Antimicrobial resistance is a global crisis, and resistant pathogens cause more than 2.8 million infections and 35,000 deaths annually. Even when bacterial cultures indicate resistance, choosing the most effective antibiotic can be challenging. The Infectious Diseases Society of America published guidelines for treating infections with the most common resistant gram-negative organisms. These guidelines do not apply to empiric treatment.

For this guideline, complicated urinary tract infections (UTIs) are defined as occurring in males or females with a genitourinary tract abnormality. After removal of hardware or treatment of urinary stasis, complicated UTI can be treated as uncomplicated.

ENTEROBACTERALES

Enterobacterales are gram-negative rods that are common in the gastrointestinal tract and have several common resistance patterns. Common pathogens include Escherichia coli, Proteus, Klebsiella, Salmonella, and Shigella.

ESBL-Producing Enterobacterales

Extended-spectrum beta-lactamase (ESBL)–producing Enterobacterales have enzymes that act against most penicillins, cephalosporins, and aztreonam but are generally susceptible to carbapenems. Non–beta-lactam agents (such as fluoroquinolones and trimethoprim/sulfamethoxazole [TMP/SMX]) are not inactivated unless organisms carry additional mutations. Enterobacterales that are most likely to produce this enzyme include E. coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis. Ceftriaxone susceptibility is usually used as a proxy to identify ESBL-producing Enterobacterales.

Carbapenem-Resistant Enterobacterales

Carbapenem-resistant Enterobacterales (CREs) demonstrate resistance to meropenem or imipenem or isolate-producing carbapenemase enzymes. When susceptibility testing shows resistance to ertapenem, but not meropenem and imipenem, meropenem is recommended for mild infections.

AmpC Beta-Lactamase–Producing Enterobacterales

Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii are the most common Enterobacterales to have induced resistance through increased AmpC.

For infections caused by organisms at high likelihood of induced AmpC resistance, guidelines suggest treatment with cefepime. If cefepime resistance is documented, a carbapenem should be used. Ceftriaxone should not be used when these organisms are present because of high induction of AmpC. Medication combining beta-lactams and beta-lactamase inhibitors can be used in cases of carbapenem resistance, although combinations that include tazobactam should be avoided. Non–beta-lactam medications can be used for these infections.

Treating Infections Caused by Resistant Enterobacterales

Uncomplicated UTI. Nitrofurantoin and TMP/SMX are safe, effective, and preferred in uncomplicated cystitis. A single intravenous dose of an aminoglycoside is an alternative that appears to be effective with minimal toxicity. To prevent development of resistance, carbapenems, ciprofloxacin, and levofloxacin should be avoided in uncomplicated cystitis. Amoxicillin/clavulanate and doxycycline are not recommended because of a lack of clinical research on effectiveness. Colistin is an alternative treatment for CRE, although there is a risk of nephrotoxicity.

Complicated UTI. TMP/SMX, ciprofloxacin, and levofloxacin are proven effective for complicated UTI and pyelonephritis. A full course of aminoglycosides can be used if the dosage is adjusted through drug monitoring. Fosfomycin and nitrofurantoin should be avoided in complicated UTI because of their low concentrations in renal parenchyma.

Carbapenems can be used for ESBL-producing Enterobacterales infections if resistance or toxicity prevents use of preferred agents, and they are preferred when patients are critically ill. Piperacillin/tazobactam (Zosyn) and cefepime should not be used in complicated UTIs caused by ESBL-producing Enterobacterales.

For complicated UTI caused by CRE infections, certain beta-lactams and beta-lactamase inhibitors are recommended, including ceftazidime/avibactam (Avycaz), meropenem/vaborbactam (Vabomere), imipenem/cilastatin/relebactam (Recarbrio), or cefiderocol (Fetroja), especially if the patient has no susceptibility to TMP/SMX or fluoroquinolones.

Infections Outside the Urinary Tract. For infections caused by ESBL-producing Enterobacterales that occur outside the urinary tract, carbapenems are preferred based on a trial showing significantly lower 30-day mortality treating this type of infection in the bloodstream with meropenem than with piperacillin/tazobactam. Although meropenem, imipenem/cilastatin, and ertapenem can be used, ertapenem is not recommended for patients who are critically ill or have hypoalbuminemia. After appropriate clinical response, therapy can be stepped down to TMP/SMX, ciprofloxacin, or levofloxacin. Medications combining beta-lactams and beta-lactamase inhibitors, including ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/reeobactam, and cefiderocol, are effective against ESBL-producing Enterobacterales infections. Combinations with tazobactam should be avoided.

