Resistant Gram-Negative Bacterial Infections

(full update June 2024)

Resistance among gram-negative bacteria is a global health threat.1 Extended-spectrum beta-lactamase (ESBL)-producing organisms are susceptible to a limited number of antibiotics, and are classified as a serious threat by the CDC.2 Carbapenem-resistant Enterobacterales (CRE; The “E” now stands for the order; previously the “E” stood for the family [Enterobacteriaceae].33) are susceptible to very few antibiotics, and are considered an urgent threat by the CDC.2 Risk factors for resistant gram-negative infections can be used to identify patients in whom empiric broad spectrum antibiotic treatment is warranted.33 Treatment failures and/or final culture and sensitivity results can identify CRE, and treatment can be escalated appropriately. It is recommended that infectious diseases specialists be consulted for the management of patients with resistant gram-negative bacterial infections.33 The chart below answers clinical questions about managing resistant gram-negative bacterial infections.

Clinical Question

Suggested Approach/Pertinent Information

How common are resistant gram-negative infections in the United States?

Infections from ESBL-producing organisms were identified in almost 200,000 hospitalized patients and lead to approximately 9,100 deaths in 2017.2

  • Between 5% to 20% of Escherichia coli and 3% to 35% Klebsiella pneumoniae in the US produce ESBL, and these rates have been steadily increasing.5,31,32

CRE organisms cause about 9,300 infections, leading to about 900 deaths each year.43 In 2021, 2.7% of Enterobacterales isolates from healthcare-associated infections were identified as CRE.3

The CDC classifies carbapenem-resistant Acinetobacter baumannii (CRAB) as an urgent threat. In 2021, 39.5% of A. baumannii isolates were carbapenem-resistant.56

What are risk factors for resistant gram-negative colonization or infection?

Risk factors for resistant gram-negative infections are similar to those for other nosocomial infections, including:6,7

  • severe illness; arterial or central venous catheters; indwelling urinary catheters; or mechanical ventilation

Additional risk factors specific to ESBL-related infections include:7

  • length of hospitalization and/or intensive care unit (ICU) stay
  • residence at a long-term care facility
  • emergency abdominal surgery or gut colonization
  • use of gastrostomy or jejunostomy tube
  • hemodialysis
  • prior use of any antibiotic

Additional risk factors specific to CRE-related infections include:10,11

  • antibiotic use within previous three months
  • use of third- or fourth-generation cephalosporins and/or carbapenems
  • trauma
  • diabetes
  • malignancy
  • organ transplantation

Which organisms are most likely to produce ESBL?

Only gram-negative organisms are capable of producing ESBL.

Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli are the most common organisms that produce ESBL.7

Other gram-negative organisms that may produce ESBL include: Acinetobacter, Burkholderia, Citrobacter, Enterobacter, Morganella, Proteus, Pseudomonas, Salmonella, Serratia, and Shigella species.7-9

Which organisms are most likely to be carbapenem resistant in the United States?

Klebsiella pneumonia, Klebsiella oxytoca, and Escherichia coli are the most common CRE.12

Carbapenem-resistant infections have also been caused by Acinetobacter baumannii, Enterobacter cloacae, and Pseudomonas aeruginosa.12-15

The most commonly reported carbapenemase is Klebsiella pneumoniae carbapenemase (KPC).3,33 This carbapenemase is not limited to Klebsiella pneumoniae isolates.33

Other carbapenemase enzymes include New Delhi MBL (NDM), Verona Integron-Encoded MBL (VIM), Oxacillinase-48-type (OXA-48), and Imipenemase MBL (IMP). These carbapenemase enzymes are more common outside the US, however, they are increasingly reported in the US and are no longer only associated with exposure to healthcare in countries where they are more prevalent.3

What are the mechanisms of resistance among gram-negative organisms?

Entry of antibiotics is limited due to decreased permeability of the bacterial outer membrane.40

Genetic mutations confer resistance through changes to drug binding sites, or by encoding for efflux pumps or loss of porin channels to effectively evade antibiotics.7,40

Bacteria produce enzymes that hydrolyze the beta-lactam ring of beta-lactam antibiotics, or cleave other antibiotics, rendering them ineffective.7,40

  • ESBL-producing organisms inactivate penicillins, cephalosporins, and aztreonam; and may be co-resistant to fluoroquinolones and aminoglycosides.7,9
  • CRE are resistant to carbapenems and co-resistant to fluoroquinolones, as well as some aminoglycosides.15,16

Which classes of antibiotics remain active against resistant gram-negative organisms?

ESBL-producing organisms usually maintain susceptibility to:4,7,14,17,18,23,33

  • carbapenems (e.g., meropenem, imipenem/cilastatin, ertapenem); preferred for severe or invasive ESBL infections.
  • ceftazidime/avibactam (however, preferentially reserved for organisms with carbapenem resistance)
  • high-dose cefepime (Use is controversial. For more details, see row titled, Are beta-lactam antibiotics ever appropriate for ESBL-related infections?)
  • high-dose, extended infusion piperacillin/tazobactam (Use is controversial. For more details, see row titled, Are beta-lactam antibiotics ever appropriate for ESBL-related infections?)

