The Search Continues for How to Best Treat Non—Carbapenemase-Producing CRE Infections

ContagionApril 2020
Volume 5
Issue 2

Infections caused by non–carbapenemase-producing carbapenem-resistant Enterobacteriaceae present challenges in the treatment paradigm. Given the limited clinical data, the preferred therapeutic approach remains unknown.

Antimicrobial resistance poses a significant threat to global public health. Carbapenem-resistant Enterobacteriaceae (CRE), in particular, were labeled an “urgent threat” in the 2013 and 2019 Antibiotic Resistance Threats in the United States reports by the US Centers for Disease Control and Prevention (CDC). The CRE threat level rivals carbapenem-resistant Acinetobacter, Candida auris, Clostridioides difficile, and drug-resistant Neisseria gonorrhoeae.

The CDC estimated that CRE were responsible for approxi­mately 13,100 hospitalizations, 1000 deaths, and $130 million in health care expenditures in 2017.1

Unfortunately, the CDC does not currently stratify these statistics by 2 CRE classifications: carbapenemase-producing (CP-CRE) and non—carbapenemase-producing (NCP-CRE). Although both are daunting and encompass urgent threats, they differ significantly. Managing infections caused by CRE is arduous because many strains tend to be resistant to nearly all antibiotics, forcing clinicians to use less effective and/or more toxic antibiotics.2


The resistance mechanism by which CP-CRE and NCP-CRE confer resistance to carbapenems differs. As the name suggests, CP-CRE produce enzymes that hydrolyze and inactivate carbap­enems. These enzymes are categorized as Ambler class A, B, or D β-lactamases and are typically carried on mobile genetic elements (MGEs; eg, plasmids, integrons, transposons), which can transfer carbapenemases to other Enterobacteriaceae.3,4 Their propensity to rapidly spread between organisms and patients has major infection control implications because CP-CRE are more likely associated with clinical outbreaks.5 This high-level carbapenem resistance may phenotypically be represented by elevated minimum inhibitory concentra­tions (MICs) to meropenem, generally >16 μg/mL in Klebsiella pneumoniae carbapenemase (KPC)—producing K pneumoniae. However, other CP-CRE (eg, KPC-producing Escherichia coli or Enterobacter spp) may present with lower MICs.6,7

Conversely, NCP-CRE lack enzymes that hydrolyze carbapenems. Rather, they resist carbapenems through other chromosomal mechanisms (eg, porin channel and/or efflux pump mutations combined with β-lactamase production).8 These mechanisms make NCP-CRE appear to be a less daunting infection control concern. Additionally, NCP-CREs may exhibit lower carbapenem MICs. As a result, probability of target attainment against NCP-CRE with carbapenems is likely higher than it is against CP-CRE with carbapenems.6,7


Patient risk factors for CRE include indwelling devices (eg, catheters) and prolonged courses of antibiotic therapy, partic­ularly if source control has not been achieved. However, CP-CRE and NCP-CRE risk factors also vary. Findings of an epidemiologic study by Marimuthu K et al on Singapore adults showed that prior carbapenem exposure and hematologic malignancies were more likely associated with NCP-CRE than with CP-CRE.9 Marimuthu K et al also conducted a national case-control study to assess risk of antecedent carbapenem exposure in patients with CRE. They concluded that patients with NCP-CRE had 3-fold higher odds of having been exposed to carbapenems 30 days prior compared with those with CP-CRE. Patients with CP-CRE were more likely to be men, have been in an intensive care unit (ICU), and have been hospi­talized within 1 year prior.10

Results of a French case-control study by Nicolas-Chanoine and colleagues determined that male gender, travel to Asia, hospitalization within 1 year prior, infection within 3 months prior, urine drainage, and mechanical ventilation were CRE risk factors; only CP-CRE cases had risk factors of previous travel and hospitaliza­tion abroad.11 Zou H et al also assessed CRE risk factors and found that old age, longer ICU stay, and cancer were more likely associated with CP-CRE compared with NCP-CRE, and NCP-CRE was more associated with longer ICU stay and venous catheterization compared with extend­ed-spectrum β-lactamase phenotypes. Of note, they discovered that prior carbapenem exposure had 7-fold higher odds of CP-CRE in contrast with Marimuthu K et al’s findings.12

