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Infectious Diseases Society of America Antimicrobial Resistant Treatment Guidance: Gram- Negative Bacterial Infections A Focus on Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), - Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR- P. aeruginosa) Guideline Summary by Kendra Suder, PharmD Candidate General Recommendations  Considerations for choosing empiric therapy: o Local susceptibility patterns/ antibiogram o Patient’s previous organisms isolated & susceptibility data in the last 6 months o exposure in the last 30 days  What if a patient was empirically placed on an antibiotic regimen that is now considered inactive against the organism based on susceptibility data? o If an inactive agent was started empirically for cystitis and patient improves, no change in antibiotic or extension of therapy is necessary o However, for other types of infections, guidelines recommend a change to an active regimen for a full treatment course (dated from the start of active therapy) Extended-Spectrum β-Lactamase-Producing Enterobacterales (ESBL-E)  Extended-spectrum β-lactamase o Enzymes that inactivate most , , and o Most commonly produced by Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis (guideline recommendations refer to ESBL-E infections caused by these organisms) o Most common type in the US is the CTX-M, especially CTX-M-15  In institutions that do not perform ESBL testing, a lack of susceptibility to (MIC >2 mcg/mL) can indicate ESBL production Recommended to Treat ESBL-E Infections Source of Infection Treatment Rationale Cystitis -Nitrofurantoin  Fluoroquinolones and : not preferred due -Trimethoprim/ to toxicities & broad spectrum of activity (reserve for sulfamethoxazole more severe/ future infections) Alternatives:  /clavulanate has higher clinical failure rate -Amoxicillin/ clavulanate compared to ciprofloxacin (possibly due to vaginal -Single-dose colonization) aminoglycosides  Aminoglycosides: lack of trial data - (E. coli only)  Fosfomycin is only for E. coli cystitis since the fosA -Ciprofloxacin gene (found in K. pneumoniae and others) can cause -Levofloxacin hydrolysis and make the drug ineffective. Also higher - failure rate vs. nitrofurantoin for uncomplicated cystitis -  Doxycycline: poor urinary excretion -/ cilastatin Pyelonephritis or -Ertapenem  All of these agents achieve high concentrations in the complicated UTI* -Meropenem urine -Imipenem/ cilastatin  Limit carbapenem exposure. If the patient is started on -Ciprofloxacin a carbapenem and the organism is susceptible to -Levofloxacin another narrower/ less toxic agent, switch to that Trimethoprim/ agent sulfamethoxazole  Fosfomycin and nitrofurantoin should not be used for pyelonephritis because they do not achieve high concentrations in the renal parenchyma 2

Source of Infection Treatment Rationale Other infection -Meropenem  For ESBL-E bloodstream infections, there is a reduced (not in urinary -Imipenem/ cilastatin 30-day mortality rate for carbapenems vs. / tract) -Ertapenem (thought to apply to other sites of Oral step-down therapy to infection) ciprofloxacin, levofloxacin,  Oral step-down therapy if patient is afebrile, or trimethoprim/ hemodynamically stable, and source-controlled sulfamethoxazole can be  For bloodstream infections, avoid de-escalation to considered (if susceptible) nitrofurantoin, fosfomycin, doxycycline, or amoxicillin/ clavulanate o These achieve poor serum concentrations *occurring in association with a structural or functional abnormality, or any UTI in a male patient Drugs to AVOID in the Treatment of ESBL-E Infections  Avoid even if susceptible Drug to Avoid Rationale Piperacillin/  A study showed inferior results for ESBL-E bloodstream infections treated with tazobactam piperacillin/tazobactam vs. carbapenems. Organisms may have increased expression of the ESBL enzyme, or there may be multiple β-lactamases  MIC testing may be inaccurate when ESBL enzymes are present  Studies have demonstrated either similar outcomes or worse outcomes for cefepime vs. carbapenems for the treatment of ESBL-E infections  MIC testing may be inaccurate when ESBL enzymes are present Other Recommendations from the Guidelines  What is the preferred treatment for infections caused by E. coli, K. pneumoniae, K. oxytoca, or P. mirabilis if the organism is not susceptible to ceftriaxone and confirmatory ESBL testing is negative? o Use susceptibility testing results to guide treatment  What should be used to treat bloodstream infections caused be E. coli, K. pneumoniae, K. oxytoca, or P. mirabilis if the organism is not susceptible to ceftriaxone and the blaCTX-M gene is not detected? o The preferred treatment is a carbapenem (at least for initial therapy) o Other ESBL genes (e.g., blaSHV, blaTEM) could still be present

