New Guidelines for Antimicrobial-Resistant Infections: Focus on Emerging Threats

IDSA publishes new guidelines for the treatment of antimicrobial-resistant infections

This document is current as of September 17, 2021 and will be updated annually. The most current versions of IDSA documents, including publication dates, are available at www.idsociety.org/practice-guideline/amr-guidance-2.0/.

The Infectious Diseases Society of America (IDSA) published new expert-reported guidelines for the treatment of antimicrobial-resistant AmpC β-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia.

The rise of antimicrobial resistance (AMR) is a global health crisis, and some experts predict it will become the next pandemic. To mitigate antimicrobial resistance, IDSA worked with 6 practicing infectious disease specialists to develop guidance with a strict approach to the treatment of these difficult infections.

Data on the treatment of AmpC-E, CRAB, and S. maltophilia are inconclusive, so experts provided "informed suggestions" rather than recommendations. Treatment suggestions assume that the causative pathogen has been identified and the in vitro activity of the antibiotics has been demonstrated.

Empirical therapy

Empirical therapy decisions should be made regarding the most likely pathogens, the severity of the patient’s illness, and the likely source of infection. Doctors should also take into account:

(1) The patient’s previous identified organisms and corresponding antibiotic susceptibility data within the past six months.

(2) Antibiotic exposures in the last 30 days.

(3) The local susceptibility patterns of the most likely pathogens.

The recommendations emphasized distinguishing bacterial colonization from infection, especially for CRAB and S. maltophilia, as unnecessary therapy can increase resistance and harm patients. Physicians are cautioned that long courses of treatment against AMR infections are not necessary.

Duration of therapy

No recommendations are provided on the duration of therapy, but clinicians are cautioned that prolonged treatment courses are not necessary against infections caused by antimicrobial-resistant pathogens per se , compared with infections caused by the same bacterial species with a more susceptible phenotype. Once antibiotic susceptibility results are available, it may be evident that inactive antibiotic therapy was initiated empirically. This may affect the duration of therapy.

For example, cystitis is usually a mild infection. If an antibiotic inactive against the causative organism was empirically administered for cystitis, but clinical improvement still occurred, the panelists agree that it is generally not necessary to repeat a urine culture, change the antibiotic regimen, or extend the course of planned treatment.

However, for all other infections, if antibiotic susceptibility data indicate that a potentially inactive agent was initiated empirically, a switch to an effective regimen is recommended for a full treatment course (dated from the start of active therapy). ).

Additionally, important host factors related to immune status, ability to achieve source control, and overall response to therapy should be considered when determining the duration of treatment for antimicrobial-resistant infections, as with the treatment of any bacterial infection.

Finally, whenever possible, gradual oral therapy should be considered , particularly if the following criteria are met:

(1) Susceptibility to an appropriate oral agent is demonstrated.

(2) The patient is hemodynamically stable.

(3) Reasonable source control measures have already occurred.

(4) There are no problems with intestinal absorption.

Admittedly, meeting these criteria can be challenging with CRAB and S. maltophilia infections.

AmpC β-lactamase-producing Enterobacterales (AmpC-E)

AmpC production in Enterobacterales generally occurs through inducible chromosomal resistance, stable chromosomal de-repression, or plasmid-mediated ampC genes. Inducible expression of ampC causes increased production of the AmpC enzyme and occurs in the presence of specific antibiotics. Once there is enough enzyme in the periplasmic space to increase MICs, the result is resistance to ceftriaxone and ceftazidime.

Enterobacter cloacae, Klebsiella aerogenes, and Citrobacter freundii have a moderate to high risk of clinically significant AmpC production. Although several β-lactam antibiotics have a relatively high risk of inducing AmpC, both the ability to induce ampC genes and the inability to resist AmpC hydrolysis should inform antibiotic decision-making.

Cefepime is suggested for the treatment of infections caused by organisms at moderate to high risk for significant AmpC production (i.e., E. cloacae, K. aerogenes, and C. freundii) when the MIC of cefepime is ≤2 mcg/mL. Carbapenem treatment is recommended when the cefepime MIC is ≥4 mcg/mL, provided carbapenem susceptibility is demonstrated.

