Treatment options for K. pneumoniae, P. aeruginosa and A. baumannii co-resistant to carbapenems, aminoglycosides, polymyxins and tigecycline: an approach based on the mechanisms of resistance to carbapenems

Abstract

The management of carbapenem-resistant infections is often based on polymyxins, tigecycline, aminoglycosides and their combinations. However, in a recent systematic review, we found that Gram-negative bacteria (GNB) co-resistant to carbapanems, aminoglycosides, polymyxins and tigecycline (CAPT-resistant) are increasingly being reported worldwide. Clinical data to guide the treatment of CAPT-resistant GNB are scarce and based exclusively on few case reports and small case series, but seem to indicate that appropriate (in vitro active) antimicrobial regimens, including newer antibiotics and synergistic combinations, may be associated with lower mortality. In this review, we consolidate the available literature to inform clinicians dealing with CAPT-resistant GNB about treatment options by considering the mechanisms of resistance to carbapenems. In combination with rapid diagnostic methods that allow fast detection of carbapenemase production, the approach proposed in this review may guide a timely and targeted treatment of patients with infections by CAPT-resistant GNB. Specifically, we focus on the three most problematic species, namely Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Several treatment options are currently available for CAPT-resistant K. pneumonia. Newer β-lactam-β-lactamase combinations, including the combination of ceftazidime/avibactam with aztreonam against metallo-β-lactamase-producing isolates, appear to be more effective compared to combinations of older agents. Options for P. aeruginosa (especially metallo-β-lactamase-producing strains) and A. baumannii remain limited. Synergistic combination of older agents (e.g., polymyxin- or fosfomycin-based synergistic combinations) may represent a last resort option, but their use against CAPT-resistant GNB requires further study.

Keywords: Acinetobacter; Carbapanemase; Klebsiella; Pandrug resistant; Pseudomonas; Treatment.

Fig. 1

Treatment options for CAPT-resistant K. pneumoniae depending on the mechanism of resistance to carbapenems. 1 Several rapid methods are available or under development that can detect both the production and the type of carbapenemases [–23]. Because rare or novel β-lactamase variants may not be detectable by some methods [, –27], susceptibility should always be confirmed with traditional growth-based methods and combination therapy may be reasonable pending such confirmation, especially in severe infections [17]. 2 CAZ/AVI is active against both Class A and some Class D carbapenemases [59] and is less affected by outer membrane permeability changes (porin mutations or efflux pumps) [85, 86]. CAZ/AVI can be combined with aztreonam to overcome resistance to MBL [–82]. Notable, however, is the potential for emergence of resistance during treatment due to KPC mutations [–66] and due to the recently described VEB-25 extended spectrum β-lactamase [26]. 3 MVB and IMI/REL are active against Class A (KPC) carbapenemase producers, but not against Class B or Class D carbapenemase producers [61, 62]. Both remain active against some KPC variants that confer resistance to CAZ/AVI [70] and against the recently described VEB-25 extended spectrum β-lactamase that has been associated with CAZ/AVI resistance [26]. MVB and IMI/REL may also be active against isolates with porin mutations, but major OmpK35 or OmpK36 disruptions may be associated with resistance [62, 88]. Emergence of resistance may be less likely compared to CAZ/AVI monotherapy [66, 71]. 4 Double carbapenem combinations may be useful if CAZ/AVI, MVB and IMI/REL are not available (or not an option due to higher cost) and have been used effectively against KPC-producing CAPT-resistant K. pneumoniae [–75]. 5 Plazomicin is active against 93% of KPC-producing, 42% of MBL-producing (co-production of 16S-rRNA-methyltransferases), 87% of OXA-producing, and 95% of carbapenemase-negative carbapenem-resistant Enterobacterales [10]. 6 Fosfomycin has been shown to be effective against XDR/PDR K. pneumoniae [93, 94], but its activity is highly variable [96]. 7 Cefiderocol is stable against hydrolysis by all carbapenemases (including MBL) and its mechanism of bacterial cell entry is independent of porin channels and efflux pumps. Therefore, cefiderocol appears to be a useful option when no other antibiotic is active [114, 115]. 8 Eravacycline is more potent compared to tigecycline and may be active against some tigecycline-resistant strains [91, 92]. 9 Options include combinations based on colistin [97, 98], fosfomycin [94, 99] and ceftazidime/avibactam [26], and combinations exploiting multiple heteroresistance [100]. 10 Beta-lactam-based regimens (double carbapenem, newer β-lactams–β-lactamases and the combination of CAZ/AVI with aztreonam) have been better studied compared to other options, and have been associated with better outcomes compared to older agents and their combinations [, –169, 171, 172]

