Background

Despite considerable advances in medicine, antimicrobial resistance, especially multidrug resistance (MDR), is a major public health concern. There are multiple contributing factors to antibiotic resistance, but one stands out above all others.

The development of antibiotics is one of the most notable medical achievements of the past century. Antibiotics have reduced the morbidity and mortality associated with infections. Not only have antibiotics saved patients’ lives and extended the average life span, they have played a major role in achieving major advances in medicine and surgery. However, the emergence of antibiotic resistance across many common bacterial pathogens is reversing some of the life-saving benefits of antibiotics.^[1] The Centers for Disease Control and Prevention (CDC) estimates more than 2 million people are infected with antibiotic-resistant organisms, resulting in approximately 23,000 deaths annually.^[2] The increase in antibiotic resistance is due, in part, to the use of antibiotics to treat infections. Up to 50% of all the antibiotics prescribed for people are not needed or are not optimally effective as prescribed. Unnecessary or suboptimal use of antibiotics increases the risk for preventable adverse events (AEs), for infections with multidrug-resistant organisms, and for Clostridium difficile infection that causes at least 250,000 infections and 14,000 deaths each year in hospitalized patients.^[2]

The emergence of antibiotic resistance among Gram-negative bacteria (GNB) is particularly concerning. Antibiotic-resistant GNB are prevalent in healthcare-associated infections (HAIs), including urinary tract infections, intra-abdominal infections, hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and bloodstream infections (BSIs). Not only are we observing increases in resistance among frequently encountered GNB, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli, but we are also witnessing a rise in the number of MDR strains throughout the world. This poses a significant burden on the healthcare system given that antibiotic-resistant infections are associated with significant increases in morbidity, mortality, and healthcare expenditures.^[2] The loss of effective antibiotics essentially undermines the ability to treat some of the most serious infections and to manage infectious complications in vulnerable patients undergoing invasive procedures. In this article we will discuss the public health threat of MDR-GNB with a focus on carbapenem-resistant Enterobacteriaceae (CRE), current treatment options and unmet needs, new and emerging agents for the treatment of CRE infections, and importantly, key elements and actions to ensure optimal antibiotic prescribing and limit overuse and misuse of antibiotics.

Specific Challenges of Carbapenem-Resistant Enterobacteriacae

The cause of the rise in MDR-GNB is multifaceted. Although numerous resistance mechanisms are thought to contribute, β-lactamases are the most important cause. β-lactamases are enzymes produced by bacteria that hydrolyze the cyclic amide bond in susceptible β-lactam molecules.^[3] β-lactamases are heterogeneous in nature, both in terms of their chemical structure and their substrate profile.^[4] The 2 primary classification schemes used for all β-lactamases are the Ambler classification based on amino acid sequences^[5] and the Bush-Jacoby classification based on functional characteristics.^[6] The more widely used Ambler structural classification divides β-lactamases into 4 classes of A, B, C, and D, while the Bush-Jacoby Classification system further classifies β-lactamases by their structure, spectrum, and ability of clavulanic acid to inhibit its activity. From an antibiotic selection standpoint, β-lactamases can be characterized as broad-spectrum β-lactamases, extended spectrum β-lactamases (ESBLs), cephalosporinases, or carbapenemases.^[4]

The carbapenemases are the most concerning β-lactamases because they hydrolyze nearly all commercially available β-lactam antibiotics. Carbapenemases are classified as Ambler Class A, B, and D. Klebsiella pneumoniae carbapenemases (KPCs) are by far the most common carbapenemase, and fall into Ambler class A. These serine carbapenemases hydrolyze all commercially available β-lactam antibiotics and are not inhibited by traditional β-lactamase inhibitors, such as tazobactam or sulbactam. Class B β-lactamases are metallo-β-lactamases (MBLs) that have a zinc ion at their active site.^[6] This class, which includes New Delhi metallo-β-lactamase (NDM), are carbapenemases that hydrolyze all available β-lactam antibiotics except the monobactam aztreonam and are not inhibited by any commercially available β-lactamase inhibitor.^[7] Despite aztreonam's stability against MBLs, organisms producing these enzymes also frequently express ESBLs, KPCs, or cephalosporinases that hydrolyze aztreonam,^[7] thus limiting its clinical utility as monotherapy. Oxacillin-hydrolysing (OXA)-type β-lactamases, which are classified as Ambler Class D, are primarily found in nonfermenting GNB, such as P aeruginosa and Acinetobacter baumannii. OXA-48 is a carbapenemase found in Enterobacteriaceae,^[8,9] but it may have limited effect on cephalosporin susceptibility.