CRE-related infections may be susceptible to:12,19,20,23,40

  • ceftazidime/avibactam
  • meropenem/vaborbactam
  • imipenem/cilastatin/relebactam
  • cefiderocol
  • colistin or Polymyxin B
  • aminoglycosides (including the newest aminoglycoside, plazomicin)
  • high-dose tigecycline
  • high-dose, extended infusion meropenem

Are beta-lactam antibiotics ever appropriate for ESBL-related infections?

Use of piperacillin/tazobactam in ESBL-related infections is controversial.7,24,25

  • Has been used successfully for ESBL-producing E. coli UTIs, but treatment failures were more common with urosepsis and/or bacteremia, especially with MICs >8 mcg/mL.25
  • In a large multicenter study, outcomes were not statistically significantly different when beta-lactam/beta-lactamase inhibitor combos (predominantly piperacillin/tazobactam) were compared to carbapenems (mostly meropenem) for ESBL-related bloodstream infections.44
  • Piperacillin/tazobactam was not able to demonstrate non-inferiority for 30-day mortality compared to meropenem in patients with E. coli or K. pneumoniae ceftriaxone-resistant, bloodstream infections [Evidence Level A-1].54
  • High dose (4.5 grams IV q6h), extended infusion (over 3 to 4 hours) improves treatment success rates.30,45

Use of cefepime in ESBL-related infections is similarly controversial.26-28

  • Cefepime MIC testing results may not be accurate or reproducible when ESBL enzymes are present.33
  • Treatment success has been reported for pneumonia using cefepime 2 grams IV q8h.26
  • In bacteremia, patients treated with cefepime had worse outcomes, even when MIC was £8 mcg/mL.27

The Infectious Diseases Society of America (IDSA) recommends to avoid use of piperacillin/tazobactam or cefepime in non-urinary tract infections caused by ESBL, even if they appear susceptible based on culture and sensitivity results.33 See the exception to this in the row below “How should ESBL- and CRE-related lower UTIs (cystitis) be treated.”

How should ESBL- and CRE-related uncomplicated lower UTIs (cystitis) be treated?

Uncomplicated lower UTIs (cystitis) may be treated with nitrofurantoin, PO fosfomycin (only when E. coli is the organism, due to resistance with other organisms that can hydrolyze fosfomycin), aminoglycosides, fluoroquinolones, sulfamethoxazole/trimethoprim or carbapenems when C&S shows susceptibility.7,21,22,33 Urinary concentrations of these antibiotics are higher than organism MIC, effectively overcoming resistance. See our chart, Urinary Tract Infections, for more on treating urinary tract infections, including use of nitrofurantoin in patients with kidney impairment.

  • Generally, give preference to nitrofurantoin or sulfamethoxazole/trimethoprim.33
  • In addition, for CRE-related uncomplicated cystitis, ciprofloxacin or levofloxacin are also considered preferred antibiotics.33 Alternatives include single dose aminoglycoside, PO fosfomycin (only if E. coli), colistin, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, or cefiderocol.33
  • If using an aminoglycoside, note that CRE isolates are more likely to be susceptible to amikacin and plazomicin, compared to other aminoglycosides.33
  • Only use meropenem for a CRE-related cystitis if CRE is resistant to ertapenem, susceptible to meropenem, and carbapenemase testing results are negative or not available.

If either cefepime or piperacillin/tazobactam is as started as empiric therapy for cystitis, the patient is clinically improving, and it is later determined the cystitis is caused by ESBL-Enterobacterales, it is ok to continue therapy.33

What regimens are preferred to treat ESBL-related infections other than uncomplicated cystitis?

Complicated UTIs and pyelonephritis: see our chart, Urinary Tract Infections, for treatment.

  • However, note that many labs do not perform ESBL testing. Instead, ceftriaxone MICs ≥2 mcg/mL are assumed to indicate ESBL production.33 Avoid ceftriaxone in these cases.33
  • The preferred treatment for ESBL-related complicated UTIs and pyelonephritis are a urinary fluoroquinolone (e.g., ciprofloxacin, levofloxacin), or sulfamethoxazole/trimethoprim.33 If resistance or toxicities prevent the use of fluoroquinolones or sulfamethoxazole/trimethoprim, ertapenem, meropenem, and imipenem-cilastatin are preferred.33 A full course of an aminoglycoside can be considered as an alternative.33

Infections outside of the urinary tract may be treated with meropenem, imipenem/cilastatin, or ertapenem.33

  • Though data are limited, consider oral step-down therapy for ESBL-related infections (based on data for bloodstream infections) under the following conditions:33
    • documented susceptibility to the oral agent
    • patients are hemodynamically stable and without fever
    • source control of infection
    • no suspected issues with gastrointestinal tract absorption

Options for oral step-down therapy include sulfamethoxazole/trimethoprim, levofloxacin, and ciprofloxacin.33

What regimens are preferred to treat CRE-related infections other than uncomplicated cystitis?a

Complicated UTIs and pyelonephritis:

  • Consider ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/relebactam, or cefiderocol if CRE is resistant to ertapenem and meropenem.
  • Consider extended-infusion meropenem for CRE resistant to ertapenem, but susceptible to meropenem if carbapenemase testing is negative or not available.