Theoretically, CP-CREs may cause more severe disease and be more difficult to eradicate than NCP-CREs. Villegas MV et al assessed the impact of monomicrobial CP-CRE and NCP-CRE bacte­remia in 7 Latin American countries and found that mortality was 4-fold higher in patients with CP-CRE. Survival rates were higher for patients with NCP-CRE at days 7 and 28. However, patients with CP-CRE were more likely to be critically ill, have undergone surgery, and be immunosuppressed. These patients were also less likely to have received active empiric and definitive therapy.13

Tamma PD et al compared outcomes with monomicrobial CP-CRE and NCP-CRE and found that 14-day mortality was 4-fold greater in patients with CP-CRE. They also found that CP-CRE were less likely to be susceptible to other non—β-lactams (eg, aminoglycosides, fluo&shy;roquinolones, tigecycline, and polymyxins). As a result, empiric regimens were less likely to be active against CP-CRE. In the same cohort, meropenem MICs to CP-CRE were more likely to be >16 μg/mL, whereas meropenem MICs to NCP-CRE were more likely to be <1 μg/mL.7

Seo H et al compared mortality between monomicrobial CP-CRE and NCP-CRE bacte&shy;remia and contrarily found that carbapene&shy;mase production was not a mortality risk factor. However, patients who achieved source control in the CP-CRE group were more likely to survive than those who did not achieve source control in the NCP-CRE group. This lack of source control in the NCP-CRE group may explain why the authors did not find carbapenemase produc&shy;tion to be a mortality risk factor. 6

The data from the recently published study, Consortium on Resistance Against Carbapenems in Klebsiella pneumoniae and Other Enterobacteriaceae II (CRACKLE-II) demonstrate that there was no difference in patient outcomes (dead versus alive without events versus alive with 1 event versus alive with 2 or 3 events), via desirability of outcome ranking analysis, between patients infected with CP-CRE, NCP-CRE, or unconfirmed CRE. 14


Although investigators discovered varying clin&shy;ical outcomes between CP-CRE and NCP-CRE, therapeutic options should be predicated upon CRE type and underlying mechanism of resistance. Tests to detect CP include chro&shy;mogenic assays, modified Hodge test, and metallo- β-lactamase Etest, but these tests do not iden&shy;tify specific carbapenemases. Various rapid diagnostic phenotypic tests (eg, Carba NP, mCIM, eCIM, and MALDI-TOF MS) may detect carbapenemase-production, whereas several rapid diagnostic genotypic tests (eg, Biofire FilmArray, Verigene System, Xpert Carba-R, GenMark ePlex) may identify specific carbapenemases.2,15

Current literature does not clarify optimal methods of treating NCP-CRE versus CP-CRE. Because currently available data suggest that CP-CRE may cause more severe infections and be more prognostically important than NCP-CRE, it may be reasonable to treat NCP-CRE less aggressively by prioritizing novel agents for patients with CP-CRE.7,13 Authors of several studies discuss potential treatment options against NCP-CRE (Table). Importantly, novel β-lactam/β-lactamase inhibitors (BLBLIs; eg ceftazidime/avibactam, meropenem/vaborbact&shy;am,imipenem/relebactam) were designed to inhibit serine carbapenemases and may not be appropriate against NCP-CRE.

In addition, because these agents do not address or bypass the resistance mechanism, unnecessarily administering them may inad&shy;vertently accelerate resistance development. Although these novel BLBLIs may not be necessary against all NCP-CREs, ceftazidime/ avibactam and imipenem/relebactam may still remain effective against NCP-CREs that produce ESBL and/or AmpC. Zou H et al found that ceftazidime/avibactam was effective in vitro against NCP-CRE with low-level resistance. The investigators also found aztreonam/avibactam effective in vitro against all strains of NCP-CRE, including more resistant strains with combined carbapenemase production and porin loss.12 However, this has yet to be studied in humans to produce outcomes data.

Although the majority of study findings demonstrate use of combination therapy more likely to be administered against CRE, particu&shy;larly CP-CRE, monotherapy versus combination therapy efficacy against NCP-CRE is yet to be elucidated. Su C et al assessed treatment outcomes against NCP-CRE K pneumoniae infections in Taiwanese hospitals. Among 67 patients receiving appropriate therapy, 61 received monotherapy (most commonly tige&shy;cycline, colistin, and carbapenems), of whom 21.3% experienced 14-day mortality versus 37.5% who experienced 14-day mortality with inappropriate therapy.16

