Extended-spectrum β-lactamases (ESBLs) are a rapidly evolving group of β-lactamases which share the ability to hydrolyze third-generation cephalosporins and aztreonam yet are inhibited by clavulanic acid. Typically, they derive from genes for TEM-1, TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the active site of these β-lactamases. This extends the spectrum of β-lactam antibiotics susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described. The presence of ESBLs carries tremendous clinical significance. The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported. ESBL-producing organisms may appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with high failure rates. There is substantial debate as to the optimal method to prevent this occurrence. It has been proposed that cephalosporin breakpoints for the Enterobacteriaceae should be altered so that the need for ESBL detection would be obviated. At present, however, organizations such as the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) provide guidelines for the detection of ESBLs in klebsiellae and Escherichia coli. In common to all ESBL detection methods is the general principle that the activity of extended-spectrum cephalosporins against ESBL-producing organisms will be enhanced by the presence of clavulanic acid. ESBLs represent an impressive example of the ability of gram-negative bacteria to develop new antibiotic resistance mechanisms in the face of the introduction of new antimicrobial agents.

Extended-spectrum beta-lactamases: a clinical update.

The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

/pdf/antibiotic-resistance-the-need-for-global-solutions-4zpn0y7k3w.pdf

Antibiotic resistance—the need for global solutions

Acinetobacter baumannii has emerged as a highly troublesome pathogen for many institutions globally. As a consequence of its immense ability to acquire or upregulate antibiotic drug resistance determinants, it has justifiably been propelled to the forefront of scientific attention. Apart from its predilection for the seriously ill within intensive care units, A. baumannii has more recently caused a range of infectious syndromes in military personnel injured in the Iraq and Afghanistan conflicts. This review details the significant advances that have been made in our understanding of this remarkable organism over the last 10 years, including current taxonomy and species identification, issues with susceptibility testing, mechanisms of antibiotic resistance, global epidemiology, clinical impact of infection, host-pathogen interactions, and infection control and therapeutic considerations.

Acinetobacter baumannii: Emergence of a Successful Pathogen

https://www.cdc.gov/coronavirus/mers/downloads/Isolation2007.pdf

2007 Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Health Care Settings.

Urinary tract infections (UTIs) are a severe public health problem and are caused by a range of pathogens, but most commonly by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis and Staphylococcus saprophyticus. High recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly increase the economic burden of these infections. In this Review, we discuss how basic science studies are elucidating the molecular details of the crosstalk that occurs at the host-pathogen interface, as well as the consequences of these interactions for the pathophysiology of UTIs. We also describe current efforts to translate this knowledge into new clinical treatments for UTIs.

/pdf/urinary-tract-infections-epidemiology-mechanisms-of-3j8ivu97xb.pdf

Urinary tract infections: epidemiology, mechanisms of infection and treatment options

Nosocomial infection or colonization due to enterococci with high-level resistance to vancomycin (minimal inhibitory concentrations [MICs] between 64 and greater than 2000 mg/L) has occurred in 41 patients with renal disease. These vancomycin-resistant enterococci were cultured from many sources including blood. All but one strain contained one or more plasmids ranging in molecular weight from 1.0 to 40 Megadaltons (MDa). Vancomycin resistance was transferable by conjugation to a susceptible recipient strain of Enterococcus faecalis but this was not always associated with plasmid DNA. The emergence of transferable high-level vancomycin resistance in enterococci causing significant clinical infections is of particular importance since vancomycin is widely regarded as a reserve drug for the management of infections with multi-resistant Gram-positive organisms.

/pdf/high-level-vancomycin-resistant-enterococci-causing-hospital-5arba67wmm.pdf

High-level vancomycin-resistant enterococci causing hospital infections.

In the last 5 years, clinical isolates of gram-positive bacteria with intrinsic or acquired resistance to glycopeptide antibiotics have been encountered increasingly. In many of these isolates, resistance arises from an alteration of the antibiotic target site, with the terminal D-alanyl-D-alanine moiety of peptidoglycan precursors being replaced by groups that do not bind glycopeptides. Although the criteria for defining resistance have been revised frequently, the reliable detection of low-level glycopeptide resistance remains problematic and is influenced by the method chosen. Glycopeptide-resistant enterococci have emerged as a particular problem in hospitals, where in addition to sporadic cases, clusters of infections with evidence of interpatient spread have occurred. Studies using molecular typing methods have implicated colonization of patients, staff carriage, and environmental contamination in the dissemination of these bacteria. Choice of antimicrobial therapy for infections caused by glycopeptide-resistant bacteria may be complicated by resistance to other antibiotics. Severe therapeutic difficulties are being encountered among patients infected with enterococci, with some infections being untreatable with currently available antibiotics.

https://cmr.asm.org/content/cmr/8/4/585.full.pdf

Current perspectives on glycopeptide resistance.