Infections outside of the urinary tract: Monotherapy with ceftazidime/avibactam, meropenem/vaborbactam, or imipenem/cilastatin/relebactam may be an option.12,23,24,33,46-52 Choose therapy based on availability of carbapenemase testing and susceptibilities:

  • Consider extended-infusion meropenem, if resistant to ertapenem, susceptible to meropenem, and carbapenemase testing is negative or not available.33
  • Consider ceftazidime/avibactam, meropenem/vaborbactam, or imipenem/cilastatin/relebactam:33
    • if resistant to meropenem and ertapenem and carbapenemase testing is negative or not available.
    • if KPC is identified or carbapenemase testing is positive, but the carbapenemase identify is unknown.
  • Consider ceftazidime/avibactam PLUS aztreonam (using commercially available ceftazidime/avibactam) if MBL-producing carbapenemase (i.e., NDM, VIM, IMP) is identified.33 Use resulted in clinical cure in several patients with MBL-producing CRE-related bacteremia.23,33,34 There is an aztreonam/avibactam drug in the pipeline (approved in the European Union in 2024).65 More data are needed to know if the new drug is effective against MBL-producing CRE infections.
  • Consider ceftazidime/avibactam if OXA-48-like carbapenemase is identified.33

Ceftazidime/avibactam has been used as mono- and combination therapy.12,23,34,46,50,51

  • Provides similar efficacy to meropenem when combined with metronidazole for intra-abdominal infections.53

Meropenem/vaborbactam has been studied as monotherapy for treatment of suspected or documented CRE infections in the bloodstream, lungs, gastrointestinal tract, and urine.35

Imipenem/cilastatin/relebactam has been studied as monotherapy for treatment of documented imipenem-nonsusceptible bacterial infections (i.e., hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection). Note that the primary pathogen identified in more than 75% of the patients in the study was Pseudomonas aeruginosa.57

Combination therapy isn’t recommended due to the availability of newer agents active against CRE. If older regimens are needed, combine meds based on the site of the infection for KPC-producing Klebsiella pneumoniae:12

  • bloodstream: carbapenem + colistin or polymyxin B (+/- tigecycline OR aminoglycoside OR rifampin)
  • pulmonary: meropenem + colistin or polymyxin B (+/- tigecycline OR aminoglycoside OR rifampin)
  • gastrointestinal tract: carbapenem + colistin or polymyxin B + tigecycline +/- rifampin

How do the newer antibiotics compare to traditional regimens for CRE-related infections?

Preliminary evidence suggests improved efficacy, safety, and survival outcomes with ceftazidime/avibactam-, meropenem/vaborbactam-, imipenem/cilastatin/relebactam-, plazomicin-, or cefiderocol-containing regimens versus traditional antibiotic combinations, such as one that includes a polymyxin.35,47-49,51,52,57,59

  • ceftazidime/avibactam
    • Ceftazidime/avibactam-containing regimens (as monotherapy or with gentamicin) improved treatment success and survival in patients with KPC-producing CRE bacteremia vs other treatments [Evidence Level B-3].51 Risk of acute kidney injury was significantly lower with ceftazidime/avibactam-containing regimens than with comparator treatments.51
    • Ceftazidime/avibactam significantly reduced 30-day all-cause mortality in patients with CRE bacteremia, pneumonia, or wound infections vs colistin-containing regimens [Evidence Level B-3].52
    • When used as salvage therapy for patients with KPC-producing CRE pneumonia, ceftazidime/avibactam-containing regimens significantly reduced mortality vs other treatments [Evidence Level B-3].47
  • meropenem/vaborbactam
    • Limited data suggest better cure rates with less nephrotoxicity and possible reduced mortality of CRE infections (infections included in the study: bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia, complicated intra-abdominal infection, complicated urinary tract infection, and acute pyelonephritis) with meropenem/vaborbactam monotherapy vs other regimens [Evidence Level B-1].35 Comparator regimens included combinations of carbapenems, polymyxin B/colistin, aminoglycosides, tigecycline, or ceftazidime/avibactam monotherapy.35
  • imipenem/cilastatin/relebactam
    • Limited data suggest better cure rates with less nephrotoxicity in patients with imipenem-nonsusceptible bacterial infections (infections included in the study: hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infections) with imipenem/cilastatin/relebactam monotherapy vs colistin plus imipenem [Evidence Level B-1].57
  • plazomicin
    • Limited data suggest reduced 28-day mortality from bloodstream, lung, and complicated UTI CRE infections with plazomicin-containing regimens vs colistin-containing regimens [Evidence Level B-3].29 Incidence of kidney function decline was significantly lower with plazomicin-containing regimens vs those containing colistin.29
  • cefiderocol
    • Limited data suggest comparable efficacy of cefiderocol vs comparator antibiotics in critically ill patients with nosocomial pneumonia, sepsis, and complicated urinary tract infections with or at risk of multidrug-resistant and carbapenem-resistant gram-negative organisms [Evidence Level B-1].58,60,61

