A panel of infectious diseases specialists formulated treatment questions.
Focuses on AMR infections in the United States due to differences in epidemiology and availability of anti-infectives internationally.
Provides preferred and alternative treatment approaches with rationales, assuming the causative organism has been identified and antibiotic susceptibility results are known.
Briefly discusses empiric treatment, transitioning to oral therapy, and duration of therapy.
Suggested approaches apply to both adult and pediatric populations, but dosages are provided only for adults.
Consultation with an infectious diseases specialist is recommended for AMR infections.
The document is current as of December 31, 2023 and will be updated periodically; the most current version is available at www.idsociety.org/practice-guideline/amr-guidance/.
AMR infections are a global crisis; in 2019, approximately 1.3 million deaths were estimated to be directly attributable to AMR pathogens internationally.
In the United States, AMR pathogens caused more than 2.8 million infections and over 35,000 deaths annually from 2012 through 2017, according to the CDC.
IDSA endorses developing guidance documents for infections where data may not be very robust and continue to rapidly evolve, such as with AMR.
Guidance documents are prepared by a small team of experts and updated annually.
Many of these pathogens have been designated urgent or serious threats by the CDC.
Each pathogen causes a wide range of infections encountered in United States hospitals of all sizes, with significant morbidity and mortality.
Guidance is presented in the form of answers to clinical questions for each pathogen.
Brief descriptions of clinical trials, resistance mechanisms, and antimicrobial susceptibility testing (AST) methods are included, but the document does not provide a comprehensive review.
GRADE methodology is not employed.
Treatment suggestions are geared toward AMR infections in the United States due to differences in the molecular epidemiology of resistance and availability of specific antibiotics internationally.
This guidance document applies to both adult and pediatric populations.
Adult antibiotic dosing is provided in Table 1, assuming normal renal and hepatic function.
Pediatric dosing is not provided.
The content of this document is current as of 31 December 2023; the most current version is available at: www.idsociety.org/practice-guideline/amr-guidance.
General Management Recommendations
Suggested treatment approaches assume the causative organism has been identified and in vitro activity of antibiotics is demonstrated.
If 2 antibiotics are equally effective, considerations include safety, cost, convenience, and local formulary availability.
Complicated Urinary Tract Infection Definition
Complicated urinary tract infections (cUTI) refer to UTIs occurring in association with a structural or functional abnormality of the genitourinary tract, or any UTI in an adolescent or adult male.
cUTI should be treated with similar agents and durations as pyelonephritis.
For cUTI where the source has been controlled, it is reasonable to select antibiotic agents and treatment durations similar to those that would be selected for uncomplicated cystitis, with day 1 of therapy being the day source control occurred.
Empiric Therapy
Empiric treatment decisions are outside the scope of this guidance document.
Empiric therapy should be informed by the most likely pathogens, severity of illness, the likely source of the infection, and patient-specific factors.
Clinicians should consider:
Previous organisms identified from the patient and associated antimicrobial susceptibility testing (AST) data in the last 12 months [3]
Antibiotic exposure within the past 3 months [3]
Local AST patterns for the most likely pathogens.
Treatment decisions should be refined based on the species and the AST profile of the pathogen, as well as on the identification of any prominent β-lactamase genes that have been identified.
A distinction between bacterial colonization and infection is important.
Unnecessary antibiotic therapy will further the development of resistance and may cause harm.
Commonly selected empiric antibiotic regimens are generally not active against CRAB and S. maltophilia infections.
The decision to target treatment for CRAB and/or S. maltophilia in empiric antibiotic regimens should involve a careful risk-benefit analysis after reviewing previous culture results, clinical presentation, individual host risk factors, and antibiotic-specific adverse event profiles.
Duration of Therapy and Transitioning to Oral Therapy
The duration of therapy should not differ for infections caused by organisms with resistant phenotypes compared to infections caused by more susceptible phenotypes [4].
If AST results indicate a potentially inactive agent was initiated empirically, this may impact the duration of therapy.
