What is the true in vitro potency of oxytetracycline for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida?

The pharmacodynamics of oxytetracycline was determined for pig respiratory tract pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Indices of potency were determined for the following: (i) two matrices, broth and pig serum; (ii) five overlapping sets of twofold dilutions; and (iii) a high strength starting culture. For A. pleuropneumoniae, minimum inhibitory concentration (MIC) was similar for the two matrices, but for P. multocida, differences were marked and significantly different. MIC and minimum bactericidal concentration (MBC) serum: broth ratios for A. pleuropneumoniae were 0.83:1 and 1.22:1, respectively, and corresponding values for P. multocida were 22.0:1 and 7.34:1. For mutant prevention concentration (MPC) serum: broth ratios were 0.79:1 (A. pleuropneumoniae) and 20.9:1 (P. multocida). These ratios were corrected for serum protein binding to yield fraction unbound (fu) serum: broth MIC ratios of 0.24:1 (A. pleuropneumoniae) and 6.30:1 (P. multocida). Corresponding fu serum: broth ratios for MPC were almost identical, 0.23:1 and 6.08:1. These corrections for protein binding did not account for potency differences between serum and broth for either species; based on fu serum MICs, potency in serum was approximately fourfold greater than predicted for A. pleuropneumoniae and sixfold smaller than predicted for P. multocida. For both broth and serum and both bacterial species, MICs were also dependent on initial inoculum strength. The killing action of oxytetracycline had the characteristics of codependency for both A. pleuropneumoniae and P. multocida in both growth media. The in vitro potency of oxytetracycline in pig serum is likely to be closer to the in vivo plasma/serum concentration required for efficacy than potency estimated in broths.

Pharmacokinetic/pharmacodynamic integration and modelling of oxytetracycline for the porcine pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida.

Pharmacokinetic-pharmacodynamic (PK/PD) integration and modelling were used to predict dosage schedules of oxytetracycline for two pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in broth and porcine serum. PK/PD integration established ratios of average concentration over 48 h (Cav0-48 h )/MIC of 5.87 and 0.27 µg/mL (P. multocida) and 0.70 and 0.85 µg/mL (A. pleuropneumoniae) for broth and serum MICs, respectively. PK/PD modelling of in vitro time-kill curves established broth and serum breakpoint values for area under curve (AUC0-24 h )/MIC for three levels of inhibition of growth, bacteriostasis and 3 and 4 log10 reductions in bacterial count. Doses were then predicted for each pathogen, based on Monte Carlo simulations, for: (i) bacteriostatic and bactericidal levels of kill; (ii) 50% and 90% target attainment rates (TAR); and (iii) single dosing and daily dosing at steady-state. For 90% TAR, predicted daily doses at steady-state for bactericidal actions were 1123 mg/kg (P. multocida) and 43 mg/kg (A. pleuropneumoniae) based on serum MICs. Lower TARs were predicted from broth MIC data; corresponding dose estimates were 95 mg/kg (P. multocida) and 34 mg/kg (A. pleuropneumoniae).

Factors influencing the potency of marbofloxacin for pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida.

For the pig respiratory tract pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida, Minimum Inhibitory Concentration (MIC) of marbofloxacin was determined in recommended broths and pig serum at three inoculum strengths. MICs in both growth matrices increased progressively from low, through medium to high starting inoculum counts, 104, 106 and 108CFU/mL, respectively. P. multocida MIC ratios for high:low inocula were 14:4:1 for broth and 28.2:1 for serum. Corresponding MIC ratios for A. pleuropneumoniae were lower, 4.1:1 (broth) and 9.2:1 (serum). MIC high:low ratios were therefore both growth matrix and bacterial species dependent. The effect of alterations to the chemical composition of broths and serum on MIC were also investigated. Neither adjusting broth or serum pH in six increments over the range 7.0 to 8.0 nor increasing calcium and magnesium concentrations of broth in seven incremental steps significantly affected MICs for either organism. In time-kill studies, the killing action of marbofloxacin had the characteristics of concentration dependency against both organisms in both growth matrices. It is concluded that MIC and time-kill data for marbofloxacin, generated in serum, might be preferable to broth data, for predicting dosages of marbofloxacin for clinical use.