What regimens are preferred to treat Pseudomonas aeruginosa with difficult-to-treat resistance (DTR)?

Multidrug resistant P. aeruginosa: NOT susceptible to one or more antibiotic in three or more classes for which susceptibility is expected: penicillins, cephalosporins, fluoroquinolones, aminoglycosides, and carbapenems.33

DTR P. aeruginosa: NOT susceptible to ANY of the following: piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem/cilastatin, ciprofloxacin, and levofloxacin.33

Treatment options vary based on source of infection. Consider these, accounting for susceptibility and formulary:33

  • Cystitis (uncomplicated): ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, cefiderocol. A single dose of tobramycin or amikacin is an alternative option.
  • Pyelonephritis/complicated UTI: ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, cefiderocol.
  • Infections outside the urinary tract: ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam. Cefiderocol is an alternative option.

Avoid meropenem/vaborbactam with carbapenem-resistant pseudomonas infections. In vitro data suggests meropenem/vaborbactam does not provide coverage for carbapenem- or beta-lactam-resistant Pseudomonas aeruginosa.23

P. aeruginosa susceptibility may be more likely with ceftolozane/tazobactam than other agents. This may be because ceftolozane has independent activity against (DTR) P. aeruginosa (i.e., does NOT rely on an inhibitor for susceptibility), unlike ceftazidime and imipenem.33

What regimens are preferred to treat CRAB-related infections?a

The management of CRAB-related infections is particularly difficult due to:33

  • problems in differentiating between colonization and true pathogens in common infection sites (lungs, wounds)
  • carbapenem resistance in Acinetobacter baumannii usually also means resistance to most other typical antibiotics
  • very limited evidence for effective treatment regimens

Preferred regimen for CRAB usually includes ampicillin/sulbactam 9 grams IV q8h (this high-dose regimen may be effective even if C&S show Acinetobacter resistance) in combination with a second antibiotic.33

  • Choose the second agent (consider polymyxin B, minocycline, tigecycline, or cefiderocol) based on site of infection (e.g., a tetracycline for pneumonia, polymyxin for bloodstream infections, colistin for urinary tract infections).33

Sulbactam/durlobactam (Xacduro) is FDA-approved for CRAB pneumonia.36

  • Consider if ampicillin/sulbactam cannot be used.
  • Evidence suggests sulbactam/durlobactam is non-inferior to colistin (both given in combination with imipenem-cilastatin) for the primary endpoint of 28-day all-cause mortality, in the treatment of hospital-acquired or ventilator-associated pneumonia caused by CRAB.64

What dosing strategies should be used for resistant gram-negative infections, other than uncomplicated cystitis?a

Higher doses are used to overcome resistance and improve success rates for ESBL- and CRE-related infections.12

