Infectious Diseases Society of America Guidance on the Treatment of AmpC β-Lactamase–Producing Enterobacterales, Carbapenem-Resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia Infections

Pranita D. Tamma, Samuel L. Aitken, Robert A. Bonomo, et al

Clinical Infectious Diseases 2022; 74(12): 2089-2114

AMPC Β-LACTAMASE–PRODUCING ENTEROBACTERALES

Question 1: Which Enterobacterales Should Be Considered at Moderate to High Risk for Clinically Significant AmpC Production Due to an Inducible ampC Gene?

Suggested Approach

Enterobacter cloacae, Klebsiella aerogenes, and Citrobacter freundii are at moderate to high risk for clinically significant AmpC production.

Question 2: What Features Should Be Considered in Selecting Antibiotics for Infections Caused by Organisms With Moderate to High Risk of Clinically Significant AmpC Production Due to an Inducible ampC Gene?

Suggested Approach

Several β-lactam antibiotics are at relatively high risk of inducing ampC genes. Both the ability to induce ampC genes and the inability to withstand AmpC hydrolysis should inform antibiotic decision making.

Question 3: What Is the Role of Cefepime for the Treatment of Infections Caused by Enterobacterales at Moderate to High 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 to high risk of significant AmpC production (ie, E. cloacae, K. aerogenes, and C. freundii) when the cefepime MIC is 2 μg/mL or less. A carbapenem is recommended when the cefepime MIC is 4 μg/mL or greater, assuming carbapenem susceptibility is demonstrated, as ESBL co-production may be present.

Question 4: What Is the Role of Ceftriaxone for the Treatment of Infections Caused by Enterobacterales at Moderate to High Risk of Clinically Significant AmpC Production Due to an Inducible ampC Gene?

Suggested Approach

Ceftriaxone (or ceftazidime) is not recommended for the treatment of invasive infections caused by organisms at moderate to high risk of clinically significant AmpC production (e.g., E. cloacae, K. aerogenes, and C. freundii). Ceftriaxone may be a reasonable treatment option for uncomplicated cystitis caused by these organisms when susceptibility is demonstrated.

Question 5: What Is the Role of Piperacillin-Tazobactam for the Treatment of Infections Caused by Enterobacterales at Moderate to High Risk of Clinically Significant AmpC Production Due to an Inducible ampC Gene?

Suggested Approach

Piperacillin-tazobactam is not suggested for the treatment of serious infections caused by Enterobacterales at moderate to high risk of clinically significant inducible AmpC production.

Question 6: What Is the Role of Newer β-Lactam and β-Lactam–β-Lactamase Inhibitor Combinations for the Treatment of Infections Caused by Enterobacterales at Moderate to High Risk of Clinically Significant AmpC Production Due to an Inducible ampC Gene?

Suggested Approach

Despite the increased potency of newer β-lactams (ie, cefiderocol) and β-lactam–β-lactamase inhibitor combination agents (ie, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and meropenem-vaborbactam) against AmpC-E infections compared with piperacillin-tazobactam, the panel suggests that these agents be preferentially reserved for treating infections caused by organisms exhibiting carbapenem resistance.

Question 7: What Is the Role of Non–β-Lactam Therapy for the Treatment of Infections Caused by Enterobacterales at Moderate to High Risk of Clinically Significant AmpC Production Due to an Inducible ampC Gene?

Suggested Approach

TMP-SMX or fluoroquinolones can be considered for the treatment of invasive infections caused by organisms at moderate to high risk of clinically significant AmpC production, either intravenously or as oral step-down therapy, as dictated by the clinical status, likely source of infection, and ability to consume and absorb oral antibiotics, after antibiotic susceptibility is demonstrated. Nitrofurantoin, TMP-SMX, or a single intravenous dose of an aminoglycoside can be considered for uncomplicated AmpC-E cystitis.

CARBAPENEM-RESISTANT ACINETOBACTER BAUMANNII

Question 1: What Is the General Approach for the Treatment of Infections Caused by CRAB?

Suggested Approach

A single active agent may be sufficient for mild infections caused by CRAB. Of available options, the panel suggests ampicillin-sulbactam as a preferred agent. Combination therapy with at least 2 agents, with in vitro activity whenever possible, is suggested for the treatment of moderate to severe CRAB infections given the limited clinical data supporting the effectiveness of any single antibiotic agent.

Question 2: What Is the Role of Combination Antibiotic Therapy for the Treatment of Infections Caused by CRAB?

Suggested Approach

Combination therapy with at least 2 active agents, whenever possible, is suggested for the treatment of moderate to severe CRAB infections, at least until clinical improvement is observed, because of the limited clinical data supporting any single antibiotic agent. A single active agent can be considered for the treatment of mild CRAB infections.

Question 3: What Is the Role of Ampicillin-Sulbactam for the Treatment of Infections Caused by CRAB?

Suggested Approach

High-dose ampicillin-sulbactam is a preferred therapy for CRAB infections when susceptibility has been demonstrated. High-dose ampicillin-sulbactam remains a treatment consideration as a component of combination therapy even when susceptibility has not been demonstrated.

Question 4: What Is the Role of the Polymyxins for the Treatment of Infections Caused by CRAB?

Suggested Approach

Polymyxin B can be considered as monotherapy for mild CRAB infections and in combination with at least 1 other agent for the treatment of moderate to severe CRAB infections. Colistin is suggested rather than polymyxin B for urinary CRAB infections.

