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Background: The aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, the potential of apramycin in the treatment of drug-resistant bloodstream infections (BSIs) has not yet been assessed., Methods: The resistance gene annotations of 40 888 blood-culture isolates were analysed. In vitro profiling of apramycin comprised cell-free translation assays, broth microdilution, and frequency of resistance determination. The efficacy of apramycin was studied in a mouse peritonitis model for a total of nine Escherichia coli and Klebsiella pneumoniae isolates., Results: Genotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistant Enterobacterales blood-culture isolates, colistin resistance was shown in 46.4% and apramycin in 2.1%. Apramycin activity against methylated ribosomes was > 100-fold higher than that for other aminoglycosides. Frequencies of resistance were < 10 -9 at 8 × minimum inhibitory concentration (MIC). Tentative epidemiological cut-offs (TECOFFs) were determined as 8 µg/mL for E. coli and 4 µg/mL for K. pneumoniae. A single dose of 5 to 13 mg/kg resulted in a 1-log colony-forming unit (CFU) reduction in the blood and peritoneum. Two doses of 80 mg/kg resulted in an exposure that resembles the AUC observed for a single 30 mg/kg dose in humans and led to complete eradication of carbapenem- and aminoglycoside-resistant bacteraemia., Conclusion: Encouraging coverage and potent in vivo efficacy against a selection of highly drug-resistant Enterobacterales isolates in the mouse peritonitis model warrants the conduct of clinical studies to validate apramycin as a drug candidate for the prophylaxis and treatment of BSI., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To evaluate the activity of meropenem-amikacin and meropenem-colistin combinations with checkerboard broth microdilution (CKBM) compared with isothermal microcalorimetry (ITMC) assays against a multi-centric collection of multi-drug-resistant Gram-negative clinical isolates; and to compare the fractional inhibitory concentration (FIC) index and time to results of CKBM and ITMC., Methods: A collection of 333 multi-drug-resistant Gram-negative clinical isolates showing reduced susceptibility to meropenem (121 Klebsiella pneumoniae, 14 Escherichia coli, 130 Pseudomonas aeruginosa and 68 Acinetobacter baumannii) isolated from different centres (Florence, Madrid, Rotterdam and Stockholm) was included in the study. The antimicrobial activity of meropenem-amikacin and meropenem-colistin combinations was evaluated with CKBM and ITMC. FIC index results were interpreted as synergistic/additive and indifferent for values ≤0.5/0.51, respectively. Whole-genome sequencing data of a subset of strains were used to evaluate their clonality., Results: In total, 254 and 286 strains were tested with meropenem-colistin and meropenem-amikacin combinations with ITMC and CKBM, respectively. Synergistic/additive effects were observed for 46 strains (20 K. pneumoniae, four E. coli, 22 P. aeruginosa) and 20 strains (three K. pneumoniae, 11 P. aeruginosa and six A. baumannii) with meropenem-amikacin and meropenem-colistin combinations, respectively, with CKBM. ITMC showed good concordance with CKBM, with 89.5% and 92.2% of cases interpreted within the same FIC index category for meropenem-amikacin and meropenem-colistin combinations, respectively. Most of the synergistic/additive effects were detected within 6 h by ITMC., Conclusions: ITMC showed very good concordance with CKBM against a large collection of multi-drug-resistant Gram-negative clinical isolates, and could be implemented for the rapid evaluation of in-vitro activity of antimicrobial combinations., (Copyright © 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Objectives: Piperacillin-tazobactam (TZP) is a frequently prescribed antibiotic in hospital settings. Reports suggest in vivo efficacy of TZP, despite in vitro resistance of isolates susceptible to cephalosporins. Escherichia coli (E. coli) isolates hyperproducing TEM-1 β-lactamase possess this phenotype. This study investigated the influence of tazobactam (TAZ) concentration on piperacillin (PIP) inhibition of such isolates and compared the in vivo efficacy of TZP with cefotaxime (CTX) in an infection model., Methods: The PIP MICs for E. coli isolates, either hyperproducing TEM-1 because of promoter substitutions (n = 4) or because of gene amplification (n = 2) or producing an inhibitor-resistant TEM-35 (IRT) (n = 1), were determined using increasing concentrations of TAZ in a checkerboard setup. Furthermore, the efficacy of TZP and CTX against the isolates was investigated in a mouse peritonitis model