For uncomplicated cystitis, if an antibiotic not active against the causative organism was administered empirically but clinical improvement occurred, it is generally not necessary to repeat a urine culture, change the antibiotic regimen, or extend the planned treatment course.
For all other infections, if AST results indicate a potentially inactive agent was initiated empirically, a change to an active regimen for a full treatment course (dated from the start of active therapy) is suggested.
Important host factors related to immune status, ability to attain source control, and general response to therapy should be considered.
Transitioning to oral therapy should be considered if:
Susceptibility to an appropriate oral agent is demonstrated
The patient is hemodynamically stable
Reasonable source control measures have occurred
Concerns about insufficient intestinal absorption are not present [6]
Table 1. Suggested Dosing of Antibiotics for the Treatment of Antimicrobial-resistant Infections in Adults
Assuming Normal Renal and Hepatic function. (See transcript for specific medication dosages)
IDSA Disclaimer
Guidance cannot always account for individual variation among patients.
Contents are assessments of current scientific and clinical information provided as an educational service.
They are not continually updated and may not reflect the most recent evidence.
They should not be considered inclusive of all available treatment approaches or as a statement of the standard of care.
They are not intended to supplant clinician judgment with respect to particular patients or special clinical situations.
Following guidance is voluntary, with the ultimate determination made by the treating clinician.
IDSA makes every effort to present accurate, complete, and reliable information but is presented “as is” without any warranty.
IDSA assumes no responsibility for any loss, damage, or claim with respect to any liabilities incurred in connection with this guidance or reliance on the information presented.
ESBLs inactivate most penicillins, cephalosporins, and aztreonam but generally remain susceptible to carbapenems.
ESBLs do not inactivate non-β-lactam agents, but organisms carrying ESBL genes often harbor additional genes or mutations expanding their resistance.
Any gram-negative organism can harbor ESBL genes, but they are most prevalent in Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis [7–9].
CTX-M enzymes, particularly CTX-M-15, are the most common ESBLs in the United States [9].
Routine EBSL testing is not performed by most clinical microbiology laboratories [15, 16].
Non-susceptibility to ceftriaxone (MICs ≥2 µg/mL) is often used as a proxy for ESBL production, although this threshold has limitations with specificity [17, 18].
ESBL-E refers to presumed or confirmed ESBL-producing E. coli, K. pneumoniae, K. oxytoca, or P. mirabilis.
Treatment suggestions assume in vitro activity of preferred and alternative antibiotics has been demonstrated.
Question 1.1: Preferred Antibiotics for Uncomplicated Cystitis Caused by ESBL-E?
Suggested approach: Nitrofurantoin and TMP-SMX are preferred; ciprofloxacin, levofloxacin, and carbapenems are alternative agents (discouraged when nitrofurantoin or TMP-SMX are active); an aminoglycoside (single dose) and oral fosfomycin (for E. coli only) are also alternative treatments.
Rationale:
Nitrofurantoin and TMP-SMX have been shown to be effective options for uncomplicated cystitis, including uncomplicated ESBL-E cystitis [5, 19–21].
Carbapenems and fluoroquinolones (ciprofloxacin or levofloxacin) are effective but discouraged when other effective options are available to preserve their activity and reduce toxicities [22, 23].
Fluoroquinolones are associated with increased risk for prolonged QT intervals, tendinitis and tendon rupture, aortic dissections, seizures, peripheral neuropathy, and Clostridioides difficile infections [24–27].
A single IV dose of an aminoglycoside is an alternative treatment option for uncomplicated ESBL-E cystitis.
Oral fosfomycin is an alternative treatment option exclusively for uncomplicated ESBL-E cystitis caused by E. coli; resistance remains rare in the United States [29, 30].
Clinical and Laboratory Standards Institute (CLSI) breakpoints are only available for E. coli for fosfomycin.
Fosfomycin is not suggested for the treatment of infections caused by K. pneumoniae and several other gram-negative organisms, which frequently carry fosA hydrolase genes that may lead to clinical failure [31, 32].