Ceftriaxone (ceftazidime) is not recommended for treating invasive infections caused by organisms with moderate to high risk of significant inducible AmpC production. However, ceftriaxone may be a treatment option for uncomplicated cystitis caused by these pathogens, assuming susceptibility is demonstrated. In particular, piperacillin-tazobactam is not recommended for the treatment of serious infections caused by Enterobacterale.

There is greater potency of the recent combination agents of β-lactams and β-lactam-β-lactamase inhibitors against AmpC-E infections compared with piperacillin-tazobactam, but the panel suggests that these drugs be reserved for the treatment of infections caused by organisms that exhibit resistance to carbapenems.

Carbapenem-resistant Acinetobacter baumannii (CRAB)

CRAB is commonly recovered from respiratory specimens or wounds.

It is particularly difficult to treat because it is not always known whether a patient is sick for reasons attributable to their underlying host state, or whether CRAB is a true pathogen capable of causing or contributing to excess mortality.

Fortunately, a single active agent may be sufficient to treat mild CRAB infections; the panel suggests treatment with ampicillin-sulbactam. Combination therapy with at least 2 agents, preferably with in vitro activity, is suggested for moderate to severe CRAB infections. This is partly due to the lack of clinical data supporting any antibiotic, but a single active agent can be considered to treat mild CRAB infections.

When susceptibility has been demonstrated, the preferred therapy for CRAB is high-dose ampicillin-sulbactam. Even without demonstrated susceptibility, high-dose ampicillin-sulbactam remains a treatment option. Cefiderocol should be limited to treating CRAB infections refractory to other antibiotics, or in cases with intolerance to other agents. The panel suggests prescribing cefiderocol as part of a combination regimen.

For mild CRAB infections, tetracycline derivatives can be considered as monotherapy in combination with at least one other agent. The panel suggests high-dose minocycline or tigecycline as an alternative agent. Until more clinical data are available, the panel does not recommend eravacycline to treat CRAB infections. High-dose extended-infusion meropenem may serve as a component of combination therapy for moderate to severe CRAB infections, but polymyxin and meropenem are not recommended without a third agent.

The panel noted promising in vitro and animal studies of rifabutin and other rifamycins, but does not favor them for treating CRAB infections in the absence of further clinical studies. The panel does not recommend the addition of nebulized antibiotics to treat respiratory infections caused by CRAB.

Stenotrophomonas maltophilia (S. maltophilia)

S. maltophilia is an aerobic, non-glucose-fermenting, gram-negative bacillus commonly found in aquatic environments.

It produces biofilm and virulence factors that allow colonization or infection in vulnerable hosts.

For mild infections, the panel recommends treatment with TMP-SMX, minocycline, tigecycline, levofloxacin, or cefiderocol alone. Of these, TMP-SMX and minocycline as preferred agents. Ceftazidime is not suggested due to the intrinsic β-lactamases produced by S. maltophilia, which likely render ceftazidime ineffective.

For moderate to severe infections, suggested approaches are:

(1) The use of combination therapy (TMP-SMX and minocycline is the preferred combination).

(2) Initiation of TMP-SMX monotherapy with a secondary agent (minocycline is preferred; other options are tigecycline, levofloxacin, or cefiderocol) if there is a delay in improvement with TMP-SMX alone.

(3) The combination of ceftazidime-avibactam and aztreonam, if intolerance or inactivity of other agents is expected.

High-dose minocycline monotherapy is a treatment to consider for mild S. maltophilia infections. High-dose minocycline in combination with a second active agent is suggested, at least until clinical improvement is seen, for moderate to severe infection. The panel prefers minocycline over tigecycline, although tigecycline is also a treatment option for S. maltophilia infections.

Levofloxacin monotherapy is a treatment option for mild S. maltophilia infections, although the emergence of resistance during levofloxacin therapy is a concern. For this reason, levofloxacin should only be considered in combination with a second active agent (TMP-SMX, minocycline, tigecycline, cefiderocol).

Cefiderocol monotherapy is a treatment for mild S. maltophilia infections, although limited clinical data are available for this agent. Therefore, cefiderocol should be administered in combination with a second active agent for moderate to severe S. maltophilia infections. Treatment with ceftazidime is not recommended, as the presence of β-lactamase genes in S. maltophilia is likely to render it inactive.

The IDSA recommended consulting with an infectious disease specialist before treating antimicrobial-resistant infections.

The complete and updated guidelines (English) can be downloaded at: https://www.idsociety.org/practice-guideline/amr-guidance-2.0