Ryan K. Shields, PharmD, MS

Hope. We could all use more of it these days, and the recently released topline results from the ATTACK study (NCT03894046) provide just that for the treatment of carbapenem-resistant 

 By any definition, treatment of CRAB infections represents a dire need for innovative therapeutics.

Current treatment decisions are motivated by desperation rather than clinical evidence, and the polymyxin class remains a cornerstone of recommended combinations.

 Thus, justifiable excitement has surrounded the preliminary results of the phase 3 ATTACK clinical trial evaluating the safety and efficacy of sulbactam-durlobactam (SUL-DUR) for treatment of patients with infections caused by CRAB. 

In this study, patients with severe CRAB infections were randomized to receive imipenem-cilastatin plus SUL-DUR or imipenem-cilastatin plus colistin. Overall, 207 patients were enrolled from 95 trial sites across 17 countries. SUL-DUR met the primary end point of 28-day all-cause mortality showing noninferiority compared with colistin in a microbiologic-modified intent-to-treat population.

Most notably, the 28-day mortality rates showed a statistical trend toward lower mortality among patients who received SUL-DUR at 19% (12/63) versus 32.3% (20/62) in the colistin arm (treatment difference, –13.2%; 95% CI, –30.0% to 3.5%). At the test-of-cure visit, rates of clinical cure were 61.9% and 40.3% for patients who received SUL-DUR and colistin, respectively (treatment difference, 21.6%; 95% CI, 2.9%-40.3%).

In a parallel, open-label arm of the study for patients who had either failed colistin or were infected by colistin-resistant CRAB, the mortality rate among 28 additional patients who received SUL-DUR was consistent with the main cohort (17.9%).

To add to the encouraging findings, the study met its primary safety objective, showing a statistically significant reduction in nephrotoxicity among patients who received at least 1 dose of SUL-DUR or colistin, reporting rates of 13.2% (12/91) and 37.6% (32/85), respectively (

.0002). Collectively, the study provides an initial glimpse into a future of improving the outcomes of patients with CRAB infections should the agent be approved by the FDA. 

These findings are the first to change the trajectory of a decade of disheartening clinical trial results for treatment of CRAB infections.

Motivated by observational cohort studies and numerous in vitro analyses demonstrating synergy of antibiotic combinations against CRAB,

 several randomized clinical trials have been now been conducted.

The first, by Durante-Mangoni et al, was a multicenter, open-label clinical trial that randomized critically ill patients to receive colistin alone or colistin plus rifampin for treatment of extensively drug-resistant (XDR) 

 A total of 209 patients were included in the analysis; nearly 70% were diagnosed with ventilator-associated pneumonia (VAP), 20% with bloodstream infections, and 10% with hospital-acquired pneumonia (HAP). The primary outcome of the study was all-cause mortality at 30 days. Secondary outcomes included infection-related death at 30 days, microbiologic eradication, and development of colistin resistance. All-cause and infection-related mortality rates did not differ among patients who received colistin alone (42.9% and 26.6%, respectively) or colistin plus rifampin (43.3% and 21.2%, respectively). No patient developed colistin resistance in either arm; however, there was a statistically significant difference in rates of microbiologic eradication among patients who received combination therapy compared with monotherapy (60.6% vs 44.8%; 

.034). Results of a smaller, single-center randomized trial corroborated these observations.

The findings were enough to justify trials of alternative combinations considering that colistin plus rifampin may not be the preferred combination agent due to high rates of resistance, drug-drug interactions, and known toxicity to patients. Thus, the combination of colistin plus fosfomycin was compared with colistin alone in a randomized, single-center trial in Thailand for patients with CRAB infections.

 In this study, 47 patients were enrolled into each arm of the open-label trial, which ultimately showed no difference in 28-day all-cause or infection-related mortality among patients who received colistin alone or with fosfomycin (

); however, the study was underpowered, and higher rates of microbiologic eradication were again documented for patients who received combination therapy.

