Multidrug-resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, have emerged to be one of the world's greatest health threats. However, not only have recent decades shown a steady decline in the number of approved antimicrobial agents but a disappointing discovery also void. The development of novel antibiotics to treat MDR Gram-negative bacteria has been stagnated over the last half century. Though few compounds have shown activities in vitro, in animal models or even in clinical studies, the global antibiotic pipeline is not encouraging. There are a plethora of unexpected challenges that may arise and cannot always be solved to cause promising drugs to fail. This review intends to summarize recent research and development activities to meet the inevitable challenge in restricting the proliferation of MDR Gram-negative bacteria, with focus on compounds that have entered into clinical development stage. In addition to new analogues of existing antibiotic molecules, attention is also directed to alternative strategies to develop antibacterial agents with novel mechanisms of action.
Aminoglycosides ; pharmacology ; therapeutic use ; Animals ; Anti-Bacterial Agents ; pharmacology ; therapeutic use ; Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Drug Discovery ; Drug Resistance, Multiple, Bacterial ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Ferrous Compounds ; pharmacology ; therapeutic use ; Gram-Negative Bacteria ; drug effects ; Gram-Negative Bacterial Infections ; drug therapy ; Humans ; Peptides ; pharmacology ; therapeutic use ; Peptidomimetics ; pharmacology ; therapeutic use ; Tetracyclines ; pharmacology ; therapeutic use ; beta-Lactamase Inhibitors ; beta-Lactams ; pharmacology ; therapeutic use

The efficacy and safety of ertapenem, 1 g once daily, were compared with that of ceftriaxone, 2 g once daily, for the treatment of adults with acute pyelonephritis (APN) and complicated urinary tract infections (cUTIs) in a prospective, multicenter, double-blinded, randomized study. After > or = 3 days of parenteral study therapy, patients could be switched to an oral agent. Of 271 patients who were initially stratified by APN (n = 210) or other cUTIs (n = 61), 66 (48.9%) in the ertapenem group and 71 (52.2%) in the ceftriaxone group were microbiologically evaluable. The mean duration of parenteral and total therapy, respectively, was 5.6 and 13.8 days for ertapenem and 5.8 and 13.8 days for ceftriaxone. The most common pathogen was Escherichia coli. At the primary efficacy endpoint 5-9 days after treatment, 58 (87.9%) patients in the ertapenem group and 63 (88.7%) in the ceftriaxone had a favorable microbiological response. When compared by stratum and severity, the outcomes in the two groups were equivalent. The frequency and severity of drug-related adverse events were generally similar in both treatment groups. The results indicate that ertapenem is highly effective and safe for the treatment of APN and cUTIs.
Acute Disease ; Anti-Bacterial Agents/*therapeutic use ; Ceftriaxone/*therapeutic use ; Double-Blind Method ; Humans ; Odds Ratio ; Pyelonephritis/complications/*drug therapy ; Republic of Korea ; Risk Factors ; Urinary Tract Infections/complications/*drug therapy ; beta-Lactams/*therapeutic use

BACKGROUNDErtapenem has been demonstrated to be highly effective for the treatment of complicated infections. The aim of this study was to compare the efficacy and safety of ertapenem with ceftriaxone.

METHODSWe searched the PubMed, EMBASE, and the Cochrane Library for published randomized controlled trials (RCTs) that compared the efficacy and safety of ertapenem with ceftriaxone for the treatment of complicated infections including community-acquired pneumonia (CAP), complicated urinary tract infections (cUTIs), and complicated intra-abdominal infections (cIAIs). Meta-analysis was performed by RevMan 5.0.

RESULTSEight RCTs, involving 2 883 patients, were included in our meta-analysis. Ertapenem was associated with similar clinical treatment success with ceftriaxone for complicated infections (1 326 patients, fixed-effect model, OR: 1.13, 95% CI: 0.75-1.71). There was no difference between the compared treatment groups with regard to the microbiological treatment success, and no difference was found with regard to the incidence of clinical and laboratory drug-related adverse events between ertapenem and ceftriaxone groups. As to local tolerability, overall, there was no difference between the compared groups; however, in the subgroup analysis, local reaction was significantly less in the ertapenem subgroup than the ceftriaxone plus ceftriaxone subgroup.

CONCLUSIONSErtapenem can be used as effectively and safely as ceftriaxone for the treatment of complicated infections. It is an appealing option for the treatment of these complicated infections.

Anti-Bacterial Agents ; therapeutic use ; Ceftriaxone ; therapeutic use ; Humans ; Intraabdominal Infections ; drug therapy ; Pneumonia ; drug therapy ; Randomized Controlled Trials as Topic ; Urinary Tract Infections ; drug therapy ; beta-Lactams ; therapeutic use