In a randomized open-label trial, a single dose of oral fosfomycin is associated with higher clinical failure than a 5-day course of nitrofurantoin [19].
Amoxicillin-clavulanic is not suggested for the treatment of ESBL-E cystitis.
A randomized clinical trial compared a 3-day regimen of amoxicillin-clavulanic acid (500 mg/125 mg twice daily) to a 3-day course of ciprofloxacin (250 mg twice daily) for 370 women with uncomplicated E. coli cystitis [22].
The panel suggests avoiding doxycycline for the treatment of ESBL-E uncomplicated cystitis.
Published nearly 50 years ago, both of these studies, however, primarily focused on P. aeruginosa, an organism not susceptible to oral tetracyclines, questioning the impact that antibiotic therapy had on clinical cure.
Question 1.2: Preferred Antibiotics for Pyelonephritis or cUTI Caused by ESBL-E?
Suggested approach: TMP-SMX, ciprofloxacin, or levofloxacin are preferred; ertapenem, meropenem, and imipenem-cilastatin are preferred when resistance or toxicities preclude the use of TMP-SMX or fluoroquinolones; aminoglycosides are alternative options.
Rationale:
TMP-SMX, ciprofloxacin, and levofloxacin are preferred based on their ability to achieve adequate and sustained concentrations in the urine, clinical trial results, and clinical experience [40–42].
Carbapenems are also preferred agents when resistance or toxicities prevent the use of TMP-SMX or fluoroquinolones, or early in the treatment course if a patient is critically ill.
Clinical relapse occurred in 2% vs 7% and increases in serum creatinine levels of ≥0.5 mg above baseline occurred in 7% vs 4% of patients in the plazomicin and meropenem groups, respectively [45].
Higher percentages of Enterobacterales, clinical isolates are susceptible to plazomicin compared to other aminoglycosides [46].
Other aminoglycosides are likely equally effective for the treatment of ESBL-E pyelonephritis or cUTI if susceptibility is demonstrated [45, 47, 48].
Nitrofurantoin does not achieve adequate concentrations in the renal parenchyma and is not advised for the treatment of pyelonephritis or cUTI.
Doxycycline is also not advised for the treatment of ESBL-E pyelonephritis or cUTIs due to its limited urinary excretion (Question 1.1) [39].
Question 1.3: Preferred Antibiotics for Infections Outside of the Urinary Tract Caused by ESBL-E?
Suggested approach: Meropenem, imipenem-cilastatin, or ertapenem are preferred; for critically ill patients and/or those with hypoalbuminemia, meropenem or imipenem-cilastatin are the preferred carbapenems; transitioning to oral TMP-SMX, ciprofloxacin, or levofloxacin should be considered if susceptibility is demonstrated.
Rationale:
A carbapenem is recommended as first-line treatment based primarily on data from a large clinical trial [60].
Ertapenem, in contrast to meropenem and imipenem, is highly protein bound leading to a relatively prolonged serum half-life [61].
The clinical trial that established carbapenem therapy as the treatment of choice for ESBL-E bloodstream infections randomized 391 patients with ceftriaxone non-susceptible E. coli or K. pneumoniae to piperacillin-tazobactam or meropenem [60].
Data from observational studies support the use of oral step-down therapy for Enterobacterales bloodstream infections, including those caused by AMR isolates, after appropriate clinical milestones are achieved [73, 74].
Nitrofurantoin and fosfomycin achieve poor serum concentrations.
Amoxicillin-clavulanic acid, omadacycline, and doxycycline have limited data to support their efficacy for ESBL-E bloodstream infections.
Question 1.4: Role for Piperacillin-tazobactam in the Treatment of Infections Caused by ESBL-E?
Suggested approach: If piperacillin-tazobactam was initiated empirically for uncomplicated cystitis and clinical improvement occurs, no change or extension is necessary. For ESBL-E pyelonephritis or cUTI, TMP-SMX, ciprofloxacin, levofloxacin, or carbapenems are suggested rather than piperacillin-tazobactam. Piperacillin-tazobactam is not suggested for infections outside of the urinary tract, even if susceptibility is demonstrated.