  • carbapenems
    • Meropenem is preferred due to risk of seizures with high doses of imipenem/cilastatin (Primaxin).12
      • Meropenem 2 grams IV q8h infused over 3 to 4 hours (adjust for kidney impairment).33,36
    • Meropenem/vaborbactam (Vabomere) combines a beta-lactamase inhibitor, vaborbactam, with meropenem to improve activity against KPC-producing CREs.29
      • Usual dose is 4 grams (2 grams meropenem/2 grams vaborbactam) IV q8h infused over 3 hours (adjust for kidney impairment).33
    • Ertapenem 1 gram IV q24h (adjust for kidney impairment)33,36
    • Imipenem/cilastatin 500 mg IV q6h over 3 hours33
    • Imipenem/cilastatin/relebactam (Recarbrio) combines a beta-lactamase inhibitor, relebactam, with imipenem/cilastatin to improve activity against KPC-producing CREs.29
      • Usual dose is 1.25 grams (imipenem 500 mg/cilastatin 500 mg/relebactam 250 mg) IV q6h infused over
        30 minutes (adjust for kidney impairment).33,36
    • ceftazidime/avibactam (Avycaz)
      • Usual dose is 2.5 grams (ceftazidime 2 grams/0.5 grams avibactam) IV q8h infused over 2 to 3 hours (adjust for kidney impairment).33,36
    • ceftolozane/tazobactam (Zerbaxa)
      • Usual dose is 3 grams (2 grams ceftolozane/1 gram tazobactam) IV q8h infused over 3 hours (adjust for kidney impairment).33,36
      • cefiderocol (Fetroja): usual dose is 2 grams IV q8h infused over 3 hours (adjust for kidney impairment).33,36
    • Newer tetracyclines (tigecycline, eravacycline)
      • tigecycline (Tygacil)
        • Loading dose of 200 mg, followed by 100 mg IV q12h to q24h (this high-dose regimen is recommended when using for treatment of CRE infections).12,33
      • eravacycline (Xerava): Usual dose is 1 mg/kg IV q12h.33
      • Consider as alternatives for intra-abdominal infections, skin and soft tissue infections, osteomyelitis, and respiratory infections.33 Note that eravacycline has less evidence for CRE infections compared to tigecycline.33
      • Avoid use for urinary or bloodstream infections due to low concentrations of drug in the urine and serum.12,33
      • Gastrointestinal adverse effects, especially nausea and vomiting, may be more severe with high-dose regimens, and could be dose-limiting.12,63
    • sulbactam/durlobactam (Xacduro):
      • Usual dose is 2 grams (1 gram sulbactam/1 gram durlobactam) IV q6h over 3 hours.36
    • colistin (Note: polymyxin B is preferred over colistin for systemic invasive infections due to kinetic profile.39)
      • Colistimethate (CMS) is a prodrug of colistin, and has more data supporting its use in CRE infections than does polymyxin B.12 Dose in mg is derived from colistin base activity (CBA).
      • Colistin achieves higher urinary concentrations, and is preferred for UTIs.12,39
      • Risk of nephrotoxicity is 50% to 60% with standard dosing and may be even higher with high-dose regimens.37,38
      • Note that pharmacokinetic data do not support a weight-based dosing strategy.39
      • Colistin loading dose:
        • 300 mg CBA IV x1.39
      • Colistin maintenance dosing:
        • Give 12 hours after the loading dose.12,39
        • non-dialysis patients:
          • Daily dose according to creatinine clearance, to achieve a target plasma colistin average steady-state level of 2 mg/L (divide daily dose q12h):39
            • ≥90 mL/min: 360 mg CBA
            • 80 to <90 mL/min: 340 mg CBA
            • 70 to <80 mL/min: 300 mg CBA
            • 60 to <70 mL/min: 275 mg CBA
            • 50 to <60 mL/min: 245 mg CBA
            • 40 to <50 mL/min: 220 mg CBA
            • 30 to <40 mL/min: 195 mg CBA
            • 20 to <30 mL/min: 175 mg CBA
            • 10 to <20 mL/min: 160 mg CBA
            • 5 to <10 mL/min: 145 mg CBA
            • 0 mL/min: 130 mg CBA
        • intermittent HD:
          • Supplement on dialysis days with 40 mg CBA IV for a 3-hour dialysis session, or 50 mg CBA IV for a 4-hour dialysis session, in addition to a total daily dose of 130 mg CBA IV (divided q12h) to achieve a target plasma colistin average steady-state level of 2 mg/L.39
            • CRRT:
              • 220 mg CBA IV q12h to achieve a target plasma colistin average steady-state level of
                2 mg/L                .39
          • polymyxin B
            • Structurally related to colistin, differing by only one amino acid.12
            • Achieves higher serum concentrations faster than colistin because no conversion to active drug is needed.12,39
            • Renal dosing adjustments are recommended by the manufacturer, but are not required.12,36,62
            • Polymyxin B loading dose: 2 mg to 2.5 mg/kg, using actual body weight12,39
            • Polymyxin B maintenance dose strategies:
              • Give 12 hours after the loading dose12
              • For patients with severe infections, 1.25 to 1.5 mg/kg q12h, using actual body weight. (Note that dose adjustment is not recommended for patients with kidney impairment).39
              • Organism MIC <1 mcg/mL: 2.5 mg/kg per day divided q12h12
              • Organism MIC 1 to 2 mcg/mL: 3 mg/kg per day divided q12h12
              • Organism MIC ≥4 mcg/mL: consider alternative agents12
            • aminoglycosides
              • Gentamicin or tobramycin (7 mg/kg), amikacin (15 mg/kg), or plazomicin (15 mg/kg) IV x one dose, then tailor additional doses to serum levels.12,33,55
              • High-dose therapy may increase risk for nephrotoxicity and ototoxicity development, and therapy should be limited to the shortest course possible.12
              • Gentamicin may be more effective for Klebsiella species, and amikacin and plazomicin are more active than others for CRE.12,41,42

What infection control strategies and stewardship practices can help limit the spread of resistant gram-negative infections?