using antibiotic exposures mimicking human conditions. Isolates producing either OXA-48 or CTX-M-15 β-lactamases were included as controls., Results: Using TAZ concentrations ≤ 64 mg/L, one isolate hyperproducing TEM-1 had a PIP MIC of 8 at TAZ 16 mg/L and two additional isolates at TAZ 64 mg/L. In the mouse peritonitis infection model, reduction of bacterial load in the peritoneum was larger for TZP than CTX only for the CTX-M-15-producing isolate. Larger reductions in bacterial load were observed after CTX treatment than TZP treatment for seven of the eight remaining test isolates., Conclusions: Piperacillin-tazobactam treatment of E. coli isolates hyperproducing TEM-1 was less effective than CTX treatment and may, for some isolates, be comparable with TZP treatment of isolates producing established resistance markers as IRT or OXA-48., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pivmecillinam, a pro-drug of mecillinam, has been used extensively in Scandinavia for the treatment of acute lower urinary tract infections (UTIs) caused by Enterobacterales. It is still an attractive first-line drug for the empirical treatment of UTIs owing to the low prevalence of resistance as well as its favourable impact on the intestinal microbiota as a pro-drug and good in vitro efficacy against extended-spectrum β-lactamase (ESBL)- and plasmid-mediated AmpC β-lactamase-producing Escherichia coli. However, optimal dosing of pivmecillinam as well as its in vivo efficacy against UTIs caused by multidrug-resistant (MDR) broad-spectrum β-lactamase-producing E. coli has not been thoroughly studied. In this study, the efficacy of two mimicked human dosing regimens of pivmecillinam (200 mg and 400 mg three times daily) against clinical E. coli strains, including isolates producing ESBLs (CTX-M-14 and CTX-M-15), plasmid-mediated AmpCs (CMY-4 and CMY-6) and carbapenemases (NDM-1 and VIM-29), in a murine UTI model was compared. Both dosing regimens reduced the number of CFU/mL in urine for all strains, including mecillinam-resistant strains. Combining the effect for all six strains showed no significant differences in effect between doses for all three fluids/organs, but for each dose there was a highly significant effect in urine, kidney and bladder compared with vehicle-treated mice. Overall, this highlights the need for further studies to elucidate the role of mecillinam in the treatment of infections caused by MDR E. coli producing broad-spectrum β-lactamases, including specific carbapenemases., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Meticillin-resistant Staphylococcus aureus (MRSA) is a rapidly spreading pathogen associated predominantly with skin infections. The lack of clinical evidence indicating the best treatment strategy to combat MRSA skin infections prompted us to investigate the efficacy of available treatment options in an experimental skin wound infection model in mice. Mice were treated either topically with retapamulin (1%), fusidic acid (2%) or mupirocin (2%) or systemically with linezolid (50-100 mg/kg/day) or vancomycin (50-200 mg/kg/day) twice daily for 3 days or 6 days and the total bacterial loads in the skin lesions were determined. Retapamulin, fusidic acid and mupirocin treatment for 3 days reduced the bacterial loads by 2.5, 2.9 and 2.0 log(10) CFU, respectively, and treatment for 6 days by 5.0, 4.2 and 5.1 log(10) CFU, respectively, compared with non-treated controls (P < 0.001). Systemic treatment with linezolid for 6 days reduced the bacterial loads by 1.6 log(10) CFU compared with non-treated mice (P < 0.001), whereas vancomycin treatment showed no effect on reducing the bacterial loads in infected skin lesions. These findings suggest that topical treatment with retapamulin and mupirocin is significantly more effective than systemic treatment with linezolid and vancomycin in eradicating MRSA in skin wounds. Retapamulin and mupirocin may provide an alternative to fusidic acid treatment of MRSA in skin wounds when resistance to fusidic acid is suspected., (Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

In response to a review titled 'Withdrawal of growth-promoting antibiotics in Europe and its effects in relation to human health', published in this Journal by Ian Phillips, we hereby comment on the review. Phillips makes use of data from the Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP) reports and studies on Campylobacter and enterococci. Unfortunately, we find these data frequently misinterpreted by Phillips, leading to false conclusions such as inferences that the ban of antibiotic growth promoters should cause an increased prevalence of resistant enterococci and Campylobacter.