The CDC and World Health Organization have both classified CRE as an immediate public health threat that requires urgent action.^[2] To complicate matters, genes that encode the various carbapenemases are frequently colocated with multiple other resistance determinants, such as fluoroquinolone resistance, on highly transmissible genetic structures, such as plasmids.^[5] Plasmids are small DNA molecules (most commonly in bacteria) that are physically separated from chromosomal DNA and can replicate independently.

Traditionally, treatment of systemic CRE infections included polymixins (colistin and polymyxin B), tigecycline, and select aminoglycosides. Fosfomycin is also considered to have anti-CRE activity, but is only available in an oral formulation and is limited to treatment of cystitis in the United States.^[10-12] There is mounting evidence to suggest an important role for combination therapy with these agents for CRE. Clinical studies in patients with invasive CRE infections, such as bacteremia, have shown improved outcomes with combination therapy compared with monotherapy.^[12,13] Although it is somewhat counterintuitive for CRE infections, carbapenems are considered an important backbone to combination therapy.^[14] Studies have shown a mortality benefit with carbapenem-containing regimens vs carbapenem-sparing regimens, particularly in the setting of lower carbapenem minimal inhibitory concentrations (MICs), eg, <8 µg/mL.^[12] Triple therapy including a carbapenem has also shown to be beneficial. In one study, triple combination therapy comprising colistin, tigecycline, and meropenem was associated with improved 30-day mortality (odds ratio, 0.27; P = .009).^[13]

The aforementioned agents appear to have a role in the treatment of CRE. However, they are last-line agents in the collective antibiotic arsenal for good reason. Polymixins are known for their high risk of nephrotoxicity, as well as neurotoxicity. Aminoglycosides also carry a known risk of nephrotoxicity, particularly with prolonged use.^[12] Tigecycline monotherapy has been associated with an increase in all-cause mortality in phase 3 and 4 clinical trials, and this was most pronounced among antibiotic-resistant pathogens. Additionally, this drug rapidly and extensively distributes to tissues, resulting in poor blood concentrations. This would, of course, pose concern when using this agent for bacteremia.

Given that the current approach to the treatment of CRE infections includes last-line and relatively toxic agents, there is a dire need for new therapies. Several new drugs with in vitro activity against CRE have recently been approved, with more agents currently in late-stage development.

Recently Approved Therapies for CRE Infection

Ceftazidime-Avibactam

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination. Ceftazidime is a third-generation antipseudomonal cephalosporin with a well-established efficacy and safety profile, and avibactam is a diazabicyclooctane β-lactamase inhibitor. Avibactam has no intrinsic activity alone, but expands the spectrum of activity of ceftazidime against Ecoli, Klebsiella spp., Enterobacter spp., and certain P aeruginosa strains by inhibiting a broad range of serine β-lactamases, including Ambler class A (ESBL and KPC), class C (AmpC), and some class D (such as OXA-48) enzymes.^[15,16] However, avibactam alone does not appreciably inhibit MBLs, such as NDM-1 and VIM-1. Recent data from 85 US medical centers participating in the International Network for Optimal Resistance Monitoring (INFORM) program indicate that ceftazidime-avibactam is very active against Enterobacteriaceae (MIC_50/90, 0.12/0.25 mg/L) regardless of the infection type. Ceftazidime-avibactam was also active against 97.5% of isolates (MIC_50/90, 0.5/2 μg/mL) at the US Food and Drug Administration (FDA) and EUCAST susceptible breakpoint of ≤ 8 mg/L. K pneumoniae represented 63.0% of the CRE isolates and the most common carbapenemases observed among CRE isolates were KPC-3 (54%), followed by KPC-2 (28%), NMC-A (1.3%), and NDM-1 (1.3%).^[17] Molecular characteristics of the ceftazidime-avibactam nonsusceptible CRE strains were not specified in this report. However, other publications indicate that ceftazidime-avibactam is highly active against most KPC-producing Enterobacteriaceae and has limited to no activity against isolates that produce MBLs.^[15]

