MECHANISMS OF BACTERIAL INTRINSIC DRUG RESISTANCE

Definition:

Intrinsic resistance is defined as inherent or innate (not acquired) antimicrobial resistance, which is bacterial species, is naturally resistant to certain antibiotic. That means these antibiotics can never be use treat infections caused by that species of bacteria. Intrinsic resistance is so common that susceptibility testing is unnecessary.

There are two different mechanisms by which bacteria mediate intrinsic resistance:

1.     Porins

2.     Efflux pumps

Porins (Reduced permeability of the outer membrane):

Influx into the bacteria cell is largely controlled by porins, which are water – filled open pores or channels that span the outer membrane and allow the passive transport of hydrophilic molecules.

 Some Gram positive bacteria and Gram negative bacteria have porins structure, which act as pores through which molecules including nutrients can pass through the membrane into the cell. Some intrinsically resistant bacteria the chemical properties or the size of porins exclude certain antibiotics. The number of the porins that is expressed (lower numbers) in the membrane is also thought to contribute to intrinsic resistance.

Efflux pumps:

Efflux pumps are a naturally present in bacteria use to excrete a solute out of the cell. Active transport mechanisms are biologically useful for removal of a variety of potentially toxic substance from cell. However, in some susceptible bacterial strains, efflux pumps can be induced by an antibiotic substrate and subverted from natural functions to quickly pump the drug out of the cell. Thereby, the bacteria become resistance to its intracellular action of the drug.

Antimicrobial resistance in clinically important bacteria:

Bacteria are classified into two major group based on the Gram staining. These are known as Gram positive and Gram negative bacteria. The differences are:

Gram positive bacteria have a thick peptidoglycan layer. Gram negative bacteria have a thin peptidoglycan layer and outer membrane containing lipopolysaccharide.

These outer membranes of gram negative bacteria are resistant to vancomycin (Glycopeptides), their extra outer membrane to prevent a large molecule of vancomycin to entering the cell.

Salmonella spp. and Shigella spp., aminoglycosides, first- and second-generation cephalosporins, and cephamycins may appear active in vitro but are not effective clinically.

Enterobacterales are also intrinsically resistant to clindamycin, daptomycin, fusidic acid, glycopeptides (vancomycin), lipoglycopeptides (oritavancin, teicoplanin, telavancin), linezolid, tedizolid, quinupristin-dalfopristin, rifampin, and macrolides (erythromycin, clarithromycin, and azithromycin). However, there are some exceptions with macrolides (eg, Salmonella and Shigella spp. with azithromycin). Citrobacter spp. is intrinsically resistant to ampicillin.

B. cepacia complex isolates have chromosomal genes that must undergo mutational changes before expressing resistance. It is not known how often these mutations occur during growth. Intrinsic resistance implies the presence of resistance mechanisms in natural or wild-type strains that result in phenotypic resistance for all or nearly all strains.

Environmental B. cepacia complex strains lacking mutations do not express resistance mechanisms. S. maltophilia is intrinsically resistant to tetracycline but not to doxycycline, minocycline, or tigecycline.

The non-fermentative gram-negative bacteria are also intrinsically resistant to penicillin like benzylpenicillin, cephalosporins I (cephalothin, cefazolin), cephalosporin II (cefuroxime), cephamycins (cefoxitin, cefotetan), clindamycin, daptomycin, fusidic acid, glycopeptides (vancomycin), linezolid, macrolides (erythromycin, azithromycin, clarithromycin), quinupristin-dalfopristin, and rifampin.

Methicillin resistant Staphylococcus sp., as defined by cefoxitin or oxacillin testing, as appropriate to the species, are considered resistant to other β-lactam agents like penicillins, β-lactam combination agents, cephems with the exception of ceftaroline, and carbapenems.

Enterococcus spp., cephalosporins, aminoglycosides (except for high-level resistance testing), clindamycin, and trimethoprim sulfamethoxazole may appear active in vitro but are not effective clinically and should not be reported as susceptible.

Gram-positive bacteria are also intrinsically resistant to aztreonam, polymyxin B/colistin, and nalidixic acid.

References:

1.    Koneman’s Color Atlas and textbook of Diagnostic Microbiology, Sixth edition by Washington et al., 2006.

2.    Clinical and Laboratory Standards Institute M100-S24, Vol.34: 2022.