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Specific Mechanisms of Resistance
◗ Penicillins and cephalosporins
Resistance to penicillin is mainly mediated by three mechanisms: (a) production of penicillin-destroying enzymes, (b) mutation genes coding for PBP, and (c) reduced permeability to drug.
Resistance to penicillins may be determined by the organism’s production of penicillin-destroying enzymes ( -lactamases). -lactamases, such as penicillinases and cephalosporinases, open the -lactam ring of penicillins and cephalosporins and abolish their antimicrobial activity. -lactamases have been described for many species of Gram-positive and Gram-negative bacteria. Some -lactamases are plasmid-mediated (e.g., penicillinase of S. aureus), while others are chromosomally mediated (e.g., manyspecies of Gram-negative bacteria such as Enterobacter spp.,Citrobacter spp., Pseudomonas spp., etc).
There is one group of -lactamases that is occasionally found in certain species of Gram-negative bacilli, usually
Klebsiella pneumoniae and E. coli. These enzymes are termedextended-spectrum -lactamases because they confer upon bac-teria an additional ability to hydrolyze the -lactam rings of cefotaxime, ceftazidime, or aztreonam.
3.Reduced permeability to drug: Low-level resistance of Neisseria gonorrhoeae to penicillin is caused by poor permeabil-ity of the drug. However, high-level resistance is mediated by a plasmid coding for penicillinase.
Cephalosporins are resistant to -lactamases in varying degrees.
Resistance to vancomycin is mediated by change in D-ALA-D-ALA part of peptide in the peptidoglycan to D-ALA-D-lactate.This results in the inability of vancomycin to bind to the bacte-ria. Vancomycin resistance in Enterococcus spp. is been increas-ingly documented in different clinical conditions.
Seven types of glycopeptide resistance have been described among enterococci (VanA, VanB, VanC, VanD, VanE, VanG, and VanL), which are named based on their specific ligase genes (e.g.,vanA, vanB, etc.). Related gene clusters have been found in non-pathogenic organisms. The common endpoint of these phenotypes is the formation of a peptidoglycan precursor with decreased affinity for glycopeptides, resulting in decreased inhibition of peptidoglycan synthesis. Peptidoglycan precur-sors ending in the depsipeptide d-alanyl-d-lactate are produced in VanA, VanB, and VanD strains, whereas VanC, VanE, and VanL (recently described in an E. faecalis strain) isolates produce precursors terminating in d-alanyl-d-serine, instead of the normally occurring d-alanyl-d-alanine.
The vanA gene cluster was originally detected in the Tn1546 transposon, and this or related genetic elements are usually carried by plamids and occasionally by host chromosome; this plamid-borne transposon also has been found in clinical isolates of S. aureus (vancomycin-resistant S. aureus strains).
Glycopeptide resistance in enterococci is classified as either intrinsic (as a species characteristic) or acquired. The former is a characteristic of the motile species Enterococcus gallinarum and Enterococcus casseliflavus/flavescens, members of which all carry thenaturally occurring vanC-1 and vanC-2/vanC-3 genes, respectively. These enterococci show variable MICs of vancomycin, with many falling in the susceptible range, and clinical failures have been reported following vancomycin use. In general, the isolation of these species does not require strict infection control isola-tion procedures, unless they are highly resistant, suggesting the added presence of potentially transferable vanA or vanB genes.
Resistance to aminoglycosides is mediated by three important mechanisms as follows:
a) Plasmid-dependent resistance to aminoglycosides enzymes is the most important mechanism. It depends on the production of plasmid-mediated phosphorylating, adenyl-ating, and acetylating enzymes that destroy the drugs.
b) Chromosomal resistance of microbes to aminoglycosides is the second mechanism. Chromosomal mutation in genes results in the lack of a specific protein receptor on the 30S subunit of the ribosome, essential for binding of drug.
c) A “permeability defect,” is the third mechanism of resistance. This leads to an outer membrane change that reduces active transport of the aminoglycoside into the cell so that the drug cannot reach the ribosome. Often this is plasmid-mediated.
Resistance to tetracyclines occurs by three mechanisms: (a) efflux, (b) ribosomal protection, and (c) chemical modifi-cation. The first two are the most important. Efflux pumps, located in the bacterial cell cytoplasmic membrane, are respon-sible for pumping the drug out of the cell. Tet gene products are responsible for protecting the ribosome, possibly through mechanisms that induce conformational changes. These con-formational changes either prevent binding of the tetracyclines or cause their dissociation from the ribosome. This is often plasmid controlled.