Carbapenem-Resistant Enterobacterales (CRE)  Definition: members of the Enterobacterales order resistant to at least one carbapenem antibiotic or producing a carbapenemase enzyme  A CRE can be resistant to one or more carbapenems  Resistance mechanisms: carbapenemase-producing and non-carbapenemase-producing  The most common carbapenemases in the United States are Klebsiella pneumoniae carbapenemases (KPCs), which can be produced by any Enterobacterales  Other common carbapenemases: New Delhi metallo-β-lactamases (NDMs), Verona integron-encoded metallo-β- lactamases (VIMs), imipenem-hydrolyzing metallo-β-lactamases (IMPs), and oxacillinase (e.g., OXA-48-like) carbapenemases Recommended Antibiotics to Treat CRE Infections Source of Preferred Alternatives Rationale Infection Treatment Cystitis -Ciprofloxacin -/  All of the preferred agents achieve high -Levofloxacin concentration in the urine -Trimethoprim/ -Meropenem/  CRE isolates tend to be susceptible to amikacin and sulfamethoxazole plazomicin vs. other aminoglycosides, and isolates -Nitrofurantoin resistant to amikacin may still be susceptible to plazomicin 3

Source of Preferred Alternatives Rationale Infection Treatment -Single dose of an -Imipenem/  Increased mortality with does not seem aminoglycoside cilastatin/ to apply to UTIs -Meropenem* relebactam  is very nephrotoxic and its use should be (standard- -Cefiderocol reserved infusion) -Colistin (if  B: not recommended due to non-renal other clearance alternatives  Fosfomycin is only for E. coli cystitis. Also higher are not failure rate vs. nitrofurantoin for uncomplicated available) cystitis Pyelonephritis -Ceftazidime/ Once-daily  Increased mortality with cefiderocol does not seem or complicated avibactam amino- to apply to UTIs UTI -Meropenem/ glycosides  Fosfomycin and nitrofurantoin should not be used vaborbactam for pyelonephritis -Imipenem/ cilastatin/ relebactam -Cefiderocol -Meropenem* (extended- infusion) Other infection Meropenem* Ceftazidime/  Most infections caused by CRE resistant to (not in urinary (extended- avibactam ertapenem but susceptible to meropenem are tract) that is infusion) caused by organisms that do not produce resistant to carbapenemases ertapenem,  Avoid meropenem if carbapenemase testing is susceptible to positive, even if susceptible meropenem,  Prefer to reserve ceftazidime/ avibactam for when and carba- the organism is resistant to all carbapenems penemase  Meropenem/ vaborbactam or imipenem/ cilastatin/ negative** relebactam do not offer significant benefits vs. extended-infusion meropenem Other infection -Ceftazidime/ -Cefiderocol  Most of these types of infections are caused by (not in urinary avibactam -Tigecycline, organisms that produce KPC-carbapenemases or tract) that is -Meropenem/ eravacycline no carbapenemases at all resistant to vaborbactam (IAIs)  The preferred agents have reduced toxicity vs. ertapenem and -Imipenem/ polymyxin-based regimens meropenem, cilastatin/  Higher mortality with cefiderocol, especially with and carba- relebactam pneumonia and bloodstream infections, so penemase recommend reserving this for when preferred negative** agents are unavailable  Tigecycline and eravacycline are generally limited to the treatment of intra-abdominal infections (IAIs) due to poor concentrations in serum & urine * only if ertapenem resistant, meropenem susceptible, AND carbapenemase testing results are either not available or negative. Avoid meropenem if carbapenemase testing is positive, even if susceptible. **or, carbapenemase testing is not available

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Recommendations based on Specific Carbapenemase Enzyme Types Enzyme Preferred Alternative Rationale Identified Treatment KPC -Ceftazidime/ -Cefiderocol  KPC is most common enzyme type in United States, so if the (or carba- avibactam -Tigecycline, carbapenemase enzyme type is unknown, assume it is a penemase- -Meropenem/ eravacycline KPC positive but vaborbactam (IAIs)  Lack of data on the preferred agents makes it difficult to exact -Imipenem/ recommend one over the others enzyme type cilastatin/  See the previous table for information about cefiderocol, unknown) relebactam tigecycline, and eravacycline Metallo-β- -Ceftazidime/ -Tigecycline,  If patient has a CRE infection of unknown type but has lactamase avibactam + eravacycline recently traveled from an area where metallo-β-lactamases (i.e., NDM, aztreonam (IAIs) are endemic (e.g., Middle East, South Asia, Mediterranean), VIM, or IMP) -Cefiderocol treat as a Metallo-β-lactamase organism infection  The preferred agents also provide activity against bacteria producing KPCs or OXA-48-like enzymes. OXA-48-like Ceftazidime/ -Cefiderocol  Meropenem/ vaborbactam and imipenem/ cilastatin/ avibactam -Tigecycline, relebactam have limited to no activity against CRE producing eravacycline OXA-48-like enzymes (IAIs) Drugs to AVOID in the Treatment of CRE Infections Drugs to Avoid Rationale Poymyxin B, Colistin  Mortality and excess nephrotoxicity with polymyxin-based regimens  also has non-renal clearance  Avoid these agents when treating CRE infections o Exception: Colistin as a last resort for uncomplicated CRE cystitis Combination therapy  Empirically, combination therapy is often used (i.e., β-lactam + an  However, once susceptibility to the β-lactam agent has been demonstrated, the aminoglycoside, second agent should be discontinued fluoroquinolone, or  Studies show that the continued use of a second agent provides no added benefit polymyxin) and only increases the risk of adverse events