Ceftazidime-avibactam is currently approved for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis, in combination with metronidazole for complicated intra-abdominal infections (cIAI), and for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP).^[18-21] It was found to be noninferior to comparators (imipenem in cUTI and meropenem in cIAI and HABP/VABP) across clinical trials, and was generally well-tolerated. The most common AEs observed across phase 3 trials were diarrhea, nausea, and vomiting. In the phase 3 cIAI trials, clinical cure rates were lower with ceftazidime-avibactam plus metronidazole relative to meropenem-treated patients in the subgroup of patients with moderate renal impairment at baseline (creatinine clearance [CrCl] 30 to 50 mL/min. Within this subgroup, it was thought that patients treated with ceftazidime-avibactam may have had worse outcomes due to underdosing as patients received a 33% lower daily dose (1.25 g intravenous infusion (IV) every 12 hours) than is currently recommended for patients with CrCl of 30 to 50 mL/min (1.25 g IV every 8 hours). However, the decreased clinical response was not observed for patients with moderate renal impairment at baseline in the phase 3 cUTI trials or in the phase 3 HABP/VABP trial. Based on these observations, ceftazidime-avibactam prescribing information warns of decreased efficacy in patients with moderate renal impairment.^[18]

To gain comparator data for patients with resistant pathogens, a phase 3 multinational, multicenter, randomized, open-label study was conducted in hospitalized adult patients with cIAI or cUTI caused by ceftazidime-non-susceptible GNB.^[22] Patients were randomized 1:1 to ceftazidime-avibactam or best available therapy. In all cases, patients received a carbapenem-containing regimen in the comparator arm, and nearly 90% received carbapenem monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were the same (>90%) for ceftazidime-avibactam and best available therapy. The report did not specify how many patients had CRE, but the finding that nearly 90% of the comparator group received carbapenem monotherapy indicates few, if any, patients were infected with CRE.

The best available comparator data for ceftazidime-avibactam in CRE-infected patients come from 2 retrospective real-world effectiveness studies (Table 1). The Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) conducted a study to compare outcomes between patients initially treated with ceftazidime-avibactam (n=38) or colistin (n=99) for CRE infections.^[23] Most patients received additional anti-CRE agents as part of their treatment. Compared with patients treated with colistin-based therapy, patients treated with ceftazidime-avibactam were less likely to die and more likely to be discharged home during the first 30 days after starting treatment. Similarly, a single-center retrospective study of patients with carbapenem-resistant K pneumoniae bacteremia found that clinical success was achieved more frequently among patients treated with ceftazidime-avibactam relative to other treatment regimens, including those comprising ≥2 agents with in vitro activity. Mortality at days 30 and 90 days and occurrence of acute kidney injury were also found to be lower among patients receiving ceftazidime-avibactam relative to other regimens.^[24] However, ceftazidime-avibactam-resistant K pneumoniae emerged in 3 patients after ceftazidime-avibactam treatment for 10 to 19 days. Further analyses of these isolates indicated that the observed resistance was not due to avibactam resistance, but was mediated by enhanced ceftazidime affinity of the KPC enzyme, which is thought to prevent binding of avibactam.^[25]

Table 1. Outcomes of Ceftazidime-Avibactam in Patients With CRE Infections: CRACKLE Study^[23]

CI = confidence interval.