Resistance to imipenem and meropenem was observed in 211 (16.5%) isolates of Pseudomonas aeruginosa recovered in a Greek university hospital during 1996 to 1998. In six isolates selected from throughout this period, high-level resistance to both carbapenems (MICs ≥ 128 μg/ml) was associated with production of the class B β-lactamase VIM-1. blaVIM-bearing isolates belonged to serotype O:12 and were indistinguishable by pulsed-field gel electrophoresis.

Outbreak of infections caused by Pseudomonas aeruginosa producing VIM-1 carbapenemase in Greece.

Background The emergence of carbapenemases in Enterobacteriaceae is driving a search for therapeutic alternatives. We tested ACHN-490, a sisomicin derivative that evades all plasmid-mediated aminoglycoside-modifying enzymes, against 82 carbapenem-resistant Enterobacteriaceae isolates. Comparators included internationally and locally available aminoglycosides. Methods The isolates variously had KPC (n?=?12), SME-1 (n?=?1), IMP (n?=?13), VIM (n?=?5), NDM (n?=?17) or OXA-48 (n?=?19) carbapenemases, or had combinations of impermeability with AmpC (n?=?5) or extended-spectrum s-lactamases (n?=?10). They included 53 Klebsiella spp., 19 Enterobacter spp., 6 Escherichia coli and 4 others; most were multiresistant. Genes were identified by PCR and sequencing; MICs were measured by CLSI agar dilution. Results ACHN-490 was active at =2 mg/L against all 65 isolates with carbapenem resistance mechanisms other than NDM enzyme, mostly with MICs of 0.12–0.5 mg/L; isepamicin was active against 63/65 at =8 mg/L. In contrast, 35% were resistant to gentamicin at 4 mg/L, 61% to tobramycin at 4 mg/L and 20% to amikacin at 16 mg/L. However, 16 of the 17 isolates with NDM-1 enzyme were resistant to ACHN-490, with MICs =64 mg/L, and these were cross-resistant to all other human-use aminoglycosides tested. Their behaviour was associated with ArmA and RmtC 16S rRNA methylases. Apramycin (a veterinary aminoglycoside) retained its full activity, with MICs of 4–8 mg/L versus strains with armA or rmtC, though resistance was seen in one Klebsiella pneumoniae with AAC(3)-IV (MIC =256 mg/L). Conclusions ACHN-490 has potent activity versus carbapenem-resistant isolates, except those also harbouring 16S rRNA methylases; isepamicin is also widely active, though less potent than ACHN-490. Evasion of 16S rRNA methylases by apramycin is noteworthy and may provide a starting point for future aminoglycoside development.

Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates

A survey was conducted of the antimicrobial susceptibilities of 595 Acinetobacter spp. isolated from routine clinical specimens in 54 sentinel laboratories throughout the UK during 2000. Isolates of the Acinetobacter baumannii complex (genomic groups 2, 3 and 13TU; n = 443) were distinguished from other genomic groups (n = 152) by PCR fingerprinting of tDNA spacer regions. MICs of amikacin, cefotaxime, ceftazidime, ciprofloxacin, colistin, gentamicin, imipenem, meropenem, minocycline, piperacillin, piperacillin/tazobactam, rifampicin, sulbactam and tetracycline were determined on IsoSensitest agar and interpreted, wherever possible, using BSAC breakpoints. Tigecycline (GAR-936), a new glycylcycline, was also tested. Resistance to cephalosporins, aminoglycosides and ciprofloxacin was widespread, but carbapenems, colistin, sulbactam, minocycline and tigecycline were each active against >80% of the isolates. Isolates of A. baumannii were more often resistant to cefotaxime, ceftazidime, piperacillin, piperacillin/tazobactam, ciprofloxacin, gentamicin and tetracyclines than those belonging to other genomic groups, but were less often resistant to colistin; no significant differences between genomic groups were noted in the susceptibilities to amikacin, carbapenems, rifampicin or sulbactam. The relative activities of the tetracyclines were minocycline > tigecycline > tetracycline. Thirteen carbapenem-resistant isolates (MICs > or =8 mg/L; 2.2%) were received from six centres; four centres sent single isolates; one sent three and one sent six. An allele of bla(IMP) was detected in one of these isolates, but the other 12 isolates either had carbapenemase-independent resistance, or undetectable carbapenemase activity combined with other resistance mechanisms. In conclusion, carbapenems, colistin and minocycline retained greatest activity against the Acinetobacter isolates collected. Tigecycline was less active than minocycline, but both agents overcame most tetracycline resistance.

/pdf/antibiotic-resistance-among-clinical-isolates-of-3csiljnap2.pdf

Neil Woodford

Papers

High-level vancomycin-resistant enterococci causing hospital infections.

Current perspectives on glycopeptide resistance.

Outbreak of infections caused by Pseudomonas aeruginosa producing VIM-1 carbapenemase in Greece.

Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates

Antibiotic resistance among clinical isolates of Acinetobacter in the UK, and in vitro evaluation of tigecycline (GAR-936)