Strict isolation precautions should be followed for patients with ESBL- or CRE-related infections.11

  • Use of proper handwashing, gloves, and gowns can limit patient-to-patient spread of infection.7,11

Indwelling catheters and devices can harbor infection, and should be removed as soon as possible.6,13

Excessive antibiotic use should be addressed by antimicrobial stewardship programs.11

  • Antibiotic coverage should be narrowed based on C&S results.
  • Restrict use of cefotaxime, cefpodoxime, ceftazidime, and ceftriaxone whenever possible.7
  • Restrict use of carbapenems to the Infectious Disease service.11,13
  • Avoid carbapenem or colistin monotherapy in CRE infections.12

See our toolbox, Antimicrobial Stewardship, for additional infection control strategies.
  1. Work with your lab for susceptibility testing. Some labs may only run susceptibility for newer antibiotics if specifically requested to do so.

Abbreviations: CDC = Centers for Disease Control and Prevention; CRAB = carbapenem-resistant Acinetobacter baumannii; CrCl = creatinine clearance; CRE = carbapenem-resistant Enterobacterales; CRRT = continuous renal replacement therapy; C&S = culture and sensitivity; ESBL = extended-spectrum beta-lactamase; HD = hemodialysis; ICU = intensive care unit; IV = intravenously; KPC = Klebsiella pneumoniae carbapenemase; MBL = metallo-beta-lactamase; MIC = minimum inhibitory concentration; PO = by mouth; UTI = urinary tract infection.

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*
  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*
  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. https://www.aafp.org/pubs/afp/issues/2004/0201/p548.html.]