Meropenem-Vaborbactam

Meropenem-vaborbactam is also a novel β-lactam/β-lactamase inhibitor combination. Meropenem is a carbapenem antibiotic, while vaborbactam is a structurally unique non-β-lactam/β-lactamase inhibitor, with a boronic ester ring at its active site. This structure allows for covalent and reversible binding to a range of Ambler class A and C β-lactamases.^[26] Limited available data suggest that vaborbactam does not appreciably inhibit OXA-type β-lactamases or MBLs. Analysis of more than 11,000 Enterobacteriaceae isolates from the 2015 meropenem-vaborbactam surveillance program showed >99% susceptibility across the tested isolates at the FDA-approved breakpoint of ≤4/8 µg/mL.^[27] More importantly, the addition of vaborbactam at a set concentration of 8 µg/mL to merepenem reduced MIC₅₀/MIC₉₀ values for Enterobacteriaceae-producing serine carbapenemases from 16/>64 µg/mL to ≤0.06/1 µg/mL.^[28] It is important to note that decreased expression of the OmpK37 porin in K pneumoniae, a critical entry pathway for both meropenem and vaborbactam, may result in elevated MICs. Additionally, upregulation of the AcrAB-TolC efflux pump may result in resistance to this agent.

The FDA recently approved meropenem-vaborbactam for the treatment of cUTI, including acute pyelonephritis (AP).^[29] Data in support of the cUTI and AP indication were generated from TANGO I, a multicenter randomized, controlled trial comparing meropenem-vaborbactam with piperacillin-tazobactam for cUTI and AP.^[30] In this study, meropenem-vaborbactam showed superiority to piperacillin-tazobactam with respect to the primary outcome of clinical success (98.4 vs 94%), defined as a composite of clinical cure or improvement and microbial eradication. Best available comparator data for use of meropenem-vaborbactam in CRE infections come from the TANGO II trial, which compared meropenem-vaborbactam with best available therapy for CRE infections; 60% of patients received an aminoglycoside- or a polymyxin-containing regimen^[31] (Table 2). This multicenter, randomized, open-label trial showed a benefit with meropenem-vaborbactam vs best available therapy in clinical cure rate at end of treatment (64.3% vs 33.3%, P = .04) and at the test-of-cure visit (57.1% vs 26.7%; P = .04). Patients treated with meropenem-vaborbactam also experienced fewer drug-related AEs (24% vs 44%) and were less likely to develop acute kidney injury (2.3% vs 8.4%) vs those treated with best available therapy.

Table 2. Outcomes of Meropenem-Vaborbactam in Patients With CRE Infections: TANGO II Study^[31]

Plazomicin

Plazomicin is a semisynthetic aminoglycoside developed from sisomicin structurally modified to maintain activity in the presence of aminoglycoside-modifying enzymes that inactivate currently marketed aminoglycosides.^[12,32] While its mechanism of action is identical to that other aminoglycosides, inhibiting bacterial protein synthesis by binding to the ribosomal 30S subunit, plazomicin has greater in vitro activity against MDR-Enterobacteriaceae, including isolates resistant to currently available aminoglycosides as well as ESBL-producing Enterobacteriaceae and CRE. In a recent surveillance study that included 5658 Enterobacteriaceae collected worldwide, plazomicin inhibited growth in 96.7% and 99.0% of the Enterobacteriaceae at MICs of ≤2 and ≤4 µg/mL, respectively. Against CRE, plazomicin inhibited growth in 90.2% (185/204) of CRE at MICs ≤4 µg/mL. In contrast, amikacin, gentamicin, and tobramycin inhibited only 70.1%, 54.4%, and 15.2%, respectively, of the isolates at the current Clinical and Laboratory Standards Institute breakpoints.^[33] As with other aminoglycosides, the presence of 16S ribosomal RNA (rRNA) methyltransferases, which modify the ribosomal binding site, leads to resistance. This has been reported in many MBL-producing CREs, but copresence can be region specific.^[34]