Rationale:
Piperacillin-tazobactam often demonstrates in vitro activity against ESBL-E [75].
First, piperacillin-tazobactam MIC testing may be inaccurate and/or poorly reproducible when ESBL enzymes are present, or in the presence of other β-lactamase enzymes such as OXA-1, making it unclear if an isolate that tests susceptible to this agent is reliably susceptible. [72, 76–79].
Second, preclinical data indicate that with increased bacterial inoculum which may be present in certain clinical infections (eg, abscesses), regrowth of ESBL-E isolates appears significantly more likely in the setting of piperacillin-tazobactam compared with meropenem; the clinical implications of these findings are unclear [80–82].
Question 1.5: Role for Cefepime in the Treatment of Infections Caused by ESBL-E?
Suggested approach: If cefepime was initiated empirically for uncomplicated cystitis and clinical improvement occurs, no change or extension is necessary. Avoid cefepime for pyelonephritis or cUTI. Cefepime is also not suggested for infections outside of the urinary tract, even if susceptibility is demonstrated.
Rationale:
ESBLs commonly hydrolyze cefepime [83, 106].
Furthermore, even if ESBL-producing isolates test susceptible to cefepime, cefepime MIC testing may be inaccurate and/or poorly reproducible with commercial AST methods [107].
Clinical trials designed to compare the outcomes of patients with ESBL-E bloodstream infections treated with cefepime or carbapenem have not been conducted.
Question 1.6: Role for the Cephamycins in the Treatment of Infections Caused by ESBL-E?
Suggested approach: Cephamycins are not suggested for ESBL-E infections until more clinical outcomes data using cefoxitin or cefotetan are available and optimal dosing has been defined.
Rationale:
The cephamycins are cephalosporins that are generally able to withstand hydrolysis from ESBL enzymes [114, 115].
Question 1.7: Role of Newer β-Lactam-β-Lactamase Inhibitor Combinations and Cefiderocol for the Treatment of Infections Caused by ESBL-E?
Suggested approach: Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, ceftolozane-tazobactam, and cefiderocol be preferentially reserved for treating infections caused by organisms exhibiting carbapenem resistance.
Rationale:
Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, ceftolozane-tazobactam, and cefiderocol exhibit activity against ESBL-E [127–129].
The carbapenem component of meropenem-vaborbactam and imipenem-cilastatin-relebactam provide sufficient activity against ESBL-E, even without the addition of a β-lactamase inhibitor.
Ceftolozane-tazobactam appears more potent against ESBL-E than piperacillin-tazobactam with ceftolozane MICs reducing several dilutions lower than piperacillin MICs, with the addition of tazobactam [136–141].
AmpC β-lactamases are enzymes that are produced at basal levels by a number of Enterobacterales and glucose non-fermenting gram-negative organisms; their primary function is to assist with cell wall recycling [147].
Question 2.1: Which Commonly Identified Enterobacterales Species Should Be Considered at Moderate Risk for Clinically Significant Inducible ampC Production?
Suggested approach: Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii are the most common Enterobacterales at moderate risk for clinically significant inducible AmpC production.
Rationale:
Quantifying the likelihood of ampC induction across bacterial species would be best defined by systematically identifying organisms initially susceptible to certain β-lactam agents that, on subsequent isolation (and after β-lactam exposure), become resistant, with genotyping and expression studies to confirm that the same organism was recovered and that AmpC production significantly increased.
Question 2.2: What Features Should Be Considered in Selecting Antibiotics for Infections Caused by Organisms at Moderate Risk of Clinically Significant AmpC Production Due to an Inducible ampC Gene?
Suggested approach: Several β-lactam antibiotics are at moderate risk of inducing ampC genes. Both the ability to induce ampC genes and the relative stability of the agent against hydrolysis by AmpC should inform antibiotic decision-making.
Question 2.3: What Is the Role of Cefepime for the Treatment of Infections Caused by Enterobacterales at Moderate Risk of Clinically Significant AmpC Production Due to an Inducible ampC Gene?