For infections caused by CRE that occur outside the urinary tract, medications combining beta-lactams and beta-lactamase inhibitors, such as ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/cilastatin/relebactam, are preferred if carbapenemase gene testing is negative or not available because only 35% of CRE isolates in the United States have positive carbapenemase gene testing. If metallo-beta-lactamase is present, aztreonam combined with ceftazidime/avibactam is preferred. Cefiderocol, a novel beta-lactam–altered cephalosporin, is likely effective for all CRE but should be reserved for serious infections. The tetracycline derivatives tigecycline (Tygacil) and eravacycline (Xerava) are alternate agents if beta-lactam agents cannot be used but should be avoided in bacteremia and urinary infections. Polymyxin B and colistin are not recommended. Adding an aminoglycoside, fluoroquinolone, tetracycline, or polymyxin to a beta-lactam medication offers no increased benefit.

PSEUDOMONAS AERUGINOSA WITH DIFFICULT-TO-TREAT RESISTANCE

The emergence of antimicrobial-resistant P. aeruginosa has led to new classifications. Multiple drug–resistant P. aeruginosa is a strain resistant to at least three antibiotic classes to which it is normally susceptible. P. aeruginosa with difficult-to-treat resistance isolates are resistant to nearly all common antibiotics used.

Urinary Tract Infections

For complicated or uncomplicated UTI due to difficult-to-treat resistant P. aeruginosa, treatment with ceftolozane/tazobactam (Zerbaxa), ceftazidime/avibactam, imipenem/cilastatin/relebactam, or cefiderocol is recommended. Alternately, uncomplicated UTI can be treated with a single intravenous dose of amikacin or tobramycin. Colistin is an alternative treatment, but it has a risk of nephrotoxicity.

Infections Outside the Urinary Tract

For infections caused by difficult-to-treat resistant P. aeruginosa that occur outside the urinary tract, ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol are recommended. All of these are effective against more than two-thirds of isolates. If the bacteria are susceptible to the agent used, combination therapy is not recommended. If not susceptible to any preferred agent, treating with the agent that is closest to susceptible combined with tobramycin or polymyxin B should be considered.

Ceftolozane/tazobactam and ceftazidime/avibactam appear to be the most likely effective treatments to cause resistance in subsequent infections. Meropenem/vaborbactam is not recommended because the addition of vaborbactam has minimal benefit over meropenem alone. Cefiderocol is likely to be effective against difficult-to-treat resistant P. aeruginosa and is the preferred treatment for those that produce metallo-beta-lactamase.

Nebulized antibiotics do not appear effective against pulmonary infections with difficult-to-treat resistant P. aeruginosa.

CARBAPENEM-RESISTANT ACINETOBACTER BAUMANNII

A. baumannii is common in pulmonary and wound infections. Infections involving carbapenem-resistant A. baumannii are difficult to treat and, when detected, may be pathogenic or colonizing bacteria. Although minimal data are available to direct treatment, combination treatment with high doses of ampicillin/sulbactam, including at least 6 g of sulbactam, with minocycline, tigecycline, or polymyxin B, is recommended. Cefiderocol can be used if susceptibility shows resistance to other antibiotics. High-dose, extended infusions of carbopenems, rifamycins, or nebulized antibiotics are not recommended.

STENOTROPHOMONAS MALTOPHILIA

S. maltophilia is common in pulmonary and wound infections in immunocompromised populations, especially those with hematologic malignancies. S. maltophilia may be pathogenic or represent colonization, and determining pathogenicity can be challenging. Treatment involves combining two of the following: TMP/SMX, minocycline, tigecycline, cefiderocol, or levofloxacin. In the case of intolerance or concern for significant illness, combining ceftazidime-avibactam with aztreonam is preferred.

Editor’s Note: Although this guideline is a consensus document based on expert opinion, it offers annually updated guidance for the most common resistant bacteria in an ever-changing landscape. For uncomplicated and complicated UTIs, treatment is similar for all but difficult-to-treat resistant P. aeruginosa. For these infections outside the urinary tract and those that include CRE, medications combining beta-lactams and beta-lactamase inhibitors are recommended, but potential emergence of resistance is concerning and highest for ceftolozane/tazobactam and ceftazidime/avibactam. Although this guideline did not meet the G-TRUST criteria for usefulness, the information is valuable in navigating ongoing drug resistance.

—Michael J. Arnold, MD, Assistant Medical Editor

The views expressed are those of the author and do not necessarily reflect the official policy or position of the Naval Undersea Medical Institute, Uniformed Services University of the Health Sciences, U.S. Navy, U.S. Department of Defense, or U.S. government.

Guideline source: Infectious Diseases Society of America

Published source: 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:ciad428.

Available at https://academic-oup-com.lib3.cgmh.org.tw:30443/cid/advance-article/doi/10.1093/cid/ciad428/7226183?login=false