IDSA Releases New Guidelines for Treating Antimicrobial-Resistant Infections

Today, the Infectious Diseasse Society of America (IDSA) released new guidelines for the treatment of AmpC β-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia infections.

The rise in antimicrobial resistance (AMR) is a global health crisis, with some experts predicting it will become the next pandemic. To mitigate AMR, the IDSA worked with 6 practicing infectious diseases specialists to develop narrowly focused guidance for treating these difficult infections.

Data about treating AmpC-E, CRAB, and S. maltophilia are inconclusive, so the experts provided “informed suggestions” instead of recommendations. The treatment suggestions assume that the causative pathogen has been identified and in vitro activity of antibiotics was demonstrated.

Empiric Therapy

Empiric therapy decisions should be made regarding most likely pathogens, severity of patient’s illness, and likely source of infection. Clinicians should also take into consideration: (1) previous organisms identified from the patient and corresponding antibiotic susceptibility data in the last six months, (2) antibiotic exposures within the last 30 days, and (3) local susceptibility patterns of the most likely pathogens.

The recommendations stressed distinguishing bacterial colonization from infection, especially for CRAB and S. maltophilia, as unnecessary therapy can drive up resistance and harm patients. Clinicians are advised that prolonged treatment courses are not necessary against AMR infections.

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

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

Enterobacter cloacae, Klebsiella aerogenes, and Citrobacter freundii are at moderate-to-high risk for clinically significant AmpC production. While several β-lactam antibiotics are relatively high-risk for inducing AmpC, both the ability to induce ampC genes and the inability to withstand AmpC hydrolysis should inform antibiotic decision-making.

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

Ceftriaxone (ceftazidime) is not recommended to treat invasive infections caused by organisms at 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. Notably, piperacillin-tazobactam is not recommended for the treatment of serious infections caused by Enterobacterale.

There is increased potency of recent β-lactams and β-lactam-β-lactamase inhibitor combination agents against AmpC-E infections compared with piperacillin-tazobactam, but the panel suggests that these agents be reserved for treating infections caused by organisms exhibiting carbapenem resistance.

Carbapenem-resistant Acinetobacter baumannii (CRAB)

CRAB is commonly recovered from respiratory specimen or wounds. It is particularly difficult to treat because it is not always known whether a patient is ill for reasons attributable to their underlying host status, or if CRAB is a true pathogen capable of causing or contributing to excess mortality.

Luckily, a single active agent may suffice for treating 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 partially due to a lack of clinical data supporting any one antibiotic agent, but a single active agent may be considered for treating mild CRAB infections.

When susceptibility has been demonstrated, high-dose ampicillin-sulbactam is the preferred therapy for CRAB. Even without demonstrated susceptibility, high-dose ampicillin-sulbactam remains a treatment option. Cefiderocol should be limited to treat 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 minocycline, or high dose 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 can 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 to treat CRAB infections in the absence of more 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, glucose non-fermenting, Gram-negative bacillus commonly found in water environments. It produces biofilm ad virulence factors that enable colonization or infection in vulnerable hosts.

For mild infections, the panel recommends treatment with TMP-SMX, minocycline, tigecycline, levofloxacin, or cefiderocol monotherapy. Of these, TMP-SMX and minocycline as the preferred agents. Ceftazidime is not suggested due to the intrinsic β-lactamases produced by S. maltophilia, which are likely to 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) the 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, or (3) the combination of ceftazidime-avibactam and aztreonam, if intolerance or inactivity of other agents are expected.

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 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, though the emergence of resistance during levofloxacin therapy is cause for 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, though there is limited clinical data 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 will likely render it inactive.

The IDSA recommended consulting with an infectious disease specialist before treating antimicrobial-resistant infections. The full updated guidelines can be found here.