Four years later, the results of the highly anticipated AIDA trial (NCT01732250) were published.6 In this landmark open-label, multicenter study, patients were randomized to receive colistin alone or colistin in combination with dose-optimized meropenem for treatment of severe infections caused by carbapenem-resistant gram-negative pathogens. Clinical outcomes were assessed by 2 investigators who were blinded to the treatment arm. The primary outcome was clinical success at 14 days, defined as survival with improvement or stability in signs and symptoms of infection. In total, 198 patients were randomly assigned to receive colistin monotherapy and 208 patients to receive colistin plus meropenem. The main pathogen in the study was CRAB (77%), and common infection types included HAP/VAP (45%) or bacteremia (43%). No significant differences were observed for clinical success, survival, or microbiologic response among patients who received colistin monotherapy versus combination therapy. For patients infected with CRAB specifically, rates of clinical failure were 83% (125/151) and 81% (130/161) among those who received colistin alone or in combination with meropenem, respectively (

.643). The corresponding rates of 28-day mortality following CRAB infection were 46% (70/151) and 52% (84/161), respectively (

These findings are largely consistent with the recently completed OVERCOME (NCT01597973) study, which is the only randomized, double-blind, placebo-controlled trial to evaluate patients who received colistin alone versus colistin in combination with a carbapenem for the treatment of bacteremia or pneumonia due to XDR gram-negative pathogens.

 In total, 467 patients were enrolled and 425 were included in the modified intent-to-treat analysis. The most frequently isolated pathogens included XDR 

(74%), carbapenem-resistant Enterobacterales (CRE; 16%), and XDR 

(10%). The primary outcome of the study was 28-day all-cause mortality, which did not differ between patients who received colistin monotherapy or combination therapy across all pathogens (43% vs 37%; 

.21), including those specifically infected with XDR 

.50). Similarly, a composite definition of clinical failure did not unveil a benefit to treatment with colistin combination therapy, resulting in XDR 

clinical failure rates of 70% and 64% among patients treated with colistin or colistin plus a carbapenem, respectively (

=.33). No differences in the rate of nephrotoxicity were reported between groups. These data strengthen findings from the AIDA trial and underscore the limited utility of combining colistin with a carbapenem specifically. In fact, post hoc analyses of both trials were unable to associate 

With the futility of combination therapy to treat CRAB infections shown in several randomized trials, the need for novel agents has never been greater. Cefiderocol was developed to overcome all known mechanisms of carbapenem resistance and was envisioned as a key addition to the antibiotic armamentarium against CRAB infections.

 Indeed, the CREDIBLE-CR study (NCT02714595) was developed with these very objectives in mind.

In this open-label, descriptive phase 3 trial, patients were randomly assigned 2:1 to receive cefiderocol or best-available therapy (BAT) for treatment of infections due to carbapenem-resistant gram-negative pathogens. Among 118 patients in the microbiologic intent-to-treat population, 56 were infected with CRAB. Overall, 83% of patients were treated with cefiderocol monotherapy compared with 26% who received monotherapy in the BAT arm, which was predominantly comprised of colistin-based combinations. Surprisingly, rates of death among patients infected with CRAB who were treated with cefiderocol (n=39) were numerically higher than those who received BAT (n=17) at the end-of-study visit (49% vs 18%, respectively). Patients assigned to the cefiderocol arm were more likely to be in the intensive care unit at the time of randomization and have ongoing septic shock than those in the BAT arm, which may explain in part, the imbalanced rates of death. Even with these factors in mind, cefiderocol was not more effectivethan BAT for CRAB infections. 

Given the totality of discouraging results, clinicians will be eager to prioritize any treatment for CRAB infections associated with improved clinical outcomes. Nonetheless, it will be important to await presentation of the full results from the ATTACK trial to know how and where to place SUL-DUR within CRAB treatment algorithms. Presumably such data will form the basis of a new drug application to the FDA in 2022, marking the first antibacterial agent specifically developed to treat a single pathogen. In the interim, the results can be viewed as extremely positive.

