Non-fermenting Gram-negative bacteria (NFGNB), have emerged as important healthcare-associated pathogens. Pseudomonas aeruginosa is the most frequently isolated bacteria, followed by Acinetobacter baumannii and Stenotrophomonas maltophilia.
They are bacteria that primarily cause opportunistic healthcare-associated infections in patients who are critically ill or immunocompromised. Routes of transmission include environment to patient either directly from contaminated water or splashes from water outlets, or indirectly from contaminated hands or equipment. Transmission from colonized patients to the environment and between patients can occur during clinical procedures.
In recent years these bacteria have emerged as a major cause of healthcare-associated infections. They are particularly associated with urinary tract infections, ventilator pneumonia, surgical site infections and bloodstream infections.
Infections caused by NFGNB constitute an emerging problem in nosocomial setting, especially in an immunocompromised host. NFGNB are very problematic because of their ubiquitous distributions in the environment and their antimicrobial resistance patterns.
NFGNB often are multidrug resistant, with increasing resistance to carbapenems. Resistance may compromise treatment, leading to increased mortality, extended hospital stay and greater healthcare costs. NFGNB are intrinsically resistant to many drugs and can acquire resistance to virtually any antimicrobial agent. Knowledge on the occurrence, distribution, and antimicrobial susceptibility of NFGNB may be highly relevant to help prevent a misuse of antibiotic agents and guide suitable therapy.
A variety of resistance mechanisms have been identified in NFGNB, including impermeable outer membranes, expression of efflux pumps, target alteration and production of antibiotic-hydrolyzing enzymes such as AmpC beta-lactamases that are either chromosomally encoded or acquired. These mechanisms may be present simultaneously, conferring multiresistance to different classes of antibiotics. These mechanisms may also allow transmission to multiple strains of bacteria.
P. aeruginosa plays an important role in hospital-acquired infections. This microorganism’s high levels of intrinsic antibiotic resistance, together with its extraordinary capacity for acquiring additional resistances through chromosomal mutations, make it a formidable pathogen.
Carbapenems remain the main antimicrobials for treating infections due to resistant P. aeruginosa, but the development of carbapenem resistance may significantly compromise their efficacy. The recent escalation of occurrences of carbapenem-resistant P. aeruginosa has been recognized globally and threatens to erode the widespread clinical utility of the carbapenem class of compounds for this prevalent health care-associated pathogen. Both ceftazidime-avibactam and ceftolozane-tazobactam are active against multiresistant P. aerugionosa, with ceftolozane-tazobactam having significantly higher inhibitory activity than ceftazidime-avibactam.
P. aeruginosa is intrinsically resistant to a number of beta-lactam antibiotics including amoxicillin, first and second generation cephalosporins, cefotaxime, ceftriaxone and ertapenem. Effective agents include ticarcillin, piperacillin, ceftazidime, cefepime, imipenem, meropenem and doripenem. Aztreonam activity is variable. Unlike tazobactam, clavulanate is a strong inducer of AmpC in P. aeruginosa. P. aeruginosa also has the ability to acquire beta-lactamases, including ESBL and carbapenemases. The P. aeruginosa genome contains several different multidrug resistance efflux pumps, which reside in the membrane and remove antimicrobials and toxins, thereby lowering their concentration inside the cell to sub-toxic levels. Overproduction of these pumps reduces susceptibility to a variety of antibiotics. The most common system is MexAB-OprM. Its overexpression confers resistance to ticarcillin, aztreonam, and at a lesser extent, meropenem. Reduced outer-membrane permeability caused by qualitative or quantitative alterations of the OprD porin, which manages the passage of imipenem through the outer membrane, confers P. aeruginosa a basal level of resistance to carbapenems, especially to imipenem.
A. baumannii has demonstrated an alarmingly sharp increase in rates of antibiotic resistance in hospital-acquired infections worldwide. A. baumannii causes a wide variety of illnesses in debilitated and hospitalized patients, especially those admitted to the intensive care units. Carbapenem-resistant A. baumannii has become increasingly prevalent worldwide, raising serious concerns about the remaining (and extremely limited) antibiotic treatment options left to clinicians.
Today, carbapenem-resistant A. baumannii only appears to be susceptible to Colistin and Tigecycline (although data supporting the efficacy of such tigecycline regimens is limited). The mechanisms of resistance in A. baumannii are various, and generally include production of beta-lactamases, impermeable outer membrane, expression of efflux pumps, and change of targets or cellular functions such as alterations in penicillin-binding proteins (PBPs). The PBPs play a crucial role in the synthesis of peptidoglycan, an essential component of the bacterial cell wall. A. baumannii naturally produces a non-inducible AmpC-type cephalosporinase (ACE-1 or ACE-2) and an OXA-51-like carbapenemase which confers, at basal levels of expression, intrinsic resistance to aminopenicillins, first and second generation cephalosporins and aztreonam. Ertapenem naturally lacks activity against non-fermenting Gram negative bacteria including A. baumannii. Overproduction of the AmpC-type cephalosporinase confers acquired resistance to carboxypenicillins, ureidopenicillins and third generation cephalosporins. The emergence of carbapenem-resistant clones of A baumannii has been reported since the late 1980s. Carbapenem resistance can result from the over-expression of OXA-51-like oxacillinase, and from the acquisition of OXA-23-like, IMP, VIM, SIM or, more recently, NDM-type carbapenemases. Acquired resistances to fluoroquinolones (mutations ingyrA and/or parC) and aminoglycosides (plasmid-borne AMEs) may be observed in ESBL as well as carbapenemase-producing A. baumannii strains. Colistin resistant isolates are now increasing worldwide. Resistance to colistin is thought to be mediated by modifications of the lipopolysaccharides of the bacterial cell membrane that interfere with the agent’s ability to bind bacterial targets.
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