Suggested approach: Cefepime is suggested for the treatment of infections caused by organisms at moderate risk of significant AmpC production (ie, E. cloacae complex, K. aerogenes, and C. freundii).
Rationale:
Cefepime is an oxyimino-cephalosporin that is relatively stable against AmpC enzymes and that also has low ampC induction potential [178, 179, 181, 182].
Question 2.4: What Is the Role of Ceftriaxone for the Treatment of Infections Caused by Enterobacterales at Moderate Risk of Clinically Significant AmpC Production Due to an Inducible ampC Gene?
Suggested approach: Ceftriaxone (or cefotaxime or ceftazidime) is not suggested for the treatment of invasive infections caused by organisms at moderate risk of clinically significant AmpC production (eg, E. cloacae complex, K. aerogenes, and C. freundii). Ceftriaxone is reasonable for uncomplicated cystitis caused by these organisms when susceptibility is demonstrated.
Question 2.5: What Is the Role of Piperacillin-Tazobactam for the Treatment of Infections Caused by Enterobacterales at Moderate Risk of Clinically Significant AmpC Production Due to an Inducible ampC Gene?
Suggested approach: Piperacillin-tazobactam is not suggested for the treatment of invasive infections caused by Enterobacterales at moderate risk of clinically significant inducible AmpC production.
Question 2.6: What Is the Role of Newer β-Lactam-β-Lactamase Inhibitor Combinations and Cefiderocol for the Treatment of Infections Caused by Enterobacterales at Moderate Risk of Clinically Significant AmpC Production Due to an Inducible ampC Gene?
Suggested approach: Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol be preferentially reserved for treating infections caused by organisms exhibiting carbapenem resistance. The panel does not suggest the use of ceftolozane-tazobactam as a treatment option for AmpC-E infections.
Question 2.7: What Is the Role of Non-β-Lactam Therapy for the Treatment of Infections Caused by Enterobacterales at Moderate Risk of Clinically Significant AmpC Production Due to an Inducible ampC Gene?
Suggested approach: Nitrofurantoin and TMP-SMX are preferred treatment options for uncomplicated cystitis caused by AmpC-E. Ciprofloxacin, levofloxacin, or an aminoglycoside (as a single dose) are alternative treatment options for AmpC-E uncomplicated cystitis. TMP-SMX, ciprofloxacin, or levofloxacin are preferred treatment options for pyelonephritis or cUTIs caused by AmpC-E. For AmpC-E infections outside of the urinary tract, transitioning from cefepime to oral TMP-SMX, ciprofloxacin, or levofloxacin should be considered, if susceptibility is demonstrated.
Section 3. Carbapenem-Resistant Enterobacterales
CRE are defined as members of the Enterobacterales order resistant to at least 1 carbapenem antibiotic (ie, ertapenem, meropenem, imipenem, doripenem) or producing a carbapenemase enzyme [214].
Question 3.1: What Are Preferred Antibiotics for the Treatment of Uncomplicated Cystitis Caused by CRE?
Suggested approach: Nitrofurantoin, TMP-SMX, ciprofloxacin, or levofloxacin are preferred treatment options for uncomplicated cystitis caused by CRE, although the likelihood of susceptibility to any of these agents is low. An aminoglycoside (as a single dose), oral fosfomycin (for E. coli only), colistin, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, or cefiderocol, are alternative treatment options for uncomplicated cystitis caused by CRE.
Question 3.2: What Are Preferred Antibiotics for the Treatment of Pyelonephritis or cUTI Caused by CRE?
Suggested approach: TMP-SMX, ciprofloxacin, or levofloxacin are preferred treatment options for pyelonephritis or cUTI caused by CRE, if susceptibility is demonstrated. Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol are also preferred treatment options for pyelonephritis or cUTIs. Aminoglycosides are alternative options for the treatment of pyelonephritis or cUTI caused by CRE.
Question 3.3: What Are the Preferred Antibiotics for the Treatment for Infections Caused by CRE Outside of the Urinary Tract that are Not Carbapenemase Producing?