Hospitals and other health care facilities currently challenged by frequent CRAB infections can find solace in knowing help is on the way. It’s also important to acknowledge that the overall landscape has improved over the past decade. Indeed, we still have much to learn about the role of cefiderocol in real-world settings, sulbactam in 2- or 3-drug combination regimens, eravacycline and other tetracyclines demonstrating in vitroactivity against CRAB, and bacteriophages as adjunctive therapy.

 In addition, several other antimicrobial agents are currently in development.

As the data accumulate, future goals may shift toward marrying improved therapeutics with molecular diagnostics. As evidenced by the mechanism-focused approach to CRE infections,

such paradigms are associated with improved outcomes for patients. For CRAB specifically, it is possible that certain AmpC or oxacillinase variants demonstrate differential responses to antimicrobial therapy, and thus, specific clones endemic in a region should inform local practice.

Ideally, the next wave of CRAB treatment options will finally retire the use of colistin and older polymyxin derivatives in clinical practice. As evidenced by the ATTACK study, reducing rates of nephrotoxicity is an important objective for new therapeutics. Taken together, the vision of successfully treating CRAB infections is within sight, and the topline findings from the ATTACK study show that hope is certainly on the horizon.

1. Entasis Therapeutics announces positive topline results for sulbactam-durlobactam (SUL-DUR) from phase 3 ATTACK trial. News release. Entasis Therapeutics Holdings Inc. October 18, 2021. Accessed November 2, 2021. https://investors.entasistx.com/news-releases/news-release-details/entasis-therapeutics-announces-positive-topline-results

2. Abdul-Mutakabbir JC, Griffith NC, Shields RK, Tverdek FP, Escobar ZK. Contemporary perspective on the treatment of Acinetobacter baumannii infections: insights from the Society of Infectious Diseases pharmacists. Published online October 14, 2021. 

3. Durante-Mangoni E, Signoriello G, Andini R, et al. Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. 

. 2013;57(3):349-358. doi:10.1093/cid/cit253

4. Aydemir H, Akduman D, Piskin N, et al. Colistin vs. the combination of colistin and rifampicin for the treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. 

. 2013;141(6):1214-1222. doi:10.1017/S095026881200194X

5. Sirijatuphat R, Thamlikitkul V. Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. 

 2014;58(9):5598-5601. doi:10.1128/AAC.02435-13

6. Paul M, Daikos GL, Durante-Mangoni E, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant gram-negative bacteria: an open-label, randomised controlled trial. 

. 2018;18(4):391-400. doi:10.1016/S1473-3099(18)30099-9

7. Kaye KS, Marchaim D, Thamlikitkul V, et al. Results from the OVERCOME trial: colistin monotherapy versus combination therapy for the treatment of pneumonia or bloodstream infection due to extensively drug resistant gram-negative bacilli. Presented at: 31st European Congress of Clinical Microbiology & Infectious Diseases; July 9-12, 2021; virtual. Accessed November 2, 2021. https://eacademy.escmid.org/escmid/2021/eccmid-2021/332468/keith.s.kaye.results.from.the.overcome.trial.colistin.monotherapy.versus.html?f=listing%3D1%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2029%2Alabel%3D22317%2Amarker%3D1333

8. Nutman A, Lellouche J, Temkin E, et al; AIDA Study Group. Colistin plus meropenem for carbapenem-resistant gram-negative infections: in vitro synergism is not associated with better clinical outcomes. 

. 2020;26(9):1185-1191. doi:10.1016/j.cmi.2020.03.035

9. Pogue JM, Rybak MJ, Stamper K, et al. The impact of in vitro synergy between colistin and meropenem on clinical outcomes in invasive carbapenem-resistant gram-negative infections: a report from the OVERCOME trial. Presented at: IDWeek 2021; September 29-October 3, 2021; virtual.

10. McCreary EK, Heil EL, Tamma PD. New perspectives on antimicrobial agents: cefiderocol. 

. 2021;65(8):e0217120. doi:10.1128/AAC.02171-20

11. Isler B, Doi Y, Bonomo RA, Paterson DL. New treatment options against carbapenem-resistant 

. 2018;63(1):e01110-e01118. doi:10.1128/AAC.01110-18

12. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America guidance on the treatment of extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). 