Fig. 2

Treatment options for CAPT-resistant P. aeruginosa depending on the mechanism of resistance to carbapenems. 1 The prevalence of carbapenemases varies substantially in different regions, but may be very high in some settings [–33, 41]. MBL are the predominant carbapenemases in P. aeruginosa, but GES carbapenemases are increasingly being reported [–47] Neither IMI/REL nor CAZ/AVI or C/T is active against MBL-producing P. aeruginosa [55, 59, 76], while GES carbapenemases may inactivate IMI/REL [46, 47] and C/T [45, 111] but not CAZ/AVI [45, 111]. Because rare or novel β-lactamase variants may not be detectable by some rapid methods [, –27], susceptibility should always be confirmed with traditional growth-based methods and combination therapy may be reasonable pending such confirmation, especially in severe infections [17]. 2 Both CAZ/AVI and C/T are unaffected by the most common mechanism of resistance in P. aeruginosa (OprD porin mutations, overexpression of efflux pumps, overexpression of AmpC) [101, 102]. Resistance to CAZ/AVI and C/T is usually the result of structural modifications of AmpC (+ overexpression of AmpC) or horizontally acquired carbapenemases [108, 109]. GES-type carbapenemases may confer resistance to C/T but not to CAZ/AVI [45]. 3 IMI/REL is unaffected by the most relevant mutation-driven β-lactam resistance mechanisms of P. aeruginosa [110]. Moreover, IMI/REL is not affected by AmpC mutations that confer resistance to ceftazidime/avibactam and ceftolozane/tazobactam [110]. IMI/REL is ineffective against MBL- and GES-producing P. aeruginosa strains [46, 47]. 4 Cefiderocol is stable against hydrolysis by all carbapenemases (including MBL) and its mechanism of bacterial cell entry is independent from porin channels and efflux pumps. Therefore, cefiderocol appears to be a useful option when no other antibiotic is active [114, 115]. 5 Alternative antibiotics (if available) may be preferable taking into account the concerns for emergence of resistance during treatment with fosfomycin [96, 117]. When fosfomycin is used it should be combined with a second antibiotic. 6 High-dose aminoglycoside therapy (such as amikacin 50 mg/kg/day) may be a useful option for CACT-resistant P. aeruginosa with borderline MIC (e.g., amikacin MIC = 16 mg/dl) and can be combined with hemodialysis to reduce nephrotoxicity [184, 186, 187]. 7 Until cefiderocol becomes widely available, synergistic combinations (e.g., based on colistin [120, 121], fosfomycin [122, 123], aminoglycosides [45] and C/T [45, 122]) may sometimes represent the only treatment option, but PK/PD and clinical studies are needed. Other options are ineffective for CAPT-resistant P. aeruginosa: The activity of MVB against P. aeruginosa is similar to that of meropenem alone [61].: Plazomicin is no better than other aminoglycosides against P. aeruginosa [10].: Similar to other tetracyclines, P. aeruginosa is resistant to eravacycline [91].: Aztreonam/avibactam cannot overcome resistance against most MBL-producing P. aeruginosa [112], but may be useful against selected strains with borderline/intermediate MICs to aztreonam or ceftazidime/avibactam [81, 113]