Background: Mycobacterium tuberculosis (Mtb) strains H37Ra and H37Rv are commonly used to study new and re-evaluate old antituberculous agents with respect to their pharmacodynamic effects in vitro. The differences in membrane proteins and, in particular, differences in carrier proteins between Mtb H37Ra and Mtb H37Rv may have an impact on antibiotic potency. The question of whether H37Ra can be used as a reliable surrogate for H37Rv and clinical strains has not been addressed sufficiently. The purpose of this study is to provide a full comparison of susceptibility data of the most common antituberculosis (TB) agents against both Mtb strains. Methods: In addition to a literature review, in vitro checkerboard susceptibility study was conducted comparing the in vitro minimum inhibitory concentration (MIC) of 16 common antituberculous drugs against H37Ra and H37Rv. Heifets–Sanchez TB agar drug susceptibility plates were utilized. Results: Half of the antibiotics demonstrated similar growth inhibition against both strains, while slightly differing MIC values were found for 7 of 16 drugs. With the exception of rifampicin, no marked difference in MIC against H37Ra and H37Rv was observed. Conclusion: While neither the attenuated (H37Ra) nor the virulent strain (H37Rv) is a clinical strain, both strains predicted MICs of clinical isolates equally well, when comparing the current in vitro results to clinical susceptibility data in the literature. H37Ra comes with the benefits of lower experimental costs and less administrative barriers including the requirement of a biosafety Level III environment.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • There are presently no published data on tramadol transfer into breast milk or on its effects in the breastfed infant. WHAT THIS STUDY ADDS • We have provided quantitative data on the absolute and relative infant doses of rac‐tramadol and it rac‐O‐desmethyl metabolite for the breastfed infant.• We have also demonstrated a novel sparse sampling data collection method for investigating infant exposure via milk.AIMS: To investigate the transfer of rac‐tramadol and its rac‐O‐desmethyl metabolite into transitional milk, and assess unwanted effects in the breastfed infant.METHODS: Tramadol HCl (100 mg six hourly) was administered to 75 breastfeeding mothers for postoperative analgesia on days 2–4 after Caesarian section. Milk and plasma samples were collected after administration of four or more doses. Rac‐tramadol and rac‐O‐desmethyltramadol were measured by high performance liquid chromatography. Milk : plasma ratio (M : P) and infant doses were calculated by standard methods. The behavioural characteristics of the exposed breastfed infants and a matched control group of infants not exposed to tramadol were also studied.RESULTS: At steady‐state, mean (95% CI) M : P was 2.2 (2.0, 2.4) for rac‐tramadol and 2.8 (2.5, 3.1) for rac‐O‐desmethyltramadol. The estimated absolute and relative infant doses were 112 (102, 122) μg kg⁻¹ day⁻¹ and 30 (28, 32) μg kg⁻¹ day⁻¹, and 2.24% (2.04, 2.44)% and 0.64% (0.59, 0.69)% for rac‐tramadol and rac‐O‐desmethyltramadol, respectively. The exposed infants and control breastfed infants had similar characteristics, including Apgar scores at birth and Neurologic and Adaptive Capacity Scores.CONCLUSIONS: The combined relative infant dose of 2.88% at steady‐state was low. The similarity of NACS in exposed infants and controls suggests that there were no significant behavioural adverse effects. We conclude that short‐term maternal use of tramadol during establishment of lactation is compatible with breastfeeding.

Introduction: Identifying the optimized dosing regimen and algorithm is critical in the development of antibiotics. Suboptimal regimens and inappropriate choice of drug give rise to drug-resistant bacteria which have limited the therapeutic utility of many commercially available antimicrobial agents. Strategies to optimize therapy of antimicrobial candidates to speed up the development process are urgently needed.Areas covered: We examined pharmacokinetics and pharmacodynamics of antimicrobial agents with modeling and simulation approaches. The approach that is based on minimum inhibitory concentration to evaluate antimicrobial dosing strategy is widely utilized in drug development. The modeling approach utilizing information from time-kill kinetic studies is a tool that can provide more information on the time-course of bacterial response to a particular dosing regimen. Animal studies of dosing regimens that mimic human pharmacokinetics are another option to evaluate antimicrobial efficacy. Empir...

Fosfomycin combined with other antimicrobials has shown good efficacy against multidrug-resistant (MDR) bacteria in both in vitro and clinical studies; however, the activity of fosfomycin combined with other antimicrobials against metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa strains has not been tested. The objective of this study was to determine the synergism and optimal intravenous dosing regimens of fosfomycin with meropenem against MDR and MBL-producing P. aeruginosa strains.

KPC-producingKlebsiella pneumoniaecauses serious infections associated with high death rates worldwide. Combination therapy consisting of fosfomycin and a carbapenem is better than monotherapy to combat multidrug-resistant microorganisms, but no dosages for the combination have been defined. The MICs of meropenem and fosfomycin were evaluated against 18 clinical isolates of KPC-2-producingK. pneumoniae. The activities of combination antimicrobials were also determined by the checkerboard method. The MIC₅₀and MIC₉₀of each agent alone and in combination were challenged against short (1.5-h) or prolonged (3-h) infusion regimens of meropenem (1 g every 8 h [q8h], 1.5 g q6h, 2 g q8h) and fosfomycin (4 g q8h, 6 g q6h, 8 g q8h) by Monte Carlo simulation to evaluate the time above the MIC of the free drug concentration as a percentage of the dosing interval (fT>MIC). The monotherapy MIC₅₀s and MIC₉₀s were 32 and 256 mg/liter for meropenem and 64 and 512 mg/liter for fosfomycin, respectively. Antimicrobial combination increased bacterial susceptibility to 1/4 the MIC₅₀s and to 1/8 to 1/16 the MIC₉₀s of monotherapy. The antimicrobial combination demonstrated a synergistic effect for at least two-thirds of the isolates. In combination therapy, fosfomycin regimens of 6 g q6h and 8 g q8h as a 3-h infusion against the MIC₅₀and MIC₉₀had better chances of achieving ≥90% probability of target attainment (PTA) of 70%fT>MIC. Meropenem regimens of 1.5 g q6h and 2 g q8h in prolonged infusion can achieve close to 90% PTA of 40%fT>MIC for MIC₅₀but not MIC₉₀. The significant reduction in the MIC values and the achievement of appropriate PTA demonstrated that regimens containing fosfomycin with meropenem can be effective against KPC-2-producingK. pneumoniae.