. 2021;72(7):e169-e183. doi:10.1093/cid/ciaa1478

Articles

Recent study results show promising new modalities.

Hope on the Horizon: Treatment for Carbapenem-Resistant Acinetobacter baumannii Infections

“Shorter is better” has become the mantra for antimicrobial stewardship programs aiming to decrease unnecessary exposures for common infection types.

 In the case of β-lactam infusion times, however, longer is almost assuredly better. In a meta-analysis of 1876 patients, prolonged infusions (≥3 hour infusion time) of antipseudomonal β-lactams were associated with lower all-cause mortality among patients with sepsis compared with shorter bolus infusions (≤1 hour infusion time; risk ratio=0.70; 95% CI 0.56-0.87).

 Indeed, prolonged or continuous β-lactam infusions achieve higher rates of pharmacokinetic-pharmacodynamic (PK-PD) target attainment, which results in a greater probability of clinical cure from severe infection.

 The contemporary PK-PD target for β-lactams to optimize efficacy is to maintain free (unbound) plasma drug concentrations above the minimum inhibitory concentration (MIC) against the causative pathogen for 100% of the dosing interval (

 Recent observational studies have further corroborated the importance of prolonged infusions for ceftolozane-tazobactam and ceftazidime-avibactam to improve clinical outcomes among patients infected with carbapenem-resistant 

 Taken together, prolonged infusion β-lactam therapy improves clinical outcomes and lowers mortality. Whether this approach will curb the risk for the emergence of resistance is less well-defined. It is an active research priority in studies assessing the clinical impact of β-lactam therapeutic drug monitoring (TDM).

is a focal point of hospital antibiograms due to the direct association with high rates of treatment failure, recurrent infections, and empiric treatment selection. Each day of antipseudomonal β-lactam therapy carries a 4% increased risk for subsequent resistance.

 In clinical trials of hospital- and ventilator-associated pneumonia (VAP) due to 

10% to 50% of patients treated with β-lactams developed resistance.

 Hopes for improved durability of newer agents such as ceftolozane-tazobactam have been dashed by recent reports documenting treatment-emergent resistance within the same range.

 Thus, a more aggressive β-lactam PK-PD target of 100% 

T>4x MIC has been proposed by consensus guidelines to both optimize efficacy and suppress the emergence of resistance.

 The recommendation accounts for several factors, including variability in MIC determination, inaccuracies of β-lactam plasma concentration measurements, exposures at the site of infection, and the relative safety of β-lactams. At the same time, it is important to highlight that clinical data linking prolonged infusions to suppression of resistance are lacking and preclinical experimental models offer mixed results.

Felton et al compared the effectiveness of bolus versus prolonged infusions of piperacillin-tazobactam to suppress resistance against 

PAO1 in a hollow-fiber infection model (HFIM).

 At low inocula (104 cfu/mL), trough piperacillin/MIC ratios of 3.4 for bolus infusions and 10.4 for prolonged infusions were required to suppress resistance; expansion of resistant subpopulations, however, occurred at similar rate with either infusion strategy. At higher inocula (107 cfu/mL), amplification of resistant subpopulations occurred with all doses (up to 17g/day piperacillin) administered as either a bolus or prolonged infusion. Extending these studies, Tam et al used classification and regression tree analysis to determine that a ceftazidime, cefepime, or meropenem trough/MIC ratio of 3.8 was required to suppress resistance against a baseline inocula of 108 cfu/mL 

The in vitrodata demonstrate that β-lactam trough concentrations of at least 3x MIC are required to suppress resistance, but resistance may not be reliably suppressed at higher bacterial inocula. These data most directly apply to patients with VAP or other high-inocula infection types where bacterial densities often exceed the natural inverse of the β-lactam mutational frequency, suggesting that resistant subpopulations are present at baseline and selected for over time.

 Accordingly, suppression of β-lactam resistance during or following treatment with prolonged infusions should be viewed through the lens of the initial bacterial burden, infecting pathogen, patient characteristics, duration of treatment, and antibiotic exposures at the site of infection.