Question 5: What Is the Role of Tetracycline Derivatives for the Treatment of Infections Caused by CRAB?

Suggested Approach

Tetracycline derivatives can be considered as monotherapy for mild CRAB infections and in combination with at least 1 other agent for the treatment of moderate to severe CRAB infections. Of these agents, the panel prefers minocycline because of the long-standing clinical experience with this agent and the availability of CLSI susceptibility interpretive criteria. High-dose tigecycline is an alternative option. The panel does not suggest eravacycline for the treatment of CRAB infections until more clinical data are available.

Question 6: What Is the Role of Extended-Infusion Meropenem for the Treatment of Infections Caused by CRAB?

Suggested Approach

High-dose, extended-infusion meropenem can be considered as a component of combination therapy for the treatment of moderate to severe CRAB infections. The combination of a polymyxin and meropenem, without a third agent, is not suggested for the treatment of CRAB infections.

Question 7: What Is the Role of Cefiderocol Therapy for the Treatment of Infections Caused by CRAB?

Suggested Approach

Cefiderocol should be limited to the treatment of CRAB infections refractory to other antibiotics or in cases where intolerance to other agents precludes their use. When cefiderocol is used to treat CRAB infections, the panel suggests prescribing the agent as part of a combination regimen.

Question 8: What Is the Role of the Rifamycins for the Treatment of Infections Caused by CRAB?

Suggested Approach

Despite promising in vitro and animal studies (particularly for rifabutin), the panel does not favor the use of rifabutin or other rifamycins as a component of CRAB therapy, until a benefit is confirmed in clinical outcomes studies.

Question 9: What Is the Role of Nebulized Antibiotics for the Treatment of Respiratory Infections Caused by CRAB?

Suggested Approach

The panel does not suggest adding nebulized antibiotics for the treatment of respiratory infections caused by CRAB.

STENOTROPHOMONAS MALTOPHILIA

Question 1: What Is a General Approach for the Treatment of Infections Caused by S. maltophilia?

Suggested Approach

For mild infections, TMP-SMX, minocycline, tigecycline, levofloxacin, or cefiderocol monotherapy are suggested treatment options; of these, the panel suggests TMP-SMX and minocycline as the preferred agents. Ceftazidime is not suggested for the treatment of S. maltophilia regardless of the severity of infection, given the intrinsic β-lactamases produced by S. maltophilia likely to render ceftazidime ineffective. For moderate to severe infections, any of 3 approaches are suggested: (1) the use of combination therapy, with TMP-SMX and minocycline as the preferred combination; (2) the initiation of TMP-SMX monotherapy with the addition of a second agent (minocycline [preferred], tigecycline, levofloxacin, or cefiderocol) if there is a delay in clinical improvement with TMP-SMX alone; or (3) the combination of ceftazidime-avibactam and aztreonam, when intolerance or inactivity of other agents are anticipated.

Question 2: What Is the Role of Trimethoprim-Sulfamethoxazole for the Treatment of Infections Caused by S. maltophilia?

Suggested Approach

TMP-SMX monotherapy is a preferred treatment agent for mild S. maltophiliainfections. TMP-SMX either as monotherapy or, preferably, in combination with another active agent is suggested for moderate to severe S. maltophilia infections.

Question 3: What Is the Role of Tetracycline Derivatives for the Treatment of Infections Caused by S. maltophilia?

Suggested Approach

High-dose minocycline monotherapy is a treatment consideration for mild S. maltophilia infections. High-dose minocycline in combination with a second active agent, at least until clinical improvement is observed, is suggested for the treatment of moderate to severe S. maltophilia infections. Because of the slightly more favorable in vitro data with minocycline, availability of CLSI breakpoints, oral formulation, and likely improved tolerability of minocycline relative to tigecycline, the panel favors minocycline over tigecycline, although tigecycline is also a treatment option for S. maltophilia infections.

Question 4: What Is the Role of Fluoroquinolones for the Treatment of Infections Caused by S. maltophilia?

Suggested Approach

Levofloxacin monotherapy is a treatment option for mild S. maltophilia infections. The emergence of resistance during levofloxacin therapy is a concern. If administered for the treatment of moderate to severe S. maltophilia infections, levofloxacin should only be considered in combination with a second active agent (TMP-SMX, minocycline, tigecycline, cefiderocol).

Question 5: What Is the Role of Cefiderocol for the Treatment of Infections Caused by S. maltophilia?

Suggested Approach

Cefiderocol monotherapy is a treatment option for mild S. maltophilia infections, acknowledging the limited clinical data available with this agent. Cefiderocol in combination with a second active agent, at least until clinical improvement is observed, is suggested for the treatment of moderate to severe S. maltophiliainfections.

Question 6: What Is the Role of Ceftazidime-Avibactam and Aztreonam for the Treatment of Infections Caused by S. maltophilia?

Suggested Approach

The combination of ceftazidime-avibactam and aztreonam is suggested for moderate to severe S. maltophilia infections when neither TMP-SMX nor minocycline are considered viable treatment options.

Question 7: What Is the Role of Ceftazidime for the Treatment of Infections Caused by S. maltophilia?

Suggested Approach

Ceftazidime is not a suggested treatment option for S. maltophilia infections due to the presence of β-lactamase genes intrinsic to S. maltophilia that are expected to render ceftazidime inactive.