inhibitory concentration) ratio for amikacin was 8:1 and Time > MIC for penicillin was 6 h. At 24 h, the mean concentration of amikacin was still above 4 µg/mL. Terminal elimination rate constants (T1/2 lambdaz) were 13.6 h and 2.8 h for amikacin and penicillin, respectively. The use of IVDLP with penicillin may therefore not be practical as rapid clearance of penicillin from the synovial fluid requires frequent perfusions to maintain acceptable therapeutic concentrations.

L'objectif de la présente étude était de déterminer la pharmacocinétique de l'amikacine et de la pénicilline G sodique lorsqu'administrées en combinaison par perfusion intraveineuse régionale d'un membre (PIVRM) à des chevaux. Sept chevaux adultes ont reçu une PIVRM dans la veine céphalique avec 2 g de sulfate d'amikacine et 10 millions d'UI de pénicilline G sodique dilués dans 60 mL de saline 0,9 %. Un tourniquet pneumatique réglé à 450 mmHg a été laissé en place pour 30 min. Du liquide synovial a été récolté de l'articulation métacarpo-phalangienne 35 min, 2, 6, 12, et 24 h après l'infusion des antimicrobiens. Les concentrations d'amikacine et de pénicilline dans le liquide synovial furent mesurées par spectrométrie de masse en tandem avec la chromatographie en phase liquide. Les concentrations thérapeutiques d'amikacine et de pénicilline pour des agents pathogènes équins sensibles ont été atteintes dans le liquide synovial. Les concentrations synoviales maximales (Cmax) [moyenne ± écart-type (EC)] pour l'amikacine et la pénicilline étaient de 132 ± 33 µg/mL et 8474 ± 5710 ng/mL, respectivement. Seulement 3 chevaux avaient des quantités détectables de pénicilline à 6 h et un seul pour l'échantillon de 12 h. La combinaison d'amikacine et de pénicilline G sodique via PIVRM a permis de rapporter des concentrations thérapeutiques des deux antibiotiques dans le liquide synovial. Le ratio Cmax-CMI (concentration minimale inhibitrice) pour l'amikacine était de 8:1 et la période de Temps > CMI pour la pénicilline était de 6 h. À 24 h, la concentration moyenne d'amikacine était toujours supérieure à 4 µg/mL. Les constantes du taux d'élimination terminal (T1/2 lambdaz) étaient 13,6 h et 2,8 h pour l'amikacine et la pénicilline, respectivement. L'utilisation de PIVRM avec la pénicilline ne serait ainsi pas pratique étant donné que la clairance rapide de la pénicilline à partir du liquide synovial requière des perfusions fréquentes pour maintenir des concentrations thérapeutiques acceptables.(Traduit par Docteur Serge Messier).