Table 3 summarizes additional comparative effectiveness studies evaluating the role of TZP for AmpC-producing infections

Table 3 summarizes additional comparative effectiveness studies evaluating the role of TZP for AmpC-producing infections. Table 3. Select Observational Comparative Effectiveness Studies Evaluating -Lactams for the Treatment of With Putative AmpC Expression spp. and provide the necessary knowledge required to make rational treatment decisions in an progressively complex multidrug-resistant gram-negative world. MECHANISMS OF RESISTANCE Chromosomally encoded genes can be induced in the appropriate environment [3]. Normally, the regulatory protein AmpR reduces AmpC -lactamase expression to very low levels [4]. Certain -lactams induce the production of cell-wall degradation products (eg, AmpC expression by more than 11-fold in an in vitro model [8]. A second recycling protein, AmpD, is responsible for cleavage of residues off cell-wall degradation SCR7 pyrazine products, reducing their ability to bind to AmpR but still allowing them to be recycled back into the cell-wall synthesis pathway [7, 9]. AmpG transports oligopeptides involved in peptidoglycan recycling and AmpC regulation into the cytosol [10]. As concentrations of degradation products increase, AmpD is unable to cleave all of the necessary peptides, leading to binding of these products to AmpR, decreasing AmpR repression and subsequently increasing transcription [9]. After -lactam exposure ceases, AmpC production levels generally return to baseline. However, if mutations occur in regulatory genes (in order of most to least common: in the presence of an inducing -lactam antibiotic that increases cell-wall degradation production to levels beyond the capacity of AmpD cleavage. Cell-wall degradation products accumulate and compete with UDP-mutation resulting in inactivation and subsequent stable derepression of AmpC. Abbreviations: PBP, penicillin binding protein; UDP, uridine diphosphate. High-level AmpC expression (ie, hyperexpression) appears to confer a fitness cost to an organism because of the cytoplasmic accumulation of degradation products [12, 13]. Despite this, in the face of a prolonged stimulus (eg, -lactam exposure) this phenotype may be sustained. In addition, by eliminating susceptible (non-derepressed) subpopulations, -lactam therapy can select for stably resistant, derepressed mutants, further contributing to the isolation of organisms no longer susceptible to specific -lactams. TRIGGERS OF AmpC HYPEREXPRESSION Antibiotics recognized as potent inducers of the previously explained pathway of AmpC production include the aminopenicillins, amoxicillin-clavulanate, narrow-spectrum (ie, first-generation) cephalosporins, and the cephamycins [5, 14]. Because common AmpC suppliers such as complex, can easily hydrolyze these brokers even at SCR7 pyrazine basal AmpC expression levels, they are intrinsically resistant to these potent inducers. Piperacillin-tazobactam (TZP), aztreonam, and expanded-spectrum (ie, SCR7 pyrazine third-generation) cephalosporins are poor inducers of AmpC hyperproduction but can be hydrolyzed if enough -lactamase is made, translating to increased drug-specific minimum inhibitory concentrations (MICs) [5]. Cefepime has the advantage of being a poor inducer while withstanding hydrolysis by AmpC -lactamases because of the formation of a stable acyl enzyme complex [15]. Imipenem is usually a potent inducer of AmpC production, but it remains stable against hydrolysis by also forming an acyl enzyme complex [14]. The rates of SCR7 pyrazine development of resistance to ceftriaxone, ceftazidime, and cefepime for 10 isolates were evaluated by daily transfer to medium made up of 2-fold serial dilutions of these antibiotics [16]. The emergence of resistance was significantly higher for ceftazidime and ceftriaxone compared with cefepime [16]. Although emergence of resistance to -lactams during therapy can occur with any agent, available clinical data appear to be in agreement with in vitro data, suggesting that this risk is usually by far the greatest with expanded-spectrum cephalosporins [17C23]. Table 1 summarizes data from available observational studies demonstrating the risk of emergence of resistance during exposure to specific -lactams due to putative AmpC production. The activity of cefepime and carbapenems consistently methods 100% against isolates that appear to be PRDI-BF1 AmpC suppliers in the absence of other relevant -lactamase enzymes (eg, coproduction of extended-spectrum -lactamases [ESBLs], carbapenemases, etc.). Data from in vitro and animal models suggest that TZP less frequently.