Production of extended-spectrum beta-lactamase (ESBL) is one of the most important resistance mechanisms that hamper the antimicrobial treatment of infections caused by Enterobacteriaceae. ESBLs are classified into several groups according to their amino-acid sequence homology. While TEM and SHV enzymes were the most common ESBLs in the 1990s, CTX-M enzymes have spread rapidly among Enterobacteriaceae in the past decade. In addition, some epidemiological studies showed that organisms producing CTX-M enzymes had become increasingly prevalent in the community setting in certain areas in the world. Several novel enzymes with hydrolyzing activity against oxyimino-cephalosporins, albeit with additional enzymatic characteristics different from those of original TEM and SHV ESBLs (e.g., inhibitor-resistance), have been discovered and pose a problem on the definition of ESBLs. Although several methods to detect the production of ESBL are available in clinical laboratories, existence of other factors contributing resistance against beta-lactams, e.g., inducible production of Amp-C beta-lactamase by some species of Enterobacteriaceae, or inhibitor-resistance in some ESBLs may hinder the detection of ESBLs with these methods. Carbapenems are stable against hydrolyzing activity of ESBLs and are regarded as the drug of choice for the treatment of infections caused by ESBL-producing Enterobacteriaceae. Although several other antimicrobial agents, such as fluoroquinolones and cephamycins, may have some role in the treatment of mild infections due to those organisms, clinical data that warrant the use of antimicrobial agents other than carbapenems in the treatment of serious infections due to those organisms are scarce for now.
Anti-Bacterial Agents/*pharmacology/therapeutic use ; Carbapenems/pharmacology/therapeutic use ; Disk Diffusion Antimicrobial Tests ; Enterobacteriaceae/drug effects/*enzymology/genetics ; Enterobacteriaceae Infections/*drug therapy/microbiology ; Fluoroquinolones/pharmacology/therapeutic use ; Humans ; Microbial Sensitivity Tests/methods ; beta-Lactamases/*biosynthesis/metabolism ; beta-Lactams/*pharmacology/therapeutic use

BACKGROUND: Extended-spectrum beta-lactamases (ESBLs) are cephalosporinases that confer resistance to a wide variety of oxyimino cephalosporins and create serious therapeutic problems. Although ESBLs have been reported with increasing frequency in Korea, their prevalence and genotypic distribution in Daejeon remain unknown. This study was designed to evaluate the occurrence and genotypic distributions of ESBL-producing Escherichia coli and Klebsiella pneumoniae in Daejeon. METHODS: We tested a total of 427 isolates of E. coli and K. pneumoniae at Chungnam National University Hospital during the period from March to September 2006. ESBL production was determined by the Clinical and Laboratory Standards Institute ESBL confirmatory test; minimum inhibitory concentrations of beta-lactam antibiotics were determined by the broth dilution method. The ceftazidime or cefotaxime resistance of the ESBL-producers was transferred to azide-resistant E. coli J53 by conjugation. Searches for ESBL genes were performed by PCR amplification, and the genotypes of ESBLs were determined by direct nucleotide sequence analysis of the amplified products. The pIs of ESBL were determined by isoelectric focusing. RESULTS: The proportion of ESBL-producers was 10% of the E. coli and 28% of the K. pneumoniae isolates. The prevalence of ESBL-positive isolates was 60% in the intensive care units and 18.7% in the general wards. The most prevalent ESBL genotype in E. coli isolates was blaCTX-M and in K. pneumoniae was blaSHV-12. CONCLUSIONS: E. coli and K. pneumoniae isolates producing SHV-12 or CTX-M-type ESBLs are widespread in Daejeon.
Anti-Bacterial Agents/therapeutic use ; Disk Diffusion Antimicrobial Tests ; Drug Resistance, Bacterial ; Escherichia coli/*drug effects/enzymology/isolation & purification ; Escherichia coli Infections/drug therapy/microbiology ; Genotype ; Humans ; Klebsiella Infections/drug therapy/microbiology ; Klebsiella pneumoniae/*drug effects/enzymology/isolation & purification ; Korea ; *beta-Lactam Resistance ; beta-Lactamases/*analysis ; beta-Lactams/therapeutic use

INTRODUCTIONImipenem and meropenem are treatment of choice for extended-spectrum betalactamase (ESBL)-positive gram-negative bacteraemia. They may select for carbapenemresistant Acinetobacter baumannii and Pseudomonas aeruginosa; ertapenem may not do so as it is inactive against these bacteria. Clinical efficacy of ertapenem in ESBL-producing gramnegative bacteraemia is limited.

MATERIALS AND METHODSRetrospective study of patients with ESBL-positive gram-negative bacteraemia treated with ertapenem was undertaken.

RESULTSForty-seven patients with multidrug-resistant gram-negative bacteraemia (79% produced ESBL) were treated with ertapenem for a median duration of 11 days. The median age was 70 years. Septic shock occurred in 19% and mechanical ventilation was needed in 17%. Klebsiella pneumoniae comprised 53% and Escherichia coli 26%. Urinary infection accounted for 61% and hepatobiliary 15%. Favourable clinical response occurred in 96%. Attributable mortality was 4%.

CONCLUSIONErtapenem is promising in culture-guided step-down therapy of ESBL-positive gram-negative bacteraemia.

Adult ; Aged ; Aged, 80 and over ; Anti-Bacterial Agents ; pharmacology ; therapeutic use ; Bacteremia ; drug therapy ; etiology ; Drug Resistance, Multiple, Bacterial ; Escherichia coli ; drug effects ; enzymology ; Escherichia coli Infections ; drug therapy ; microbiology ; Female ; Gram-Negative Bacteria ; drug effects ; enzymology ; Gram-Negative Bacterial Infections ; drug therapy ; microbiology ; Humans ; Klebsiella Infections ; drug therapy ; microbiology ; Klebsiella pneumoniae ; drug effects ; enzymology ; Male ; Microbial Sensitivity Tests ; Middle Aged ; Retrospective Studies ; Urinary Tract Infections ; complications ; drug therapy ; beta-Lactamases ; biosynthesis ; beta-Lactams ; pharmacology ; therapeutic use