Most studies use carbapenems in combina&shy;tion with polymyxins, tigecycline, aminogly&shy;cosides, and/or fluoroquinolones. Seo H et al associated definitive combination therapy with decreased mortality.6 Findings have shown that carbapenems may be effective against CRE with MICs up to 16 μg/mL if dosing regi&shy;mens are optimized, though CRE type was not differentiated.17,18 Using these data, Tamma PD et al used standard-infusion meropenem 2 g every 8 hours for CRE with MIC <4 μg/mL (more likely NCP-CRE) and extended-infusion meropenem 2 g every 8 hours, infused over 3 hours, for CRE with MIC >8 μg/mL (more likely CP-CRE). Carbapenems were used in combination with another agent in 84% of patients with CP-CRE and 95% of patients with NCP-CRE.7 Other antibiotics may be viable alternatives against NCP-CRE as long as they are susceptible and the isolate does not have resistance mechanisms against it (eg, antibiotic-modifying enzymes or target site, porin, and/or efflux pump mutations), potentially permitting novel non—β-lactams (eg, eravacycline, plazomicin) and β-lactams with novel mechanisms (eg, cefiderocol).

Treating CRE infections is complex. Evaluating patient-specific risk factors may help clinicians select appropriate empiric therapy against specific CRE types. Determining CRE type is important for infection control because CP-CRE spread more rapidly, and it is paramount for treatment purposes because NCP-CRE may cause less severe disease and potentially be managed without novel BLBLIs, allowing these agents to be reserved for CP-CREs. Further studies are needed to elucidate optimal antibi&shy;otic treatment against NCP-CRE.

Maniara is the clinical pharmacy coordinator for infectious diseases and antimicrobial stewardship at Northwell Health—Long Island Jewish Valley Stream in New York. He also serves as the immediate past president of Royal Counties of New York Society of Health-System Pharmacists, a chapter of the New York State Council of Health-System Pharmacists.


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2. Carbapenem-resistant Enterobacteriaceae (CRE). US Centers for Disease Control and Prevention website. Updated November 5, 2019. Accessed December 14, 2019.

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9. Marimuthu K, Venkatachalam I, Khong WX, et al; Carbapenemase-Producing Enterobacteriaceae in Singapore (CaPES) Study Group. Clinical and molecular epidemiology of carbapenem-resistant Enterobacteriaceae among adult inpatients in Singapore. Clin Infect Dis. 2017;64(suppl 2):S68-S75. doi: 10.1093/cid/cix113.

10. Marimuthu K, Ng OT, Cherng BPZ, et al; CaPES Study Group. Antecedent Carbapenem exposure as a risk factor for non-carbapenemase-producing carbapenem-resistant Enterobacteriaceae and carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2019;63(10). doi: 10.1128/AAC.00845-19.

11. Nicolas-Chanoine MH, Vigan M, Laouénan C, Robert J; E-carb Study Group. Risk factors for carbapenem-resistant Enterobacteriaceae infections: a French case-control-control study. Eur J Clin Microbiol Infect Dis. 2019;38(2):383-393. doi: 10.1007/s10096-018-3438-9.

12. Zou H, Xiong S-J, Lin Q-X, Wu M-L, Niu S-Q, Huang S-F. CP-CRE/non-CP-CRE stratification and CRE resistance mechanism determination help in better managing CRE bacteremia using ceftazidime-avibactam and aztreonam-avibactam. Infect Drug Resist. 2019;12:3017-3027. doi: 10.2147/IDR.S219635.

13. Villegas MV, Pallares CJ, Escandón-Vargas K, et al. characterization and clinical impact of bloodstream infection caused by carbapenemase-producing Enterobacteriaceae in seven Latin American countries. PLoS One. 2016;11(4). doi: 10.1371/journal.pone.0154092.

14. van Duin D, Arias CA, Komarow L, et al. Multi-Drug Resistant Organism Network Investigators. Moelcular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study. Lancet Infect Dis. 2020 Mar 6. pii: S1473-3099(19)30755-8. doi: 10.1016/S1473-3099(19)30755-8. [Epub ahead of print]

15. Sakarikou C, Ciotti M, Dolfa C, Angeletti S, Favalli C. Rapid detection of carbapenemase-producing Klebsiella pneumoniae strains derived from blood cultures by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS). BMC Microbiol. 2017;17. doi: 10.1186/s12866-017-0952-3.

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18. Roberts JA, Kirkpatrick CMJ, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother. 2009;64(1):142-150. doi: 10.1093/jac/dkp139.

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