Difficult-to-Treat Resistance (DTR) Pseudomonas Aeruginosa  Definition of multidrug-resistant P. aeruginosa: o Not susceptible to at least one antibiotic in at least 3 classes for which P. aeruginosa susceptibility is generally expected: penicillins, cephalosporins, fluoroquinolones, aminoglycosides, and carbapenems.  Definition of DTR- P. aeruginosa: o P. aeruginosa exhibiting non-susceptibility to all of the following: piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem-cilastatin, ciprofloxacin, and levofloxacin. Recommended Antibiotics for DTR-Pseudomonas Infections Source of Preferred Alternatives Rationale Infection Treatment Cystitis -Ceftolozane/ Colistin  Increased mortality with cefiderocol does not seem to tazobactam apply to UTIs -Ceftazidime/  Plazomicin is unlikely to be beneficial if the organism avibactam shows resistance to all other aminoglycosides -Imipenem/  Caution: nephrotoxicity with colistin relebactam  P. aeruginosa intrinsically has the fosA gene= high -Cefiderocol clinical failure rate 5

Source of Preferred Alternatives Rationale Infection Treatment -Single dose of an aminoglycoside Pyelonephritis -Ceftolozane/ Once-daily  Increased mortality with cefiderocol does not seem to or tazobactam amino- apply to UTIs complicated -Ceftazidime/ glycosides  Plazomicin is unlikely to be beneficial if the organism UTI avibactam shows resistance to all other aminoglycosides -Imipenem/  Avoid fosfomycin for pyelonephritis cilastatin/ relebactam -Cefiderocol Other -Ceftolozane/ -Cefiderocol  More P. aeruginosa isolates tend to be susceptible to infection (not tazobactam -Amino- ceftolozane/ tazobactam vs. similar agents in urinary tract) -Ceftazidime/ glycoside o Ceftolozane alone has activity against P. avibactam monotherapy: aeruginosa -Imipenem/ limited to  Ceftazidime & imipenem are both inactive against P. cilastatin/ uncomplicated aeruginosa when used alone relebactam bloodstream  Cross-resistance between ceftolozane/ tazobactam & infections with ceftazidime/ avibactam complete  Higher mortality with cefiderocol, especially with source control* pneumonia and bloodstream infections, so recommend reserving this for when preferred agents are unavailable  Aminoglycosides ONLY for uncomplicated, source- controlled bloodstream infections when no alternatives available o Plazomicin is unlikely to be beneficial if the organism shows resistance to all other aminoglycosides *bloodstream infection due to a urinary source or a catheter-related bloodstream infection with removal of the infected vascular catheter Recommendations Regarding Combination Therapy  If the organism is not susceptible to a preferred β-lactam agent, combination therapy can be considered as a last resort Susceptibility Preferred Treatment Rationale Aminoglycoside- Aminoglycoside + (ceftolozane/  Use the β-lactam-β-lactamase inhibitor agent for susceptible tazobactam, ceftazidime/ which the MIC is closest to the breakpoint avibactam, or imipenem/  Unknown whether this is more effective than cilastatin/ relebactam) cefiderocol Aminoglycoside- Polymyxin B + (ceftolozane/  Use the β-lactam-β-lactamase inhibitor agent for resistant tazobactam, ceftazidime/ which the MIC is closest to the breakpoint avibactam, or imipenem/  Polymyxin B has more reliable plasma cilastatin/ relebactam) concentrations and is less nephrotoxic vs. colistin Reference: Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America guidance on the treatment of antimicrobial resistant gram-negative infections. A focus on extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR- P. aeruginosa). IDSA. Epub 8 Sep 2020. Available from: https://www.idsociety.org/practice-guideline/amr-guidance/