To illustrate the importance of these factors on suppression of resistance, Yusuf et al showed that receiving meropenem for greater than 8 days was independently associated with the emergence of meropenem-resistant 

infections after adjustment for age, gender, severity of illness, and length of stay.

 Interestingly, rates of resistance were nearly identical for patients receiving prolonged (45.5%, n=46) or bolus (43.5%, n=11) meropenem infusions. Similarly, Dhaese et al found no difference in the risk for resistance among patients receiving continuous versus bolus infusions of piperacillin-tazobactam or meropenem after multivariate adjustment.

 Although only 11.7% (24/205) of patients developed resistance in this retrospective cohort study, 34% (14/41) of patients infected with 

developed resistance, which was the only factor independently predictive of emergent resistance. TDM and molecular analysis of resistant isolates were not performed in either study. In contrast, real-time TDM was performed in a recent study by Cojutti et al. They used continuous infusions of meropenem to target a meropenem/MIC ratio of 4:8 among patients with febrile neutropenia.

 Twenty percent of patients in this study had documented gram-negative infections (n=15; 4 with 

), and no patients developed CRE colonization within 3 months of treatment. TDM-guided β-lactam therapy provides important supportive data to institute prolonged infusions and optimize exposures necessary to suppress resistance that has been shown to vary across patient populations. In a prospective, observational study of critically ill patients in the Netherlands, only 37% achieved a PK-PD target of 100% 

 Factors associated with lower rates of target attainment included an eGFR of 90 mL/min/1.73m2 or greater and higher BMI. To demonstrate the utility of TDM-guided therapy, Al-Shaer et al reported outcomes of 206 patients who had β-lactam levels measured as standard of care.

 Overall, 8% (17/206) of patients developed resistance, but more importantly, attainment of β-lactam exposures 100% 

T>4x MIC was independently associated with suppression of new resistance (

Identifying and characterizing the emergence of β-lactam resistance in clinical trials is a major challenge due to short observation periods, sparse microbiologic sampling, and a reliance upon categorical MIC interpretations. In randomized and observational studies assessing the impact of β-lactam prolonged infusion,

 microbiologic eradication is often assumed and not measured. Confounding interpretation of these data, resistance is typically defined by a single representative isolate that may not be related to the isolate identified at baseline. Population estimates derived from clinical breakpoints also have been used.

 Neither approach, however, interrogates the within patient evolution of resistant or heteroresistant bacterial populations that are common for 

and other multidrug-resistant gram-negative pathogens. On the whole, the impact of β-lactam prolonged infusion on suppression of resistance has not been appropriately delineated, and mixed clinical results are not surprising. Moving forward, additional real-world data are needed to inform β-lactam dosing strategies within well-defined patient populations and specific infection types. Current studies can be advanced by capturing outcomes over time that include both clinical efficacy and microbiologic end points derived from studying bacterial populations rather than single isolates or clones. Until such time, prolonged infusions of β-lactams undeniably improve patient outcomes and should be implemented whenever possible. The full benefits of this approach, however, are still to be determined.

Ryan K. Shields, PharmD, MS, associate director, Antibiotic Management Program, Division of Infectious Diseases at the University of Pittsburgh in Pennsylvania. Shields also is content editor for the Multidrug-Resistant Infections section of 

1. Spellberg B, Rice LB. Duration of Antibiotic Therapy: Shorter Is Better. 

2. Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME. Prolonged versus short-term intravenous infusion of antipseudomonal beta-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials. 

 2018;18:108-20. 3. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. 

4. Abdul-Aziz MH, Alffenaar JC, Bassetti M, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper. 

5. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? 

 : an official publication of the Infectious Diseases Society of America 2014;58:1072-83.

6. Tamma PD, Beisken S, Bergman Y, et al. Modifiable Risk Factors for the Emergence of Ceftolozane-Tazobactam Resistance. 

 : an official publication of the Infectious Diseases Society of America 2020.