Resistance to macrolides, such as erythromycin, is caused by a plasmid-encoded enzyme that methylates the 23S ribosomal RNA, thereby blocking binding of the drug.
Resistance to sulfonamide is caused by plasmid-mediated transport system that actively exports the drug out of bacteria. It is also caused by chromosomal mutation in the gene that codes for the target enzyme dihydrofolate synthetase, resulting in reduced binding affinity of the drug.
Resistance to trimethoprim is caused by a chromosomal mutation in the gene coding for dihydrofolate reductase, the enzyme that reduces dihydrofolate to tetrahydrofolate.
Resistance to quinolone occurs mainly due to chromosomal mutations that modify the bacterial DNA gyrase. Resistance is also caused by changes in the outer membrane proteins of the bacteria, which results in reduced uptake of drug into bacteria.
Metronidazole is a bactericidal drug that acts by inhibiting DNA synthesis. It is effective against anaerobes and protozoa.
Microorganisms resistant to chloramphenicol produce the enzyme chloramphenicol acetyltransferase that destroys drug activity. Production of this enzyme is usually mediated by a plasmid.
Rifampin resistance results from a change in RNA poly-merase due to a chromosomal mutation that occurs with high frequency.
Antitubercular drugs include isoniazid, ethambutol, rifampi-cin, pyrazinamide, and streptomycin.
· Isoniazid is a bacteriostatic agent. It penetrates well into tissue, fluid, and also acts on intracellular organisms. Resistance to iso-niazid is mainly due to loss of enzyme catalase that activates iso-niazid to active metabolites that inhibit synthesis of mycolic acid.
· Ethambutol acts by interfering RNA metabolism. The bac-teria develop resistance due to mutation in the gene coding for arabinosyl transferase, which synthesizes arabinogalac-tan in the mycobacterial cell wall.
· Rifampin inhibits RNA synthesis. The bacteria develop resistance due to mutation in the gene coding for DNA-dependent RNA polymerases.
· Pyrazinamide resistance is due to mutation of gene coding for bacterial amidase, which converts it to its active form, pyrazinoic acid.
Combination therapy in tuberculosis is, therefore, essential to prevent emergence of drug resistance.
Production of carbapenemases including NDM metallo-betalactamase: New Delhi metallo-beta-lactamase-1 (NDM-1)isan enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of car-bapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections. The gene for NDM-1 is one member of a large gene family that encodes beta-lactamase enzymes called carbapenemases. Bacteria that produce carbap-enemases are often referred to in the news media as “superbugs” because infections caused by them are difficult to treat. Such bac-teria are usually susceptible only to polymyxins and tigecycline.
NDM-1 was first detected in a K. pneumoniae isolate from a Swedish patient of Indian origin in 2008. It was later detected in bacteria in India, Pakistan, the United Kingdom, the United States, Canada, Japan, and Brazil. The most common bacteria that make this enzyme are Gram-negative such as E. coliand K. pneumoniae, but the gene for NDM-1 can spread from onestrain of bacteria to another by horizontal gene transfer.
The NDM-1 enzyme was named after New Delhi, the capi-tal city of India, as it was first described in December 2009 in a Swedish national who fell ill with an antibiotic-resistant bacterial infection that he acquired in India. The infection was unsuccessfully treated in a New Delhi hospital, and, after the patient’s repatriation to Sweden, a carbapenem-resistant K. pneumoniae strain bearing the novel gene was identified. Itwas concluded that the new resistance mechanism “clearly arose in India, but there are few data arising from India to sug-gest how widespread it is.” Its exact geographical origin, how-ever, has not been conclusively verified. In March 2010, a study in a hospital in Mumbai found that most carbapenem-resistant bacteria isolated from patients carried the blaNDM-1 gene.
In May 2010, a case of infection with E. coli expressing NDM-1 was reported in Coventry in the United Kingdom. The patient was a man of Indian origin who had visited India 18 months previously, where he had undergone dialysis. In initial assays, the bacterium was fully resistant to all antibiotics tested, while later tests found that it was susceptible to tigecycline and colis-tin. It is believed that international travel and patients’ use of multiple countries’ healthcare systems could lead to the “rapid spread of NDM-1 with potentially serious consequences”.
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