Two hundred and ninety-two staphylococci were tested using fusidic acid Neosensitabs, a semiconfluent inoculum on Mueller Hinton agar and three blood containing agar media in order to investigate the interpretative zone diameters published by the manufacturer (Rosco). Zone diameters were, as expected, smaller on blood containing agar compared with Mueller Hinton agar. Many susceptible strains were intermediate on Danish Blood agar using the current breakpoints. We suggest that the interpretative zone diameters be changed to S>or=32, Ror=24, R

Antibiotic treatment of urinary tract infection (UTI) depends on the antibiotic being able to inhibit the growth or to kill the bacteria present in the urinary tract. The pharmacokinetics of antibiotics in the urinary tract including the kidneys, the bladder and the prostate are briefly reviewed. The conclusion is that high urinary antibiotic concentrations can eradicate bacteria in the urine, but in the kidney tissue levels must surpass the MIC of the infecting pathogen to achieve effect. Pharmacodynamic studies in UTI are relatively scarce, but recent studies have shown, that as for other types of infections, beta-lactam antibiotic treatment of UTI depends on the T(>MIC), i.e. the time the antibiotic concentration remains above the MIC. This counts for activity against bacteria in the kidneys as well as in the urine. Bacterial counts in the bladder are curiously resistant to the activity of most antibiotics. For drugs with concentration dependent time-kill activity such as the fluoroquinolones and the aminoglycosides, the effect in UTIs is dependent on the peak/MIC ratio or AUC/MIC ratio. The aminoglycosides are difficult to evaluate in this context, since they are bound in high concentrations to the renal cortex. For clinical studies the author reviews the literature for aminopenicillins (ampicillin and amoxycillin) as representatives of beta-lactam antibiotics. Data from 16 studies of uncomplicated UTI encompassing 20 treatment groups showed a significant correlation between the cumulative T(>MIC) and bacteriological cure, such that a cumulative T(>MIC) of 30 h was necessary for a maximal cure rate of 80-90%. Incorporating these data including the T(>MIC) for the aminopenicillins, the optimal dose with minimal consumption of drug can be calculated, i.e. for amoxycillin 500 mg TID for 4 days. Further research is needed to calculate optimal dosages for other types of antibiotics, especially in order to prevent development of resistance.

The pharmacodynamic (PD) parameters most often used in studies of antibiotic effect include the following relationships between the antibiotic concentration curve in serum as a surrogate marker for the antibiotic concentration at the infection site, the peak/minimal inhibitory concentration (MIC) ratio, the area under the curve (AUC)/MIC ratio and the duration of time the concentration exceeds the MIC (T(>MIC)). The MIC plays an important role also as a PD marker, and its precision in this respect is discussed. The predictive role of T(>MIC) is important for drugs showing minimal concentration dependent effect such as the beta-lactam antibiotics, the macrolides and others. The time can be calculated as the chronological time measured or as the (cumulative) per cent of the dosing interval covered by the dose. Several clinical studies have confirmed this relationship. It can be deduced from experimental as well as clinical studies that there is a minimal effective time (MET), which needs to be covered by the antibiotic concentration at the site of infection in order to achieve cure. Dosing according to this MET will result in the least antibiotic needed for the shortest duration. In several cases a single dose will suffice to cover the MET. If this is not possible the antibiotic should be dosed in a way, that each dose will surpass the MIC for at least 40-50% of the dosing interval. For antibiotics with a clear concentration-dependent bacterial killing effect the most important pharmacokinetic/pharmacodynamic (PK/PD) index is the peak/MIC ratio (or the AUC/MIC ratio). This is the case for aminoglycosides and fluoroquinolones, and for both classes a peak/MIC ratio of at least 10 within the first 24 h of treatment has been shown to result in around 90% bacteriological as well as clinical cure. One consequence of clinical dosing has been the once-a-day (OD) dosing for aminoglycosides, which is the standard mode of therapy in many countries. Clinical studies in the field of antibacterial PD are still relatively scarce, and much information is needed to enable relevant dosing strategies for all types of antibiotics against all common infections and micro-organisms.