7. Tumbarello M, Raffaelli F, Giannella M, et al. Ceftazidime-avibactam use for KPC-Kp infections: a retrospective observational multicenter study. 

 : an official publication of the Infectious Diseases Society of America 2021.

8. Teshome BF, Vouri SM, Hampton N, Kollef MH, Micek ST. Duration of Exposure to Antipseudomonal beta-Lactam Antibiotics in the Critically Ill and Development of New Resistance. 

9. Fink MP, Snydman DR, Niederman MS, et al. Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group. 

10. Rea-Neto A, Niederman M, Lobo SM, et al. Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open-label, multicenter study. 

11. Haidar G, Philips NJ, Shields RK, et al. Ceftolozane-Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections: Clinical Effectiveness and Evolution of Resistance. 

 : an official publication of the Infectious Diseases Society of America 2017;65:110-20.

12. Guilhaumou R, Benaboud S, Bennis Y, et al. Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the 

French Society of Pharmacology and Therapeutics (Societe Francaise de Pharmacologie et Therapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Societe Francaise d'Anesthesie et Reanimation-SFAR). Critical care 

13. Felton TW, Goodwin J, O'Connor L, et al. Impact of Bolus Dosing versus Continuous Infusion of Piperacillin and Tazobactam on the Development of Antimicrobial Resistance in Pseudomonas aeruginosa. 

14. Tam VH, Chang KT, Zhou J, et al. Determining beta-lactam exposure threshold to suppress resistance development in Gram-negative bacteria. 

The Journal of Antimicrobial Chemotherapy

15. Zedtwitz-Liebenstein K, Schenk P, Apfalter P, et al. Ventilator-associated pneumonia: Increased bacterial counts in bronchoalveolar lavage by using urea as an endogenous marker of dilution. 

16. Yusuf E, Van Herendael B, Verbrugghe W, et al. Emergence of antimicrobial resistance to Pseudomonas aeruginosa in the intensive care unit: association with the duration of antibiotic exposure and mode of administration. 

17. Dhaese SAM, De Kezel M, Callant M, et al. Emergence of antimicrobial resistance to piperacillin/tazobactam or meropenem in the ICU: Intermittent versus continuous infusion. A retrospective cohort study. 

18. Cojutti PG, Lazzarotto D, Candoni A, et al. Real-time TDM-based optimization of continuous-infusion meropenem for improving treatment outcome of febrile neutropenia in oncohaematological patients: results from a prospective, monocentric, interventional study. 

19. Abdulla A, Dijkstra A, Hunfeld NGM, et al. Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT). 

20. Al-Shaer MH, Rubido E, Cherabuddi K, Venugopalan V, Klinker K, Peloquin C. Early therapeutic monitoring of beta-lactams and associated therapy outcomes in critically ill patients. 

This approach can help with clinical outcomes and mortality, but resistance is not as well defined.

Do β-Lactam Prolonged Infusions Suppress the Emergence of Resistance?

The US Food and Drug Administration (FDA) approved ceftazidime-avibactam for clinical use in February 2015, effectively changing the landscape for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infec&shy;tions. Compared with traditional salvage agents (including aminoglycosides, colistin, and tigecycline), treatment with ceftazidime-avibactam is safer and more effective.

 Despite these encouraging findings, the emergence of ceftazidime-avi&shy;bactam resistance has been reported and may pose a serious threat to patients. Over the past 4 years, new insights into the molecular mechanisms and predisposing factors associated with ceftazidime-avibactam resistance have been described.

Avibactam is a novel diazabicyclooctane β-lactamase inhib&shy;itor that reversibly inhibits Ambler classes A, C, and some class D β-lactamases. Avibactam does not inhibit class B metallo-β-lactamases (MBLs). In surveillance studies, the combination of ceftazidime-avibactam demonstrated potent in vitro activity against a wide spectrum of gram-negative pathogens, including multidrug-resistant Enterobacteriaceae and CRE.