Plazomicin was recently approved by FDA for the treatment of cUTI, including AP^.[35] As only limited clinical safety and efficacy data are available, reserve plazomicin for use in patients who have limited or no alternative treatment options. Plazomicin is administered at a dosage of 15 mg/kg every 24 hours by IV infusion over 30 minutes to patients 18 years of age or older with CrCl ≥ 90 mL/min. The recommended duration of treatment is 4 to 7 days for cUTI, including pyelonephritis. CrCl should be assessed in all patients prior to initiating therapy and daily during therapy.^[35] The phase 3 randomized, double-blind, multinational EPIC study compared plazomicin 15 mg/kg IV once daily vs meropenem 1 g IV every 8 hours followed by optional oral levofloxacin therapy or an alternative oral therapy in case of levofloxacin resistance or intolerance and evaluated response among patients with cUTI (n=107 vs n=119, respectively) and AP (n=84 vs n=78, respectively). In the combined group, plazomicin was noninferior to meropenem with respect to the coprimary efficacy endpoints of composite cure rate at day 5 (88% vs 91.4%, respectively) and the test-of-cure visit at days 15-19 (81.7% vs 70.1%, respectively). Benefit with plazomicin vs meropenem was seen in composite cure at test-of-cure visit in the subgroup of patients with cUTI only (78.5% vs 68.9%, respectively) and AP only (85.7% vs 71.8%, respectively).^[36,37] At approximately 2 to 3 weeks after the end of IV therapy, composite cure rates were higher compared with meropenem, and there was a lower incidence of microbiological recurrence and clinical relapse (Table 3).^[38]

Table 3. Outcomes of Plazomicin in Patients With cUTI and AP Due to CRE Infection: EPIC Study^[36,38]

Plazomicin has also been studied in patients with blood stream infections (BSIs) due to CRE. The phase 3, open-label, multicenter CARE trial included 2 cohorts.^[41,42] In Cohort 1, patients with BSI or HABP/VABP due to CRE were randomized to plazomicin (n=18) or colistin (n=21), each in combination with meropenem or tigecycline. In Cohort 2, patients with BSI, HABP/VABP, cUTI, or AP due to CRE who were not eligible for inclusion in Cohort 1 were treated with plazomicin and observed. Rates of all-cause mortality at day 28 or significant disease-related complications was substantially lower with plazomicin- vs colistin-based therapy in the full Cohort 1 (23.5% vs 50%, respectively) and in the subgroup of patients with BSI (14.3% vs 53.3%, respectively) (Table 4). Incidence of acute kidney injury was also lower in the plazomicin group relative to the colistin group, and no ototoxicity events were reported.

Table 4. Plazomicin in Patients With BSI and HABP/VABP Due to CRE Infection in the CARE Study^[39]

Antibiotics in Late Stage Development for CRE Infection

Imipenem-Relebactam

Imipenem-relebactam is a β-lactam/β-lactamase inhibitor combination with potential for use in infections caused by CRE. Relebactam is a bicyclic diazabicyclooctane β-lactamase inhibitor, structurally similar to avibactam, but with a positively charged piperidine ring added to the carbonyl group that may prevent expulsion of relebactam from bacterial cells.^[40] Analysis of ESKAPE (Enterococcus faecium, Staphylococcus aureus, K pneumoniae, A baumannii, P aeruginosa, and Enterobacter spp) pathogens from the 2015 SENTRY database showed improvements in susceptibility with imipenem-relebactam vs imipenem alone for K pneumoniae and Enterobacterspp., with the addition of relebactam restoring imipenem susceptibility to 74.1% (20/27) and 100% (8/8) of tested isolates, respectively.^[41] Similar results were observed in a study of ESKAPE pathogens recovered from patients from 11 hospitals in New York city between November 2013 and January 2014, in which imipenem-relebactam restored susceptibility to 97% of KPC-producing K pneumoniae. Similar to meropenem-vaborbactam, K pneumoniae porins appear to play a significant role in imipenem-relebactam susceptibility. In vitro resistance has been reported with OmpK36 porin mutations in K pneumoniae, as well as in organisms producing MBLs or OXA-48-like β-lactamase.^[26]

