New Antibiotics in Pulmonary and Critical Care Medicine

†, * University of the Pacific, School of Pharmacy Stockton, California, and Kendle International, Inc.;   †Maine Medical Center, Portland, Maine, and University of Vermont, College of Medicine, Burlington, Vermont

Semin Respir Crit Care Med. 2000;21(1) 

In This Article

Concepts In Resistance And Advances In Cephalosporins

Because the infectious etiology of pneumonia varies significantly based on community versus nosocomial acquisition, empirical antimicrobial treatment strategies in the CCU must reflect these differences. The increasing complexity of patients admitted to the CCU because of advanced age and severity of underlying condition underscores the need for optimal initial therapy. Because these patients are often treated with multiple antibiotics in or prior to admission to the CCU, they are in essence reservoirs for multiply resistant pathogenic bacteria. As a result, further consideration must be given to organisms harboring altered or reduced susceptibilities to traditionally used treatment selections.

The evolving process of bacterial resistance has not changed since Fleming's discovery of penicillin that revolutionized the treatment of infectious diseases. Soon after the widespread introduction of penicillin and its availability as an oral dosage form, staphylococci that were once routinely susceptible progressively resisted the effects of this powerful agent. Ominously, Fleming predicted this in an interview with the New York Times in 1945 in which he proclaimed that the misuse of penicillin would lead to the selection of mutant strains untreatable by penicillin, a situation that he had already simulated in his laboratory. Resistance would be amplified when an oral formulation became available, Fleming predicted, because unlike the controlled hospitalized environment, appropriate outpatient use would be unmonitored and difficult to control. Unfortunately, today, the appropriate use of anti-infective agents, both in inpatient and outpatient venues, is often difficult to control despite educational efforts regarding the continual increase in bacterial resistance.

The less sophisticated ß-lactamases produced by mutant staphylococci over time disallowed the use of penicillin for the treatment of staphylococcal infections. Similar situations subsequently occurred in Haemophilus influenzae and Neisseria gonorrhea isolates in the decades that followed. At the present time, we are rapidly losing once-potent therapies in the ongoing battle with the mighty microbe. ß-lactamases continue to rapidly evolve, requiring molecular experts to monitor and classify (and reclassify) them. This is often burdening and confusing for the practicing clinician treating these patients. Therefore, the following sections will focus on the newer ß-lactamases and their clinical relevance.

Once uniformly susceptible bacteria are now frustrating even our most potent antimicrobial therapies, in particular the ß-lactams. Resistance mechanisms to ß-lactam antibiotics include alteration of target binding sites (e.g., penicillin binding proteins), decreased permeability into the bacterial cell (e.g., altered porin channels), and, most commonly, the production of ß-lactamases. Similar to the earlier described penicillin-staphylococci situation, many clinically important Enterobacteriaceae have developed resistance to ß-lactams through the elaboration of more complex chromosomal or plasmidmediated ß-lactamases, or both. The result of these increasingly common mutants has precluded the use of the third-generation cephalosporins (e.g., ceftazidime) in many institutions and has unfortunately led to the increased use of carbapenems (e.g., imipenem, meropenem) in some hospitals. Therapeutic issues concerning chromosomally mediated Class C (Bush group 1) ß-lactamases and the plasmid-mediated extended spectrum ß-lactamases (ESBLs) will be discussed.

The class C ß-lactamase, first documented following the introduction of the potent ß-lactamase inducer cefoxitin in 1978, is particularly worrisome because its expression confers resistance to all cephalosporins (except the newer fourth-generation agents), all penicillins, aztreonam, and ß-lactamase inhibitors (e.g., tazobactam, clavulanate, sulbactam).[51] The gene encoding class C ß-lactamases (amp C gene) is naturally present in many species of enteric and some nonenteric bacteria, including P. aeruginosa, Enterobacter spp., Citrobacter spp., Morganella spp., and Serratia marcescens, organisms that are responsible for infection in the respiratory tract, gastrointestinal tract, wounds, and urinary tract. Although the amp C gene is present in all of these mentioned bacteria, clinical expression of the ß-lactamase does not always occur. The dormant gene must be activated and can be done so by induction or, even more devastating, by the selection of a permanently activated (stably derepressed) mutant.

