The antibiotic pipeline for multi-drug resistant gram negative bacteria: what can we expect?

INTRODUCTION: A real concern in the medical community is the increasing resistance of bacteria, especially that of Gram-negative types. New antibiotics are currently under clinical development, promising to tackle severe infections caused, especially, by multi-drug resistant (MDR) bacteria and broaden the armamentarium of clinicians. AREAS COVERED: We searched PUBMED and GOOGLE databases. Combinations of already approved ß-lactams or monobactams with new ß-lactamase inhibitors [imipenem-cilastatin/MK-7655 (relebactam), meropenem/RPX7009 (vaborbactam), ceftaroline/avibactam, aztreonam/avibactam], new ß-lactams (S-649266, BAL30072), aminoglycosides (plazomicin), quinolones (finafloxacin) and tetracyclines (eravacycline) were included in the review. Expert commentary: For the majority of the upcoming antibiotics the currently available data is limited to their microbiology and pharmacokinetics. Their effectiveness and safety against infections due to MDR bacteria remain to be proved. Significant issues are also the impact of these antibiotics on the human intestinal microbiota and their possible co-administration with already-known antimicrobial agents in difficult-to-treat-infections; further studies should be conducted for these objectives.

Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections.

Here we review the effectiveness and safety of high-dose tigecycline (200mg daily). A systematic search was performed in PubMed and Scopus databases as well as of abstracts presented at scientific conferences. Eight studies (263 patients; 58% critically ill) were included, comprising one randomised controlled trial (RCT), four non-randomised cohorts and three case reports. Klebsiella pneumoniae was the most commonly isolated pathogen (reported in seven studies). In the RCT, response in the clinically evaluable patients was 85.0% (17/20) in the 100mg every 12h (q12h) group and 69.6% (16/23) in the 75mg q12h group (P=0.4). More episodes of diarrhoea, treatment-related nausea and vomiting developed in the high-dose group (14.3% vs. 2.8%, 8.6% vs. 2.8% and 5.7% vs. 2.8%, respectively; P>0.05 for all comparisons). Three (8.6%) and 7 (19.6%) patients died in the 200mg and 150mg daily dose groups, respectively. The cohort studies enrolled patients with severe infections, including ventilator-associated pneumonia and complicated intra-abdominal infections. Mortality with high-dose tigecycline (100mg q12h) in the cohort studies ranged from 8.3% to 26%; mortality in the low-dose groups (50mg q12h) ranged from 8% to 61% and depended on the severity of the underlying infection. There are limited available data regarding the effectiveness and safety of high-dose tigecycline. Most of the data come from critically ill patients with difficult-to-treat infections. Pharmacokinetic/pharmacodynamic properties of tigecycline suggest that high-dose regimens may be more effective than low-dose regimens. Candidates for administration of high-dose tigecycline should be also defined.

Impact of vancomycin minimum inhibitory concentration on clinical outcomes of patients with vancomycin-susceptible Staphylococcus aureus infections: a meta-analysis and meta-regression.

Although the vancomycin minimum inhibitory concentration (VMIC) susceptibility breakpoint for Staphylococcus aureus was recently lowered to ≤2 mg/L, it is argued that isolates in the higher levels of the susceptible range may bear adverse clinical outcomes. Clinical outcomes (all-cause mortality and treatment failure) of patients with S. aureus infections by 'high-VMIC' (conventionally defined as VMIC >1 mg/L but ≤2 mg/L) and 'low-VMIC' (VMIC≤1 mg/L) isolates were compared by performing a systematic review and meta-analysis. The effect of potential confounders was assessed by univariate meta-regression analyses. In total, 33 studies (6210 patients) were included. Most studies were retrospective (28/33), used the Etest (22/33) and referred to meticillin-resistant S. aureus (MRSA) infections (26/33) and bacteraemia (23/33). Irrespective of VMIC testing method, meticillin resistance and site of infection, the high-VMIC group had higher mortality [relative risk (RR)=1.21 (95% confidence interval 1.03-1.43); 4612 patients] and more treatment failures [RR=1.67 (1.26-2.21); 2049 patients] than the low-VMIC group. The results were not affected by the potential confounders and were reproduced in the subset of patients with MRSA infections [mortality, RR=1.19 (1.02-1.40), 2956 patients; treatment failure, RR=1.69 (1.26-2.25), 1793 patients]. In conclusion, infection by vancomycin-susceptible S. aureus with VMIC>1mg/L appears to be associated with higher mortality than VMIC≤1mg/L. Further research is warranted to verify these results and to assess the impact of VMIC on meticillin-susceptible S. aureus infections. Evaluation of alternative antimicrobial agents also appears justified.

Impact of antibiotic MIC on infection outcome in patients with susceptible Gram-negative bacteria: a systematic review and meta-analysis.

The objective of this study was to analyze the impact of MIC values within the susceptible range of antibiotics on the outcomes of patients with Gram-negative infections. The PubMed and Scopus electronic databases were searched. We identified 13 articles (1,469 patients) that studied the impact of antibiotic MICs on the outcomes of infections; ß-lactams were studied in 10 of them. Infections due to Salmonella enterica strains with high fluoroquinolone MICs were associated with more treatment failures than those due to strains with low MICs (relative risk [RR], 5.75; 95% confidence interval [CI], 1.77 to 18.71). Among non-Salmonella enterobacteriaceae, there was no difference in treatment failures depending on the MIC value (RR, 1.18; 95% CI, 0.71 to 1.97); however, a higher all-cause mortality was observed for patients infected with strains with high MICs (RR, 2.03; 95% CI, 1.05 to 3.92). More treatment failures were observed for patients infected with nonfermentative Gram-negative bacilli when strains had high MICs (RR, 5.54; 95% CI, 2.72 to 11.27). The mortality rate for patients with infections with Gram-negative nonfermentative bacilli with high MICs was also higher than for those with low MICs (RR, 2.39; 95% CI, 1.19 to 4.81). The limited available data suggest that there is an association between high MICs, within the susceptible range, and adverse outcomes for patients with Gram-negative infections.