References

  1. World Health Organization. Antimicrobial resistance. November 21, 2023. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance. (Accessed May 8, 2024).
  2. CDC. Antibiotic resistance threats in the United States. 2019. https://www.cdc.gov/antimicrobial-resistance/media/pdfs/2019-ar-threats-report-508.pdf?CDC_AAref_Val=https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. (Accessed May 23, 2024).
  3. CDC. Carbapenem-resistant Enterobacterales. https://arpsp.cdc.gov/profile/arln/cre. (Accessed May 23, 2024).
  4. Zhanel GG, Lawrence CK, Adam H, et al. Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-β-Lactamase Inhibitor Combinations. Drugs. 2018 Jan;78(1):65-98.
  5. Thaden JT, Fowler VG, Sexton DJ, Anderson DJ. Increasing Incidence of Extended-Spectrum β-Lactamase-Producing Escherichia coli in Community Hospitals throughout the Southeastern United States. Infect Control Hosp Epidemiol. 2016 Jan;37(1):49-54.
  6. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-spectrum beta-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc. 2011 Mar;86(3):250-9.
  7. Jacoby GA, Munoz-Price LS. The new beta-lactamases. N Engl J Med. 2005 Jan 27;352(4):380-91.
  8. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev. 2005 Oct;18(4):657-86.
  9. Thomson KS. Controversies about extended-spectrum and AmpC beta-lactamases. Emerg Infect Dis. 2001 Mar-Apr;7(2):333-6.
  10. Schwaber MJ, Klarfeld-Lidji S, Navon-Venezia S, et al. Predictors of carbapenem-resistant Klebsiella pneumoniae acquisition among hospitalized adults and effect of acquisition on mortality. Antimicrob Agents Chemother. 2008 Mar;52(3):1028-33.
  11. Marchaim D, Chopra T, Bhargava A, et al. Recent exposure to antimicrobials and carbapenem-resistant Enterobacteriaceae: the role of antimicrobial stewardship. Infect Control Hosp Epidemiol. 2012 Aug;33(8):817-30.
  12. Morrill HJ, Pogue JM, Kaye KS, LaPlante KL. Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections. Open Forum Infect Dis. 2015 May 5;2(2):ofv050.
  13. Gupta N, Limbago BM, Patel JB, Kallen AJ. Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention. Clin Infect Dis. 2011 Jul 1;53(1):60-7.
  14. Sader HS, Castanheira M, Flamm RK, et al. Antimicrobial activity of ceftazidime-avibactam against Gram-negative organisms collected from U.S. medical centers in 2012. Antimicrob Agents Chemother. 2014;58(3):1684-92.
  15. Fraimow HS, Tsigrelis C. Antimicrobial resistance in the intensive care unit: mechanisms, epidemiology, and management of specific resistant pathogens. Crit Care Clin. 2011 Jan;27(1):163-205.
  16. Bratu S, Tolaney P, Karumudi U, et al.Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents. J Antimicrob Chemother. 2005 Jul;56(1):128-32.
  17. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. Hospitals (2011-2012). Antimicrob Agents Chemother. 2013 Dec;57(12):6305-10.
  18. Harris PN, Tambyah PA, Paterson DL. β-lactam and β-lactamase inhibitor combinations in the treatment of extended-spectrum β-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic options? Lancet Infect Dis. 2015 Apr;15(4):475-85.
  19. Castanheira M, Farrell SE, Krause KM, et al. Contemporary diversity of β-lactamases among Enterobacteriaceae in the nine U.S. census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent β-lactamase groups. Antimicrob Agents Chemother. 2014;58(2):833-8.
  20. Metan G, Akova M. Reducing the impact of carbapenem-resistant Enterobacteriaceae on vulnerable patient groups: what can be done? Curr Opin Infect Dis. 2016 Dec;29(6):555-560.
  21. Salvatore DJ, Resman-Targoff BH. Treatment options for urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. J Acad Hosp Med 2015;7:1-4. https://medicine.missouri.edu/sites/default/files/Treatment%20Options%20for%20Urinary%20Tract%20Infections%20Caused%20by%20Extended-Spectrum%20%CE%92-Lactamase-Producing%20Esch.pdf. (Accessed May 23, 2024).
  22. Pullukcu H, Tasbakan M, Sipahi OR, et al. Fosfomycin in the treatment of extended spectrum beta-lactamase-producing Escherichia coli-related lower urinary tract infections. Int J Antimicrob Agents. 2007 Jan;29(1):62-5.
  23. Pogue JM, Bonomo RA, Kaye KS.Ceftazidime/Avibactam, Meropenem/Vaborbactam, or Both? Clinical and Formulary Considerations. Clin Infect Dis. 2019 Jan 18;68(3):519-524.
  24. Bassetti M, Peghin M, Pecori D. The management of multidrug-resistant Enterobacteriaceae. Curr Opin Infect Dis. 2016 Dec;29(6):583-594.
  25. Retamar P, López-Cerero L, Muniain MA, et al. Impact of the MIC of piperacillin-tazobactam on the outcome of patients with bacteremia due to extended-spectrum-β-lactamase-producing Escherichia coli. Antimicrob Agents Chemother. 2013 Jul;57(7):3402-4.
  26. Zanetti G, Bally F, Greub G, et al. Cefepime versus imipenem-cilastatin for treatment of nosocomial pneumonia in intensive care unit patients: a multicenter, evaluator-blind, prospective, randomized study. Antimicrob Agents Chemother. 2003 Nov;47(11):3442-7.
  27. Lee NY, Lee CC, Huang WH, et al. Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spectrum beta-lactamase-producing Enterobacteriaceae: MIC matters. Clin Infect Dis. 2013 Feb;56(4):488-95.
  28. Chopra T, Marchaim D, Veltman J, et al. Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and Escherichia coli. Antimicrob Agents Chemother. 2012 Jul;56(7):3936-42.
  29. Durante-Mangoni E, Andini R, Zampino R. Management of carbapenem-resistant Enterobacteriaceae infections. Clin Microbiol Infect. 2019 Aug;25(8):943-950.
  30. Ng TM, Khong WX, Harris PN, et al. Empiric Piperacillin-Tazobactam versus Carbapenems in the Treatment of Bacteraemia Due to Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae. PLoS One. 2016 Apr 22;11(4):e0153696.
  31. Raphael E, Glymour MM, Chambers HF. Trends in prevalence of extended-spectrum beta-lactamase-producing Escherichia coli isolated from patients with community- and healthcare-associated bacteriuria: results from 2014 to 2020 in an urban safety-net healthcare system. Antimicrob Resist Infect Control. 2021 Aug 11;10(1):118.