Suggested approach: For infections caused by Enterobacterales isolates that are NOT carbapenemase producing that exhibit susceptibility to meropenem and imipenem (ie, MICs ≤1 µg/mL) but are not susceptible to ertapenem (ie, MICs ≥1 µg/mL), the use of extended-infusion meropenem (or imipenem-cilastatin) is suggested. For infections caused by Enterobacterales isolates that are NOT carbapenemase producing and that do not exhibit susceptibility to any carbapenem, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are preferred treatment options.
Question 3.4: What Are the Preferred Antibiotics for the Treatment of Infections Outside of the Urinary Tract Caused by CRE if KPC Production is Present?
Suggested approach: Meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam are preferred treatment options for KPC-producing Enterobacterales infections. Cefiderocol is an alternative option.
Question 3.5: What Are the Preferred Antibiotics for the Treatment of Infections Outside of the Urinary Tract Caused by CRE if NDM or Other MBL Production is Present?
Suggested approach: Ceftazidime-avibactam in combination with aztreonam, or cefiderocol as monotherapy, are preferred treatment options for NDM and other MBL-producing Enterobacterales infections.
Question 3.6: What Are the Preferred Antibiotics for the Treatment of Infections Outside of the Urinary Tract Caused by CRE if OXA-48-Like Production is Present?
Suggested approach: Ceftazidime-avibactam is the preferred treatment option for OXA-48-like-producing Enterobacterales infections. Cefiderocol is an alternative treatment option.
Question 3.7: What Is the Likelihood of the Emergence of Resistance of CRE Isolates to the Newer β-Lactam Agents When Used to Treat CRE Infections?
Suggested approach: The emergence of resistance is a concern with all β-lactam agents used to treat CRE infections. Available data suggest the frequency may be highest for ceftazidime-avibactam.
Question 3.8: What Is the Role of Tetracycline Derivatives for the Treatment of Infections Caused by CRE?
Suggested approach: Although β-lactam agents remain preferred treatment options for CRE infections, tigecycline and eravacycline are alternative options when β-lactam agents are either not active or unable to be tolerated. Tetracycline derivatives are not suggested for the treatment of CRE urinary tract infections or bloodstream infections.
Question 3.9: What Is the Role of Polymyxins for the Treatment of Infections Caused by CRE?
Suggested approach: Polymyxin B and colistin are not suggested for the treatment of infections caused by CRE. Colistin is an alternative agent for uncomplicated CRE cystitis.
Question 3.10: What Is the Role of Combination Antibiotic Therapy for the Treatment of Infections Caused by CRE?
Suggested approach: Combination antibiotic therapy is not suggested for the treatment of infections caused by CRE.
Section 4. Pseudomonas Aeruginosa with Difficult-To-Treat Resistance
MDR P. aeruginosa is defined as P. aeruginosa not susceptible to at least 1 antibiotic in at least 3 antibiotic classes for which P. aeruginosa susceptibility is generally expected: penicillins, cephalosporins, fluoroquinolones, aminoglycosides, and carbapenems [381].
In this guidance document, DTR is defined as P. aeruginosa exhibiting non-susceptibility to all of the following: piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem-cilastatin, ciprofloxacin, and levofloxacin.
Question 4.1: What Are Preferred Antibiotics for the Treatment of Infections Caused by MDR P. Aeruginosa?
Suggested approach: When P. aeruginosa isolates test susceptible to both traditional non-carbapenem β-lactam agents (ie, piperacillin-tazobactam, ceftazidime, cefepime, aztreonam) and carbapenems, the former are preferred over carbapenem therapy. For infections caused by P. aeruginosa isolates not susceptible to any carbapenem agent but susceptible to traditional β-lactams, the administration of a traditional non-carbapenem β-lactam as high-dose extended-infusion therapy is suggested. For critically ill patients or those with poor source control with P. aeruginosa isolates resistant to carbapenems but susceptible to traditional β-lactams, use of newer β-lactam agents to which P. aeruginosa test susceptible is also a reasonable treatment approach.