Induction, or the temporary expression of the amp C ß-lactamase resulting in a mild elevation in MIC from baseline occurs as a result of burdening the amp D enzyme that is responsible for recycling cell wall fragments (Fig. 4). Potent inducers of the class C ß-lactamase include ceftazidime, cefoxitin, and the carbapenems. Permanent production of this ß-lactamase occurs when the amp D enzyme undergoes a significant mutational event, allowing the buildup of murein cell wall fragments within the bacterial cell, leading to the subsequent unrelenting production of the amp C ß-lactamase (e.g., stably derepressed mutant). The last of these mechanisms results in clinically significant elevations in MIC values for organisms expressing these enzymes that, as will be discussed later, have led to treatment failures.

Chromosomially mediated ß-lactamase production (Adapted from Medeiros [52] ).

ESBLs, first described in 1983 following the introduction of cefotaxime to clinical use, are mutant derivatives of the basic and well-described TEM and SHV ß-lactamases.[53] ESBLs have been gradually increasing in prevalence since their original description, and, although described in numerous Enter-obacteriaceae, they are most commonly associated with Escherichia coli and Klesiella pneumoniae. In contrast to the class C ß-lactamase-producing organisms discussed before, bacteria expressing ESBLs typically acquire the ability to produce such enzymes via plasmids, rather than by uniformly possessing the chromosome that encodes the ß-lactamase. Plasmids are often exchanged by bacteria to one another via conjugation. Possessing an ESBL confers resistance to the cephalosporin group of antibiotics with the exception of the cephamycins (e.g., cefoxitin and cefotetan) and the fourth- generation cephalosporins (e.g., cefepime and cefpirome). Unlike with the class C ß-lactamases, ß-lactamase inhibitor combinations (e.g., piperacillin-tazobactam and ticarcillin-clavulanate) remain active against ESBLs. Characteristically, plasmids encoding ESBLs may also encode for additional resistance mechanisms that confer resistance to the aminoglycosides (e.g., via aminoglycoside-modifying enzymes) and fluoroquinolones (e.g., via efflux pumps). Alarmingly, plasmids containing the chromosomal class C ß-lactamase have recently been identified conferring resistance to additional agents. Metallo-ß-lactamases, another type of plasmid-mediated enzyme produced by Stenotrophomonas maltophilia, that render the carbapenems inactive have also been identified.

Recently published studies have again showed that squeezing one end of the balloon merely leads to inflation of resistance somewhere else.[54,55] Rahal and colleagues[52] restricted ceftazidime use during an outbreak of ESBL producing K. pneumoniae infections resulting in increased carbapenem use. The result, although not unexpected, was the eradication of the ESBL producing Klebsiella spp. at the expense of an increase in resistance to P. aeruginosa. The removal of potent ß-lactamase inducers from the environment seems justified at this point in time. What should replace them, however, is less obvious.

Paterson et al[56] reviewed more than 400 consecutive isolates and their resulting infections caused by K. pneumoniae, 80 of which were associated with ESBL-producing strains. The primary end-point was mortality, a crude estimate of efficacy, that may or may not be associated with antibiotic efficacy depending on various other factors, such as underlying disease. Carbapenems (e.g., imipenem and meropenem) were used to treat the majority of cases resulting in the lowest mortality rate (5%). The mortality rate of patients receiving ciprofloxacin was 21%. Only eight patients were treated with either cefepime or piperacillin and tazobactam, four each. Two of four patients treated with cefepime died. The majority of all isolates tested during the study period were susceptible to cefepime (87%). Two of four patients who were treated with piperacillin and tazobactam died as well, and, interestingly, only 38% of Klebsiella isolates were susceptible to this agent. Difficulties with this study are the endpoint used to evaluate antibiotic efficacy, and, with the exception of the number of patients receiving a carbapenem, the sample sizes were too small to make meaningful conclusions regarding other therapies. The interesting observation that only 38% of the ESBL-producing Klebsiella isolates were susceptible to piperacillin and tazobactam, an agent that has demonstrated activity against the ESBL-producing organisms, suggests the presence of additional mechanisms of resistance, possibly including chromosomally mediated ß-lactamases.

The role of the fluoroquinolones, piperacillin and tazobactam or the fourth-generation cephalosporins in the treatment of ESBL outbreaks is still not well-established, and further comparative studies should be designed to answer this question. The good in vitro activity of ciprofloxacin (82%) and cefepime (87%) in this study should warrant further studies with these agents.

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