Potency of marbofloxacin for pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida: Comparison of growth media.

Pharmacodynamic properties of marbofloxacin were established for six isolates each of the pig respiratory tract pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Three in vitro indices of potency were determined; Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC) and Mutant Prevention Concentration (MPC). For MIC determination Clinical Laboratory Standards Institute guidelines were modified in three respects: (1) comparison was made between two growth media, an artificial broth and pig serum; (2) a high inoculum count was used to simulate heavy clinical bacteriological loads; and (3) five overlapping sets of two-fold dilutions were used to improve accuracy of determinations. Similar methods were used for MBC and MPC estimations. MIC and MPC serum:broth ratios for A. pleuropneumoniae were 0.79:1 and 0.99:1, respectively, and corresponding values for P. multocida were 1.12:1 and 1.32:1. Serum protein binding of marbofloxacin was 49%, so that fraction unbound (fu) serum MIC values were significantly lower than those predicted by correction for protein binding; fu serum:broth MIC ratios were 0.40:1 (A. pleuropneumoniae) and 0.50:1 (P. multocida). For broth, MPC:MIC ratios were 13.7:1 (A. pleuropneumoniae) and 14.2:1 (P. multocida). Corresponding ratios for serum were similar, 17.2:1 and 18.8:1, respectively. It is suggested that, for dose prediction purposes, serum data might be preferable to potency indices measured in broths.

Activity of florfenicol for Actinobacillus pleuropneumoniae and Pasteurella multocida using standardised versus non-standardised methodology.

Four indices of antimicrobial potency were determined for florfenicol and the pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), mutant prevention concentration (MPC) and time-kill curves were determined in two matrices, broth and pig serum. Five overlapping sets of two-fold dilutions were used to increase accuracy of the measurements. MIC and MBC serum:broth ratios for A. pleuropneumoniae were 0.96:1 and 1.07:1, respectively, and corresponding values for P. multocida were 0.72:1 and 0.50:1. The percentage binding of florfenicol to serum protein was 65.4%, and fraction unbound (fu) serum MICs were significantly lower, by 2.71-fold and 3.82-fold, respectively, than predicted for free serum concentrations for A. pleuropneumoniae and P. multocida. Similar culture medium differences were obtained for MBC and MPC. MICs in serum and broth were increased significantly and progressively for high, medium and low initial inoculum counts. Serum MPC:MIC ratios for A. pleuropneumoniae and P. multocida were 12.5:1 and 13.6:1, respectively; ratios for broth were similar. The killing action of florfenicol had the characteristics of concentration dependency for both species in both growth media. These data indicate the value of using a biological medium, when determining microbiological potency indices, to predict dosage for clinical use.

Primary hyperparathyroidism during the third trimester of pregnancy.

Primary hyperparathyroidism during pregnancy has been reported in 36 women; 1 new case is reported here. Screening by determining serum calcium levels is a valuable method of diagnosing the disease. Radioimmunoassay of serum parathyroid hormone (PTH) greatly aids in the diagnosis. Amniotic fluid PTH values are discussed. Hyperparathyroidism has a high association with progressive renal insufficiency, renal calculi, hypertension, and bone disease. During pregnancy, there is an increased incidence of stillborns, premature labor, and neonatal tetany. Acute hyperparathyroid crisis may result in maternal death. This is the first reported case surgically treated during the third trimester of pregnancy. Surgery should be considered when the diagnosis is made late in pregnancy, as this may protect the infant from neonatal tetany.

Hormonal contraception and platelet function.

