Understanding Antimicrobial Resistance

Lauren Floris, PharmD; David Cluck, PharmD, BCPS, BCIDP, AAHIVP; Abby Singleton, PharmD, BCPS

Disclosures

US Pharmacist. 2020;45(3):HS-10--HS-16. 

In This Article

Resistance Mechanisms

There are two types of bacterial resistance: intrinsic and acquired. In intrinsic resistance, the antibiotic never possessed activity against the pathogen (Table 3).[3–5]Acquired resistance is achieved through the transfer of genetic material that confers resistance. Some bacterial genes are carried on plasmids—small, circular, double-stranded DNA molecules that are distinct from chromosomal DNA.[12]Plasmids are transferred from one bacterium to another through conjugation, and this exchange can occur between bacteria of different species. The strategies that bacteria use to develop acquired resistance are encoded on plasmids and may be classified into four mechanisms: 1) decreased permeability of the cell wall to antibiotics; 2) modification of enzymes to inactivate antibiotics; 3) drug target site changes; and 4) efflux pumps that remove antibiotics from the cell.[4] Drug inactivation through enzymes is the predominant mechanism used by bacteria, and the expression of genes that encode these enzymes may be induced by particular medications (facultative) or constantly expressed (constitutive).

Multidrug-resistant Enterococcus

Enterococci, which are predominantly benign gut bacteria, may be the best-known family of microbes equipped with intrinsic and acquired antibiotic resistance. Of particular concern are E faecium and Enterococcus faecalis. These organisms can have multiple acquired resistance mechanisms, thereby resulting in multidrug resistance.[13] High levels of resistance may exist to beta-lactams (through beta-lactamase enzymes and altered binding proteins), vancomycin (via changes in peptidoglycan synthesis; known as VRE), and aminoglycosides (through enzymatic degradation).[14,15] Ampicillin remains the drug of choice for susceptible Enterococcus infections, but few options remain to treat systemic multidrug-resistant Enterococcus infections; these include linezolid, daptomycin, and tigecycline.[3,14]

Methicillin-resistant Staphylococcus Aureus (MRSA) and MecA

MRSA first appeared in the early 1960s, shortly after the introduction of methicillin.[16] As with most gram-positive organisms, the cell wall serves as the main target for antimicrobial agents and consequently fosters acquired antimicrobial resistance. For S aureus to be considered MRSA, the bacterium must possess the mecA gene, which encodes for a structural change in penicillin-binding protein 2a (PBP2a).[17] This change prevents beta-lactam antibiotics from binding to the cell wall. Laboratory testing for S aureus susceptibility to methicillin is not commonly performed, owing to the instability of methicillin plates; rather, MRSA is determined by a similar beta-lactam: oxacillin. The Clinical Laboratory Standards Institute defines methicillin resistance as an oxacillin mean inhibitory concentration of at least 4 mcg/mL, and isolates resistant to oxacillin are resistant to all beta-lactams, with few exceptions (e.g., ceftaroline).[18]

Extended-spectrum Beta-lactamase (ESBL)–Producing Organisms

Many gram-negative species of bacteria have been found to possess acquired resistance to beta-lactam antibiotics through the production of beta-lactamase. This enzyme deactivates the agent's antimicrobial properties by hydrolyzing its beta-lactam ring.[19] The first beta-lactamase to be isolated was a penicillinase identified in E coli in 1940, before penicillin entered medical use. New agents were developed over the years to resist the effects of this enzyme, including broad-spectrum cephalosporins. Predictably, the introduction of these antibiotics led to resistance against broader-spectrum agents, giving rise to the ESBL enzyme. Currently, more than 150 ESBLs are found in many different Enterobacteriaceae species and in P aeruginosa.[20]

Carbapenems have remained the drug of choice for ESBL-producing pathogens. This beta-lactam antibiotic subgroup includes meropenem, ertapenem, doripenem, and imipenem-cilastatin. All of these agents—with the exception of ertapenem, which does not have activity against Acinetobacter or Pseudomonas—have demonstrated efficacy against ESBLs.[3] Similar to the selective development of ESBL enzymes following the introduction of broad-spectrum cephalosporins, there has been an emergence of carbapenem-resistant pathogens capable of hydrolyzing carbapenems through the activity of a carbapenemase enzyme.