Question 4.2: Are There Differences in Percent Activity Against DTR P. Aeruginosa Across Available β-Lactam Agents?
Suggested approach: Differences in DTR P. aeruginosa isolates susceptibility percentages to newer β-lactams exist, in part due to regional differences in enzymatic mechanisms of resistance.
Rationale:
Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol are β-lactam antibiotics which may be active against DTR P. aeruginosa clinical isolates.
The panel suggests always obtaining AST results for the four newer β-lactam agents for DTR P. aeruginosa infections to guide treatment decisions.
Summary of breakpoints and MIC for P. Aeruginosa (CLSI values):
\begin{itemize}
\item MIC ≤ 4→ Susceptible to Cefiderocol.
\item MIC ≤4/4 → Susceptible to Ceftolozane-tazobactam
\item MIC ≤8/4 → Susceptible to Ceftazidime-avibactam
\item MIC ≤2/4 → Susceptible to Imipenem-relebactam
\end{itemize}
Question 4.3: What Are Preferred Antibiotics for the Treatment of Uncomplicated Cystitis Caused by DTR P. Aeruginosa?
Suggested approach: Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol are the preferred treatment options for uncomplicated cystitis caused by DTR P. aeruginosa. Tobramycin or amikacin (as a single dose) and colistin are alternative treatment options for uncomplicated cystitis caused by DTR P. aeruginosa.
Question 4.4: What Are Preferred Antibiotics for the Treatment of Pyelonephritis or cUTI Caused by DTR P. Aeruginosa?
Suggested approach: Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol are preferred treatment options for pyelonephritis or cUTI caused by DTR P. aeruginosa. Once-daily tobramycin or amikacin are alternative agents for the treatment of DTR P. aeruginosa pyelonephritis or cUTI.
Question 4.5: What Are Preferred Antibiotics for the Treatment of Infections Outside of the Urinary Tract Caused by DTR P. Aeruginosa?
Suggested approach: Ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam are preferred options for the treatment of infections outside of the urinary tract caused by DTR P. aeruginosa. Cefiderocol is an alternative treatment option for infections outside of the urinary tract caused by DTR P. aeruginosa.
Question 4.6: What Are Preferred Antibiotics for the Treatment of DTR P. Aeruginosa that Produce Metallo-β-Lactamase Enzymes?
Suggested approach: For patients infected with DTR P. aeruginosa isolates that are MBL-producing, the preferred treatment is cefiderocol.
Question 4.7: What Is the Likelihood of the Emergence of Resistance of DTR P. Aeruginosa Isolates to the Newer β-Lactam Agents When Used to Treat DTR P. Aeruginosa Infections?
Suggested approach: The emergence of resistance is a concern with all β-lactams used to treat DTR P. aeruginosa infections. Available data suggest the frequency may be the highest for ceftolozane-tazobactam and ceftazidime-avibactam, although fewer data are available investigating this issue for imipenem-cilstatin-relebactam and cefiderocol.
Question 4.8: What Is the Role of Combination Antibiotic Therapy for the Treatment of Infections Caused by DTR P. Aeruginosa?
Suggested approach: Combination antibiotic therapy is not suggested for infections caused by DTR P. aeruginosa if susceptibility to ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, or cefiderocol has been confirmed.
Question 4.9: What Is the Role of Nebulized Antibiotics for the Treatment of Respiratory Infections Caused by DTR P. Aeruginosa?
Suggested approach: The panel does not suggest the use of nebulized antibiotics for the treatment of respiratory infections caused by DTR P. aeruginosa.
The management of CRAB infections is difficult for several reasons.
Question 5.1: What Is the General Approach for the Treatment of Infections Caused by CRAB?
Suggested approach: The use of an antibiotic regimen which includes a sulbactam-containing agent is suggested for the treatment of CRAB infections. The preferred regimen is sulbactam-durlobactam in combination with a carbapenem (ie, imipenem-cilastatin or meropenem). An alternative regimen