The synthesis of large numbers of antibiotics over the past three decades has caused complacency about the threat of bacterial resistance. Bacteria have become resistant to antimicrobial agents as a result of chromosomal changes or the exchange of the exchange of genetic material via plasmids and transposons. Streptococcus pneumoniae, Streptococcus pyogenes, and staphylococci, organisms that cause respiratory and cutaneous infections, and members of the Enterobacteriaceae and Pseudomonas families, organisms that cause diarrhea, urinary infection, and sepsis, are now resistant to virtually all of the older antibiotics. The extensive use of antibiotics in the community and hospitals has fueled this crisis. Mechanisms such as antibiotic control programs, better hygiene, and synthesis of agents with improved antimicrobial activity need to be adopted in order to limit bacterial resistance.

https://science.sciencemag.org/content/sci/257/5073/1064.full.pdf

The Crisis in Antibiotic Resistance

Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

https://courses.washington.edu/medch582/PDFs/2015_Feb9_David.pdf

A new antibiotic kills pathogens without detectable resistance

Enterococci are important human pathogens that are increasingly resistant to antimicrobial agents. These organisms were previously considered part of the genus Streptococcus but have recently been reclassified into their own genus, called Enterococcus. To date, 12 species pathogenic for humans have been described, including the most common human isolates, Enterococcus faecalis and E. faecium. Enterococci cause between 5 and 15% of cases of endocarditis, which is best treated by the combination of a cell wall-active agent (such as penicillin or vancomycin, neither of which alone is usually bactericidal) and an aminoglycoside to which the organism is not highly resistant; this characteristically results in a synergistic bactericidal effect. High-level resistance (MIC, greater than or equal to 2,000 micrograms/ml) to the aminoglycoside eliminates the expected bactericidal effect, and such resistance has now been described for all aminoglycosides. Enterococci can also cause urinary tract infections; intraabdominal, pelvic, and wound infections; superinfections (particularly in patients receiving expanded-spectrum cephalosporins); and bacteremias (often together with other organisms). They are now the third most common organism seen in nosocomial infections. For most of these infections, single-drug therapy, most often with penicillin, ampicillin, or vancomycin, is adequate. Enterococci have a large number of both inherent and acquired resistance traits, including resistance to cephalosporins, clindamycin, tetracycline, and penicillinase-resistant penicillins such as oxacillin, among others. The most recent resistance traits reported are penicillinase resistance (apparently acquired from staphylococci) and vancomycin resistance, both of which can be transferred to other enterococci. It appears likely that we will soon be faced with increasing numbers of enterococci for which there is no adequate therapy.

The life and times of the Enterococcus.

An estimated 2 million patients develop nosocomial infections in the United States annually. The increasing number of antimicrobial agent-resistant pathogens and high-risk patients in hospitals are challenges to progress in preventing and controlling these infections. While Escherichia coli and Staphylococcus aureus remain the most common pathogens isolated overall from nosocomial infections, coagulase-negative staphylococci (CoNS), organisms previously considered contaminants in most cultures, are now the predominant pathogens in bloodstream infections. The growing number of antimicrobial agent-resistant organisms is troublesome, particularly vancomycin-resistant CoNS and Enterococcus spp. and Pseudomonas aeruginosa resistant to imipenem. The active involvement and cooperation of the microbiology laboratory are important to the infection control program, particularly in surveillance and the use of laboratory services for epidemiologic purposes. Surveillance is used to identify possible infection problems, monitor infection trends, and assess the quality of care in the hospital. It requires high-quality laboratory data that are timely and easily accessible.

An overview of nosocomial infections, including the role of the microbiology laboratory.

A PCR assay that allows simultaneous detection of glycopeptide resistance genotypes and identification to the species level of clinically relevant enterococci (Enterococcus faecium, E. faecalis, E. gallinarum, and E. casseliflavus) was developed. This assay was based on specific amplification of internal fragments of genes encoding D-alanine:D-alanine ligases and related glycopeptide resistance proteins. The specificity of the assay was tested on 5 well-characterized glycopeptide-resistant strains and on 15 susceptible enterococcal type strains. Clinical isolates of enterococci that could not be identified to the species level by conventional methods were identified by the PCR test. This assay offers a specific and rapid alternative to antibiotic susceptibility tests, in particular for detection of low-level vancomycin resistance.

Detection of glycopeptide resistance genotypes and identification to the species level of clinically relevant enterococci by PCR.

THE glycopeptide antibiotic agents vancomycin and teicoplanin are useful in the treatment of severe infections due to gram-positive bacteria.1 2 3 Staphylococci, streptococci, and enterococci are a...

Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium.

Transfer of mobilizable shuttle cloning vectors by conjugation from Escherichia coli to Staphylococcus aureus occurred at a very low frequency (10−9 transconjugants per donor colony-forming unit after the mating period). It was observed that subinhibitory concentrations of penicillins (oxacillin or penicillin G) in the mating medium resulted in increased transfer frequency by conjugation of the shuttle vector pAT18 from E. coli SM10 to S. aureus 80CR5 Str (54-fold) and to Listeria monocytogenes LO17RF (45-fold). These results were interpreted as indicating that the cell wall of Gram-positive bacteria constitutes an important barrier for conjugative transfer of genetic information demonstrated that presence of a restriction system(s) in S. aureus recipients represented a major barrier to introduction of foreign DNA.

Enhanced conjugative transfer of plasmid DNA from Escherichia coli to Staphylococcus aureus and Listeria monocytogenes

https://www.amjmed.com/article/0002-9343(91)90348-2/pdf

Eliane Derlot

Papers

Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium.

Enhanced conjugative transfer of plasmid DNA from Escherichia coli to Staphylococcus aureus and Listeria monocytogenes

Mechanisms and implications of glycopeptide resistance in enterococci.