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

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

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