Imipenem-relebactam has recently completed clinical studies in cIAI and cUTI. In both trials, clinical efficacy was >95% for all treatment groups, demonstrating noninferiority for imipenem-relebactam vs imipenem alone or imipenem/cilastatin.^[42,43] Each of these trials included patients with any recovered pathogen, and were not limited to MDR-GNB. RESTOTRE IMI, a multicenter, randomized, double blind trial comparing imipenem-relebactam (n=21) vs imipenem plus colistin (n=10) for nosocomial pneumonia, cIAI, or cUTI caused by imipenem-nonsusceptible organisms, found a lower 28-day mortality with imipenem-relebactam (9.5% vs 30.0%), although the difference was not statistically significant.^[44] Favorable clinical response at 28 days was significantly higher in the imipenem-relebactam group (71.4% vs 40.0%), although favorable overall response was comparable between groups (71.4% vs 70%). Drug-related AEs were lower in the imipenem-relebactam group (16.1% vs 31.3%) as was treatment-emergent nephrotoxicity (10% vs 56%, P <.01).

Eravacycline

Eravacycline is a novel, fully synthetic fluorocycline antibiotic that binds to the bacterial 30S ribosomal subunit, thereby preventing bacterial chain elongation.^[45] Due to 2 modifications to the D-ring of its tetracycline core (fluorine atom at the C-7 position and a pyrrolidinoacetamido group at the C-9 position), eravacycline has increased activity and stability against tetracycline-specific efflux and resistance due to ribosomal protection proteins.^[46] In an in vitro analysis of more than 2213 gram-negative bacilli, eravacycline MIC₉₀ ranged from 0.25 to 2 µg/mL against the Enterobacteriaceae tested (n=2067) and its MIC₉₀ values were ≥2-fold lower than tigecycline for the majority of organisms tested, including isolates that were resistant to third-generation cephalosporins.^[47] Although activity against CRE was not specified in this analysis, another report demonstrated 2-fold greater activity (MIC₅₀ and MIC₉₀) of eravacycline vs tigecycline against CRE, including 96 KPC-producing K pneumoniae.^[48] These findings were consistent with another analysis of over 4000 gram-negative isolates from 11 medical centers in New York City in which eravacycline was found to have reliable in vitro activity against gram-negative isolates with KPC and OXA carbapenemases.^[49]

In phase 3 trials of patients with cIAI, eravacycline (1 mg/kg IV every 12 hours) was found to be noninferior to ertapenem 1 g IV every 24 hours (IGNITE1)^[50] and meropenem 1 g IV q8h (IGNITE4).^[51] Although there were no serious drug-related AEs observed across these phase 3 clinical trials, gastrointestinal AEs, including nausea and vomiting, were the most commonly reported, which is consistent with other tetracycline antibiotics. No data on patients with CRE infections are available from these studies.

Eravacycline was also investigated for the treatment of cUTI and AP. In 2 phase 3 trials (IGNITE2 and IGNITE3) eravacycline was found to be inferior to comparator therapy. In IGNITE2, IV-to-oral eravacycline was compared with IV-to-oral levofloxacin (minimum of 3 days IV); eravacycline failed to meet the 10% noninferiority margin.^[52] In IGNITE3, IV-only once daily eravacycline (1.5 mg/kg every 24 hours) was compared with eratapenem 1 g IV every 24 hours in a subsequent cUTI and AP phase 3 study and also did not achieve statistical noninferiority.^[53]

Cefiderocol

Cefiderocol is a first-in-class siderophore cephalosporin.^[54] Similar to other β-lactam antibiotics, cefiderocol exerts a bactericidal effect by binding to penicillin-binding proteins (PBPs), thereby inhibiting cell wall synthesis. Cefiderocol also has a distinctive mechanism for efficiently penetrating the outer membrane of GNB. However, in contrast to other commercially available β-lactam antibiotics, cefiderocol penetrates the outer membrane of GNB via active iron transporters, which incorporate this essential nutrient for bacteria. This results in high concentrations of cefiderocol in the periplasmic space where it can then bind to PBPs and inhibit cell wall synthesis. It is also stable to both serine- and metallo-carbapenemases. Data from global surveillance studies for cefiderocol demonstrated potent in vitro activity against a wide spectrum of MDR-GNB, including carbapenem-resistant A baumannii, P aeruginosa, Enterobacteriaceae, and S maltophilia.^[55-58] A phase 3 trial of cefidercol in patients with cUTI proved noninferior vs imipenem/cilastin in achieving a composite primary endpoint of clinical cure and microbiological eradication at test-of-cure visit (72.6% vs 54.6%).^[59] Additional studies in patients with carbapenem-resistant pathogens at various infection sites and in HABP/VABP are underway.

