Treatment of Antimicrobial Resistant Gram-Negative Infections

ESBL-E

• Fosfomycin continues to not be suggested for pyelonephritis and complicated urinary tract infections (cUTI); however, the uncertainty of the additive benefit of additional doses of oral fosfomycin for these indications was highlighted in light of recent clinical data.
• Amoxicillin-clavulanic acid continues to not be a preferred agent for uncomplicated ESBL-producing cystitis; however, it was acknowledged that there may be occasions where it is prescribed if resistance or toxicities preclude the use of alternative oral antibiotics and there is a preference to avoid IV antibiotics. It is advised that caution be given to patients about the potential increased risk of recurrent infection if amoxicillin-clavulanic acid is administered for this indication.
• Additional details on the mechanistic reasons why piperacillin-tazobactam is not anticipated to be effective for ESBL-E infections are provided.
• Piperacillin-tazobactam continues to not be preferred for the treatment of pyelonephritis and cUTI; however, it was acknowledged that if piperacillin-tazobactam was initiated for pyelonephritis or cUTI caused and clinical improvement occurs, the decision to continue piperacillin-tazobactam should be made with the understanding that theoretically there may be an increased risk for microbiological failure with this approach.
• A re-review of available data and newer data indicate that ceftolozane-tazobactam is likely to be effective against ESBL-E; however, it suggested that this agent be preserved for the treatment of DTR aeruginosa or polymicrobial infections (e.g., both DTR P. aeruginosa and ESBL-E).

AmpC-E

• The term “moderate to high risk” clinically significant AmpC production was replaced with “moderate risk” throughout.
• It was clarified that even without upregulation of AmpC production, basal production of AmpC β-lactamases by organisms with inducible ampC expression leads to intrinsic resistance to ampicillin, amoxicillin-clavulanate, ampicillin-sulbactam, and first- and second-generation cephalosporins.
• The suggestion that cefepime is not advised for Enterobacter cloacae, Citrobacter freundii, and Klebsiella aerogenes with cefepime MICs of 4-8 µg/mL because of concerns for an increased risk of ESBL production in this cefepime MIC range was removed in light of newer data and a rereview of existing data.

CRE

• An increase in the prevalence of CRE isolates producing metallo-beta-lactamases (MBL) in the United States (e.g., NDM, VIM, IMP) is acknowledged.
• A description of a Clinical and Laboratory Standards Institute (CLSI) endorsed method (i.e., broth disk elution method) to test for activity of the combination of ceftazidime-avibactam and aztreonam for MBL-producing Enterobacterales is discussed.
• Dosing suggestions for ceftazidime-avibactam in combination with aztreonam are updated in Table 1 and Supplemental Material. Both agents are suggested to be administered every 8 hours to facilitate simultaneous administration in clinical practice.

DTR P. aeruginosa

• For infections caused by P. aeruginosa isolates not susceptible to any carbapenem agent but susceptible to traditional β-lactams (e.g., cefepime), administration of a traditional agent as high-dose extended-infusion therapy continues to be suggested, although the panel no longer emphasizes the importance of repeating AST on the initial isolate before administration of the traditional agent given the frequency with which this susceptibility profile occurs.
• A new question (i.e., Question 4.2) has been added “Are there differences in percent activity against DTR aeruginosa across available β-lactam agents?” Differences in DTR P. aeruginosa susceptibility percentages to the newer β-lactams are described along with regional differences in enzymatic mechanisms of resistance that contribute to some of these differences.
• Once-daily tobramycin or amikacin were added as alternative treatment options for pyelonephritis or cUTI caused by DTR aeruginosa given the prolonged duration of activity of these agents in the renal cortex and the convenience of once daily dosing.

CRAB

• Sulbactam-durlobactam, in combination with meropenem or imipenem-cilastatin, was added as the preferred agent for the treatment of CRAB infections.
• High-dose ampicillin-sulbactam in combination with at least one other agent has been changed from a preferred to an alternative regimen if sulbactam-durlobactam is not available.
• The suggested dosing of high-dose ampicillin-sulbactam has been adjusted to be 27 grams of ampicillin-sulbactam (18 grams ampicillin, 9 grams sulbactam) daily.

S. maltophilia

• Questions have been adjusted to list agents in order of preference (i.e., cefiderocol [with a second agent at least initially], ceftazidime-avibactam and aztreonam, minocycline [with a second agent], TMP-SMX [with a second agent], or levofloxacin [with a second agent].
• A description of a CLSI endorsed method (i.e., broth disk elution method) to test for activity of the combination of ceftazidime-avibactam and aztreonam for maltophilia activity is discussed.
• Tigecycline has been removed as a component of combination therapy.
• Updated guidance from the CLSI advising against the testing of ceftazidime for maltophilia infections has been added.