  32. McDanel J, Schweizer M, Crabb V, et al. Incidence of Extended-Spectrum β-Lactamase (ESBL)-Producing Escherichia coli and Klebsiella Infections in the United States: A Systematic Literature Review. Infect Control Hosp Epidemiol. 2017 Oct;38(10):1209-1215.
  33. Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. Clin Infect Dis. 2023 Jul 18:ciad428.
  34. Science News. Novel antibiotic combination therapy overcomes deadly drug-resistant bacteria. March 9, 2017. https://www.sciencedaily.com/releases/2017/03/170309171129.htm. (Accessed May 23, 2024).
  35. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial. Infect Dis Ther. 2018 Dec;7(4):439-455.
  36. Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2024. http://www.clinicalkey.com. (Accessed May 23, 2024).
  37. Vicari G, Bauer SR, Neuner EA, Lam SW. Association between colistin dose and microbiologic outcomes in patients with multidrug-resistant gram-negative bacteremia. Clin Infect Dis. 2013 Feb;56(3):398-404.
  38. Pogue JM, Lee J, Marchaim D, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis. 2011 Nov;53(9):879-84.
  39. Tsuji BT, Pogue JM, Zavascki AP, et al. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019 Jan;39(1):10-39.
  40. Suay-García B, Pérez-Gracia MT. Present and Future of Carbapenem-resistant Enterobacteriaceae (CRE) Infections. Antibiotics (Basel). 2019 Aug 19;8(3):122.
  41. Livermore DM, Mushtaq S, Warner M, et al. Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother. 2011 Jan;66(1):48-53.
  42. Castanheira M, Sader HS, Jones RN. Antimicrobial susceptibility patterns of KPC-producing or CTX-M-producing Enterobacteriaceae. Microb Drug Resist. 2010 Mar;16(1):61-5.
  43. Bradley N, Lee Y. Practical Implications of New Antibiotic Agents for the Treatment of Carbapenem-Resistant Enterobacteriaceae. Microbiol Insights. 2019 Apr 4;12:1178636119840367.
  44. Gutierrez-Gutierrez B, Perez-Galera S, Salamanca E, et al. A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae. Antimicrob Agents Chemother. 2016 Jun 20;60(7):4159-69.
  45. Patel GW, Patel N, Lat A, et al. Outcomes of extended infusion piperacillin/tazobactam for documented Gram-negative infections. Diagn Microbiol Infect Dis. 2009 Jun;64(2):236-40.
  46. Rodríguez-Baño J, Gutiérrez-Gutiérrez B, Machuca I, Pascual A. Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae. Clin Microbiol Rev. 2018 Feb 14;31(2):e00079-17.
  47. Tumbarello M, Trecarichi EM, Corona A, et al. Efficacy of Ceftazidime-Avibactam Salvage Therapy in Patients With Infections Caused by Klebsiella pneumoniae Carbapenemase-producing K. pneumoniae. Clin Infect Dis. 2019 Jan 18;68(3):355-364.
  48. Mackow NA, van Duin D. Reviewing novel treatment options for carbapenem-resistant Enterobacterales. Expert Rev Anti Infect Ther. 2024 Jan-Jun;22(1-3):71-85.
  49. McKinnell JA, Dwyer JP, Talbot GH, et al. Plazomicin for Infections Caused by Carbapenem-Resistant Enterobacteriaceae. N Engl J Med. 2019 Feb 21;380(8):791-793.
  50. King M, Heil E, Kuriakose S, et al. Multicenter Study of Outcomes with Ceftazidime-Avibactam in Patients with Carbapenem-Resistant Enterobacteriaceae Infections. Antimicrob Agents Chemother. 2017 Jun 27;61(7):e00449-17.
  51. Shields RK, Nguyen MH, Chen L, et al. Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia. Antimicrob Agents Chemother. 2017 Jul 25;61(8):e00883-17.
  52. van Duin D, Lok JJ, Earley M, et al. Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae. Clin Infect Dis. 2018 Jan 6;66(2):163-171.
  53. Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence. 2017 May 19;8(4):403-416.
  54. Harris PNA, Tambyah PA, Lye DC, et al. Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial. JAMA. 2018 Sep 11;320(10):984-994. doi: 10.1001/jama.2018.12163. Erratum in: JAMA. 2019 Jun 18;321(23):2370.
  55. Connolly L, Riddle V, Cebrik D, et al. A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis. Antimicrob Agents Chemother. 2018 Mar 27;62(4):e01989-17.
  56. CDC. Carbapenem-resistant Acinetobacter. https://arpsp.cdc.gov/profile/antibiotic-resistance/carbapenem-resistant-acinetobacter. (Accessed May 24, 2024).
  57. Motsch J, Murta de Oliveira C, Stus V, et al. RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections. Clin Infect Dis. 2020 Apr 15;70(9):1799-1808.
  58. Wu JY, Srinivas P, Pogue JM. Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms. Infect Dis Ther. 2020 Mar;9(1):17-40.
  59. Viale P, Sandrock CE, Ramirez P, et al. Treatment of critically ill patients with cefiderocol for infections caused by multidrug-resistant pathogens: review of the evidence. Ann Intensive Care. 2023 Jun 15;13(1):52.
  60. Wunderink RG, Matsunaga Y, Ariyasu M, et.al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2021 Feb;21(2):213-225.
  61. Bassetti M, Echols R, Matsunaga Y, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021 Feb;21(2):226-240.
  62. Product information for polymyxin B injection. Eugia US. E. Windsor, NJ 08520. June 2023.
  63. Huang PY, Hsu CK, Tang HJ, Lai CC. Eravacycline: a comprehensive review of in vitro activity, clinical efficacy, and real-world applications. Expert Rev Anti Infect Ther. 2024 May 8:1-12.
  64. Kaye KS, Shorr AF, Wunderink RG, et al. Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK). Lancet Infect Dis. 2023 Sep;23(9):1072-1084.
  65. Pfizer. European Commission approves Pfizer’s Emblaveo for patients with multidrug-resistant infections and limited treatment options. April 22, 2024. https://www.pfizer.com/news/press-release/press-release-detail/european-commission-approves-pfizers-emblaveor-patients. (Accessed May 25, 2024)

Cite this document as follows: Clinical Resource, Resistant Gram-Negative Infections. Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber Insights. June 2024. [400619]

Related Articles