Fosfomycin

Fosfomycin is a first-in-class, broad-spectrum antibiotic with coverage against many common MDR gram-positive and gram-negative pathogens. Fosfomycin inhibits the first step in bacterial peptidoglycan synthesis by irreversibly binding to cytoplasmic enzyme uridine diphosphate N-acetylglucosamine enolpyruvyl transferase.^[60] It is available in both oral and IV formulations, but the poor bioavailability of oral formulations limits its use for serious systemic infections. A multicenter, randomized, double-blind phase 2/3 trial of patients with cUTI and AP (n=465) treated with fosfomycin 6 g as a 1-hour IV infusion every 8 hours (18 g total daily dose) demonstrated noninferiority vs piperacillin-tazobactam in patients with cUTI and AP.^[61] No comparator data for the treatment of CRE are available at this time, but there are observational noncomparator reports of fosfomycin in combination with other drugs for the treatment CRE. Data indicate fosfomycin is generally well tolerated and the most commonly reported AEs associated with its use include hypokalemia, nausea, vomiting, and diarrhea.

Improving the Use of Antibiotics

Improving the use of antibiotics is an important patient safety and public health issue, as well as a national priority. The CDC proposes 7 core elements of hospital antibiotic stewardship programs:^[62]

• Leadership commitment: dedicating necessary human, financial and information technology resources
• Accountability: appointing a single leader responsible for program outcomes
• Drug expertise: appointing a single pharmacist leader responsible for working to improve antibiotic use
• Action: implementing at least 1 recommended action
• Tracking: monitoring antibiotic prescribing and resistance patterns
• Reporting: regular reporting of information on antibiotic use and resistance to doctors, nurses, and other relevant staff
• Education: educating clinicians about resistance and optimal prescribing

Individual healthcare providers are encouraged to focus on the element Action by asking:^[62]

• Does my healthcare facility have a policy that requires prescribers to document in the medical record or during order entry a dose, duration, and indication for all antibiotic prescriptions?
• Does my facility have facility-specific treatment recommendations, based on national guidelines and local susceptibility, to assist with antibiotic selection for common clinical conditions?
• Is there a formal procedure for all clinicians to review the appropriateness of all antibiotics 48 hours after the initial orders (eg, antibiotic time-out)?
• Do specified antibiotic agents need to be approved by a physician or pharmacist prior to dispensing (ie, pre-authorization) at my facility?

As an individual healthcare provider, you can actively participate in antibiotic stewardship by rethinking a standard approach to antibiotic prescribing, such as defaulting to a go-to or standby antibiotic. Use antibiotics prudently. Get cultures before starting antibiotics; start the right drug promptly at the right dose for the right duration; reassess the antibiotic selection within 48 hours based on tests and patient exam; document the dose, duration and indication for every antibiotic prescription for every patient; stay up to date on antibiotic resistance patterns in your healthcare facility; and follow hand hygiene and other infection control measures with every patient.

Summary and Conclusions

Infections due to CRE pose a significant healthcare burden. Serious infections, such as bacteremia, are associated with mortality rates as high as 50%. This may be due not only to delays in time to appropriate antibiotic therapy, but also to the limited number of effective therapies in our current antibiotic arsenal. While studies in the last 10 years have identified combination therapy as the "optimal" approach with traditional agents, these regimens typically contain last-line and frequently toxic medications. Additionally, many of these studies are retrospective and observational, limiting our ability to draw definitive conclusions about the best possible treatment approach. Antibiotic development initiatives over the last several years have introduced new therapies with novel mechanisms that are beginning to show promise in the treatment of CRE. Based on the limited available data, several of these therapies appear to be effective and relatively safe treatment options for invasive CRE infections.