 Categorized by the FDA-approved susceptibility breakpoint (≤8/4 μg/mL), ceftazidime-avibactam was active against 97.5% of contemporary CRE isolates.

carbapenemase (KPC)- producing CRE were susceptible.5 Against OXA-48 producing CRE, ceftazidime-avibactam was active against 100% of isolates in a recent clinical study.

In the United States, inherent resistance to ceftazidime-avi&shy;bactam is rare, but has been reported. Against CRE blood&shy;stream isolates, Aitken and colleagues described unusually high rates of resistance; however, 86% of resistant isolates harbored a New Delhi metallo-β-lactamase that is refractory to avibactam inhibition.

isolate, Nelson and colleagues demonstrated that a higher copy number of 

KPC-3 plus decreased outer membrane permeability may manifest in resistance to ceftazidime-avi&shy;bactam.

 Decreased outer membrane permeability contrib&shy;uted to a resistant phenotype in one other KPC 

 Although drug efflux does not appear to be a major contributor to resistance,

 a rare 4 amino acid insertion into penicillin binding protein 3 (PBP3) has been implicated in decreased susceptibility against a single KPC 

Taken together, the data suggest combinations of increased 

KPC copy number, impaired outer membrane permeability, and/or variant PBP3 may contribute to decreased ceftazidime-avibactam suscepti&shy;bility in a minority of KPC-producing isolates not previously exposed to the agent.

Of greater concern to clinicians are recent reports describing the emergence of ceftazidime-avibactam resistance following treatment. In a study of 77 patients treated for CRE infections, resistance emerged in 10%, including 14% of patients infected by 

KPC-3 Ω-loop mutations that encoded variant KPC-3 enzymes. The most common variant featured a tyrosine for aspartic acid substitution at Ambler amino acid position 179 (D179Y),

 which was successfully predicted by prior in vitro passage studies.

KPC-3 Ω-loop mutations have been validated as the cause of ceftazidime-avibactam resistance by targeted gene deletion and laboratory transfer of mutant genes into competent 

 KPC variants demonstrate enhanced ceftazidime affinity that prevents avibactam binding,16-18 and a decreased ability to hydrolyze carbapenems that results in restoration of carbapenem susceptibility in some isolates.

 These data attest to the significance of mutations within β-lac&shy;tamase genes that lead to substantial changes in the hydrolytic profile of the resulting enzyme.

 KPC-3 evolved from KPC-2 and differs by a single amino acid at Ambler position 273 (H273Y).22 This substitution results in a ~30-fold increase in the catalytic efficiency against ceftazidime,

 and consequently higher ceftazi&shy;dime-avibactam MICs against clinical 

isolates harboring KPC-3 compared with KPC-2.

 It is unclear if these factors predispose KPC-3 

to ceftazidime-avi&shy;bactam resistance among patients. Recently, 2 cases of resis&shy;tance were reported among 

isolates carrying KPC-2 variants with characteristic D179Y substitutions.

To date, 16 cases of treatment-related or emergent ceftazi&shy;dime-avibactam resistance have been reported in the litera&shy;ture,

 and at least 4 other cases have been described in preliminary reports at conference proceedings.

 Details of 13 available cases are summarized in the Table (see online). All but 1 case has been observed in 

Remarkably, ceftazidime-avibactam resistance has emerged within varying clonal backgrounds of KPC 

 including sequence type (ST) 258, the predominant international clone

isolate harboring both CTX-M-14 and OXA-48.

 Overall, rates of resistance following ceftazidime-avibactam treatment are not well defined, but have ranged from 2% to 10% of treated patients in KPC-endemic regions.

 Notably, no cases of resistance were reported among 57 patients treated with ceftazidime-avibactam for infections caused by OXA-48-producing Enterobacteriaceae.

Durations of drug exposure preceding the identification of resistance have ranged from 7 to 54 days. Among patients in whom resistance emerged, more than half have been solid-organ transplantation recipients and all had deep-seated sites of CRE infection, including intra-abdominal infections and pneumonia. Fifty percent of patients required renal replace&shy;ment therapy (RRT) during their treatment course, which has been identified as a risk factor for the emergence of ceftazidime-avibactam resistance.