PIP: 73 healthy women (29 controls, 25 using OCs, and 19 using Norplant) were selected from the clinic population at North Oakland Medical Center for inclusion in this study after obtaining informed consent. Age, race, height, weight, blood pressure, and cigarette smoking were recorded for each subject. 12 patients were on monophasic OCs while 13 were on triphasic preparations. Both hormonal contraceptive groups had used their particular contraceptive for at least 3 months prior to blood drawing. Platelet tests were performed within 2 hours of sample collection: platelet counts (PLC) and mean platelet volume (MPV) were determined on an Automated Platelet Counter (Baker 810 Platelet Analyzer). Whole blood aggregation was performed on a platelet aggregometer (Chrono-Log, Model 550) using both ADP (ADP, 5 mM) and collagen (COLL, 2 mcg/ml) as inducing agents. Demographic differences were not significant (p 0.05) among the 3 treatment groups, whose average age was 25.3-25.8 years old. Furthermore, no significant differences (p 0.05) in platelet function were detected among controls or subjects receiving either oral contraceptives or Norplant, compared to control patients. The mean platelet counts (X 10/9/L) were 223 for OC users, 231 for Norplant users, and 232 for controls. The respective platelet aggregation (ADP, ohms) values were 12.5, 18.0, and 19.2 as well as (COLL, ohms) 35.6, 40.7, and 39.0. These results demonstrated that there is no evidence for altered platelet function, with the testing methods employed, in women using either Norplant or combination low dose oral contraceptives. To date, several studies have examined this issue, with contradictory reports about the effects of hormonal contraceptives in platelet function. After controlling for differences between various steroid preparations and other such confounding variables, some of these conflicting conclusions could be the result of a lack of uniformity among the methods used to evaluate platelet aggregation. The ability to draw conclusions regarding altered in vivo thrombotic potential from these studies is thus questionable.^ieng

Androgens in preeclampsia.

OBJECTIVE: The purpose of the study was to determine whether maternal serum levels of androgens, especially testosterone, are higher in patients with preeclampsia than in matched normotensive control subjects. STUDY DESIGN: Serum testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin, and estradiol levels were measured in 16 subjects in the third trimester of pregnancy with documented preeclampsia and 26 healthy, normotensive women with similar maternal and gestational ages. All subjects were primigravid women with singleton pregnancies who were seen in the labor and delivery department at North Oakland Medical Centers in Pontiac, Mich. RESULTS: Total testosterone and free testosterone levels were significantly higher in patients with preeclampsia (213.6 +/- 25.9 ng/dL and 0.5 +/- 0.1 ng/dL, respectively) than in the control group (154.5 +/- 14.8 ng/dL and 0. 3 +/- 0.03 ng/dL, respectively). There were no significant differences in sex hormone binding globulin, dehydroepiandrosterone sulfate, and estradiol concentrations. There were also no significant differences in maternal age, gestational age, body mass index, and neonatal sex. CONCLUSION: Levels of the potent androgen testosterone were significantly higher in primigravid women with preeclampsia than in normotensive women with similar gestational and maternal ages. This difference may indicate a role for testosterone in the pathogenesis of preeclampsia.

Thrombosis and hormone replacement therapy in postmenopausal women.

OBJECTIVE: The effects of postmenopausal hormone replacement therapy on thrombosis remain controversial. We tested the hypothesis that estrogen or progesterone has no significant effect on thrombosis by means of newly developed markers of blood clotting, specifically prothrombin fragment 1 + 2, a marker of factor Xa generation, and thrombin-antithrombin III complex, a marker of thrombin generation. STUDY DESIGN: A prospective study that included 106 women, 68 postmenopausal women on hormone replacement therapy and 38 postmenopausal controls, was performed. Plasma levels of prothrombin fragment 1 + 2 and thrombin-antithrombin III complex were measured by enzyme-linked immunosorbent assay. Multivariate analysis of the covariance was used for statistical analysis, controlling for patient's age because the hormone replacement therapy group was older. RESULTS: There were no statistically significant differences between the hormone replacement therapy and control groups in either of the clotting parameters measured. A comparison of the levels of prothrombin fragment 1 + 2 and thrombin-antithrombin III complex in patients receiving estrogen alone or estrogen plus progestin also revealed no differences. CONCLUSIONS: Current doses of postmenopausal hormone replacement therapy do not appear to enhance in vivo clotting. Thromboembolic complications among postmenopausal women receiving hormone replacement therapy may therefore be secondary to congenital or other acquired coagulation defects.