Carbapenemase Enzyme

Carbapenems are the broadest-spectrum antibiotics available and are favorable choices for many resistant gram-negative nosocomial infections.[21] As effective as these agents are, there has been an increase in carbapenem-resistant organisms as a result of carbapenem overuse, leaving patients with limited to no treatment options. Carbapenem-resistant Enterobacteriaceae (CRE) and Acinetobacter are associated with a combined hospitalization of 21,600 patients and 1,800 deaths each year in the U.S.[6] Other possible carbapenemase-producing organisms include K pneumoniae, P aeruginosa, and E coli.[21]

In order to preserve these antibiotics, carbapenem-sparing agents with activity against ESBL-producing pathogens should be used whenever possible. Such agents include piperacillin-tazobactam, cefepime, and ceftolozane-tazobactam.[22] However, carbapenems are preferred for certain infection sites, including the bloodstream and lungs. In the MERINO trial, 30-day mortality was higher in patients with ESBL E coli or K pneumoniae–associated bacteremia that was treated with piperacillin-tazobactam versus a carbapenem.[23]

Much effort has gone into developing new antibiotics to combat these bacteria. A new cephalosporin, cefiderocol, which was approved in 2019 to treat UTIs, has activity against CRE. Recent beta-lactam combinations (meropenem-vaborbactam and ceftazidime-avibactam) have shown good in vitro activity against CRE and are becoming available on many hospital formularies to treat UTIs, intraabdominal infections, and respiratory tract infections.[24] The polymyxins (colistin and polymyxin B), an older antibiotic class, have fallen out of favor because of their renal and neurologic toxicities; however, they are effective against carbapenem-resistant pathogens and may be useful for salvage therapy.[25] Both polymyxin agents are highly similar and have a narrow therapeutic window, requiring careful dosing and close monitoring of renal function, although polymyxin B is associated with less nephrotoxicity than colistin.

P Aeruginosa

Pseudomonas is an opportunistic gram-negative pathogen responsible for a large number of nosocomial infections. Antimicrobial agents used to treat Pseudomonas include beta-lactams, fluoroquinolones, and aminoglycosides, but this genus can display multiple mechanisms of resistance. Intrinsically, Pseudomonas has a relatively low membrane permeability (up to 100 times lower than that of E coli).[26] The acquired-resistance mechanisms potentially expressed by Pseudomonas include any of the four previously described strategies. Fluoroquinolones exhibit antimicrobial activity by targeting bacterial enzymes involved in DNA replication.[9,10] Fluoroquinolone-resistant strains of Pseudomonas avoid this effect by mutating the genes encoding for those enzymes. Aminoglycoside-resistant Pseudomonas is capable of producing aminoglycoside-modifying enzymes. Beta-lactam resistance in Pseudomonas is due to modifications in penicillin-binding proteins, overexpression of efflux pumps, and enzymatic drug inactivation.[26]

Increased exposure of Pseudomonas to an antipseudomonal beta-lactam antibiotic has been shown to increase the risk of developing resistance.[27] In a retrospective cohort study of 7,118 patients, each additional day of antipseudomonal beta-lactam therapy was associated with a 4% increased risk of new resistance at 60-day follow-up. To avoid continuing resistance, diligent efforts should be made to limit beta-lactam exposure to the shortest effective duration.

Enterobacteriaceae and AmpC

More than 100 species of Enterobacteriaceae exist, but a few pathogens in this family (Serratia marcescens, Morganella morganii, Proteus vulgaris, Citrobacter species, and Enterobacter species) possess an inducible beta-lactamase enzyme known as ampC.[28] The ampC enzyme, which is normally not expressed, does not appear to confer resistance against many antibiotics upon first glance at a culture and sensitivity report, but this may be deceiving. Many penicillins and first- to third-generation cephalosporins do not show resistance, but these agents activate ampC and will induce resistance. The presence of ampC is not detectable by most laboratories, but if resistance to cefoxitin is displayed on culture and sensitivity reports, this can serve as a surrogate marker for ampC, in which case penicillins and narrow-spectrum cephalosporins should be avoided.[29]

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