 Unfortunately, there are no ceftazidime-avibactam dosing recommendations for patients receiving continuous RRT, and thus the doses administered to patients have varied (

 It is unclear if inad&shy;equate drug exposures promoted the emergence of resistance in these patients or if such patients share underlying host factors that may be contributing.

Ongoing research efforts have focused on the suppression of ceftazidime-avibactam resistance through combination treat&shy;ment strategies. Interestingly, the available evidence would suggest that resistance has emerged despite combination therapy in some patients.

 Notwithstanding, combination treatment against CRE has historically fared better than monotherapy when salvage agents are used.

 In the case of ceftazidime-avibactam, potential partner agents include the aminoglycosides (including plazomicin), carbapenems, tetracyclines (including eravacycline), colistin, and fosfomycin. In vitro colistin does not potentiate the killing of ceftazidime-avibactam against KPC 

and may select for ceftazidime-avibactam resistant subpopula&shy;tions.

 Carbapenem combinations may mitigate the emergence of 

KPC mutations or treat ceftazi&shy;dime-avibactam resistant subpopulations should they arise. Against KPC 

synergy between meropenem and ceftazidime-avibactam has been reported41 and shown to prevent the emergence of resistance in preliminary studies.

 A key factor that may influence the activity of the combination is reverted carbapenem suscep&shy;tibility, which varies by 

KPC mutation and the presence or absence of porin gene mutations.

Additional studies are needed to define optimized ceftazidime-avibactam combinations in vitro

Until such data are available, clini&shy;cians should exercise caution when implementing combination approaches in patients.

Susceptibility testing should be performed routinely when ceftazidime-avibactam is being considered for treatment. Of the commercially available methods, testing by disk diffu&shy;sion may overcall resistance at the currently proposed cutoff values.

 Gradient strip testing, on the other hand, has been shown to reliably correlate with the gold-standard broth microdilution method.

 Importantly, clinicians and micro&shy;biologists now have a better understanding of the nuances in detecting ceftazidime-avibactam resistance. Because auto&shy;mated susceptibility testing systems tend to lag behind FDA approval of new antibiotics, routine surveillance for resistance is rarely employed. Testing ceftazidime-avibactam through reflex algorithms or by clinician request may fail to trigger testing against KPC-variant isolates with restored carbapenem susceptibility.

 In such cases, clinicians and laboratories must work collaboratively to recognize relevant phenotypes against isolates collected from patients with a history of CRE infection and recent ceftazidime-avibactam exposure.

In conclusion, clinical development of ceftazidime-avibactam has marked a major advance for treatment of CRE infections. The emergence of resistance following treatment is concerning, but not surprising given the fate of other antibiotics after regulatory approval.

 Clinicians should be particularly vigi&shy;lant in monitoring for resistance among CRE-infected patients with deep-seated sources of infection and other predisposing factors, such as immunosuppression and receipt of RRT. The most common mechanisms by which resistance is mediated are mutations within the 

KPC gene that encodes variant KPC enzymes with altered spectra of activity, that may include reverted susceptibility to carbapenems. As use of ceftazi&shy;dime-avibactam expands, it is likely that other mechanisms of resistance will be identified. Future research efforts are needed to define effective dosing regimens and combination strategies that will preserve the effectiveness of ceftazidime-avibactam and limit resistance. Taking everything into consideration, the real-world experience with ceftazidime-avibactam has helped to shift CRE treatment paradigms away from older, less effective strategies while setting the bar for other new agents to be measured by. Ongoing reporting of the real-world experiences for each of these agents will be essential in further defining their therapeutic niche in the landscape of CRE management.

Dr. Shields serves as an associate professor in the department of medicine at the University of Pittsburgh where he directs a research laboratory to study antimicrobial-resistant bacteria. He is also a clinical pharmacist in infectious diseases at the University of Pittsburgh Medical Center.

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Ceftazidime-avibactam is a novel treatment for CRE infections, but reports of resistance are increasing.

Ryan K. Shields, PharmD, MS

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