Resist the Resistance: A Summary of the IDSA Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections

By: Dr. Joseph T. Martinez, PharmD

Introduction

Clinicians and researchers have observed a continual rise in antimicrobial resistance (AMR). In collaboration with other international agencies, the World Health Organization (WHO) offers estimations about the health and economic cost of the current resistance trajectory. Drug-resistant infections and diseases may cause ten million deaths annually by 2050, damaging the economy and livelihood of millions worldwide.1

To address this concern in a timely manner, the Infectious Diseases Society of America (IDSA) sought to provide guidance on the rapidly changing treatment of resistant infections. Due to the time it takes to develop a treatment guideline and the timeliness of this issue, the IDSA instead provided a focused update on difficult-to-treat infections. As a result, a comprehensive review was developed, mainly composed of clinical experience and expert opinion, to guide decision-making and to provide an annual update.

The IDSA, in addressing a few select types of infections, released two versions of the Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections in March 2022. Version 1.0 covers infections caused by extended-spectrum β-lactamaseproducing enterobacterales (ESBL-E), carbapenem-resistant enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTRPA). Version 2.0 covers infections caused by AmpC β-lactamaseproducing Enterobacterales (AmpC-E), carbapenem-resistant Acinetobacter baumannii species (CRAB), and Stenotrophomonas maltophilia 2 This document reviews Version 1.0, with these infections designated as urgent or serious threats by the Centers for Disease Control and Prevention.3

This review discusses the resistant pathogens of concern, the approach to treatment, current resistance to novel treatment, and approaches to reduce/delay resistance to therapy.

Resistant Pathogens

ESBL-Es are gram-negative bacteria that are resistant to most β-lactams. Resistance occurs by opening the cyclic amide back- bone of most penicillin, cephalosporins, and aztreonam. This resistance is commonly found in Escherichia coli, Klebsiella spp, and Proteus mirabilis. Although not considered a first-line treatment, most carbapenems show activity against ESBL-Es. Testing for this resistance is not routine; ceftriaxone susceptibility with a minimum inhibitory concentration of ≥2mg/L is often used as a proxy for ESBL production. However, the high rates of false positives due to the high sensitivity and low specificity of this method should caution healthcare providers.4,5

CREs present with resistance to at least one carbapenem or produce a carbapenemase, a type of β-lactamase that is effective in opening the β-lactam ring of a carbapenem. These examples include Klebsiella pneumoniae carbapenemase (KPC) and Metallo-β-lactamases (MBL). Oxacillinases (OXA), another type of β-lactamase, have also shown resistance to carbapenems. In addition to the opening of the cyclic amide ring, CREs maintain resistance through the disruption of outer membrane porins, preventing the entry of antibiotics into the bacterium through passive diffusion.

DTR-PA is a more significant form of resistance than is typically seen with P. aeruginosa. A difference is noted between DTR and multidrug resistance, which is resistance to at least one antibiotic in ≥3 of the following drug classes; penicillins, cephalosporins, fluoroquinolones, aminoglycosides, and carbapenems. DTR is defined as resistance to piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem-cilastatin, ciprofloxacin, and levofloxacin. This occurs through multiple mechanisms: decreased expression of outer membrane porins, excess AmpC cephalosporinases, excess efflux pumps, and mutations in the penicillin-binding proteins.

Treatment Approach

Many considerations are universal for all three types of infections. First, susceptibility testing must be performed to direct therapy, along with consideration for the recommended agents for each infection. This should be repeated if the patient does not improve or worsens. The exception to this rule is if a CRE organism tests positive for carbapenemases, no carbapenem should be given, even if they are found susceptible.

Second, the duration of treatment varies based on the type of infection, patient sex, and agent. The total time should include empiric and narrowed regimens, including a change from intravenous to oral therapy. The clinical response must be considered when deciding if a range is provided.

The duration of each medication is provided in Tables 1-3.6

If able, the most effective agents should be preserved to delay resistance and maintain their effectiveness for future use. These agents include carbapenems and the novel β-lactams (ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam). Additionally, fluoroquinolones should be limited to preserve their efficacy and avoid toxicities such as QT prolongation, C. difficile infections, tendonitis/tendon rupture, seizures, and peripheral neuropathy. Finally, combination therapy should be avoided due to the greater risk of toxicity without improvement of outcomes. Exceptions to this include empiric treatment, tetracycline regimens, and non-urinary alternatives for CRE.

Uncomplicated Cystitis

The first-line agents from the IDSA 2010 guideline on uncomplicated cystitis may be considered if susceptibility is found, except in the case of P. aeruginosa (Table 1).7 Fluoroquinolones may be considered for CRE as firstline options. If a patient resists ertapenem, standard infusion meropenem can be used; CRE resistance to one carbapenem does not correlate with all carbapenems. However, they should not be used if carbapenemase testing is positive, regardless of susceptibility results. Single-dose aminoglycosides are effective while reducing the risk of toxicity from prolonged use.

Complicated UTIs and Pyelonephritis

For the progression to complicat- ed infections, the IDSA guidance recommends the earlier introduction of more-effective agents compared to cystitis (Table 2).7 Many of these options can include a combination of parenteral and oral therapy if a transition is appropriate. Compared to the cystitis recommendations, once-daily (not single-dose) aminoglycosides may be used with proper renal, otic, and neurotoxicity monitoring. Extended infusion meropenem (not standard) may be used for ertapenem resistance if carbapenemase testing is unknown or negative. Fosfomycin may still be used for E. coli prostatitis; fosfomycin is not recommended for other complicated infections, even in confirmed E. coli patients.

Although not listed as guidance recommended options, piperacillin-tazobactam, and cefepime may be continued if used empirically and the patient improves. There is no need to change or extend therapy for these two medications. However, neither agent is recommended outside of the urinary tract due to decreased efficacy, even if susceptibility is found; other agents would be preferred.

Non-Urinary Infections

Carbapenems are first-line agents for all three types of infections, with a β-lactamase inhibitor used in combination to treat CRE and DTR-PA (Table 3). In the case of CRE, determining the kind of carbapenemase resistance that is present (if any) can help to guide therapy. KPC-producing or ertapenem/meropenem-resistant CRE may be treated with ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-cilastatin-relebactam. MBL-producing CRE may be treated with ceftazidime-avibactam plus aztreonam or cefiderocol monotherapy. OXA-48-producing CRE may be treated with ceftazidime-avibactam or cefiderocol.

Tetracyclines (tigecycline and eravacycline) may be used with other agents as an alternative to β-lactams. Standard doses may be used for intra-abdominal infections, with other infections being considered at high doses. Polymyxins and aminoglycosides should be avoided due to the risk of toxicity. Inhaled antibiotics are not recommended due to the risk of bronchoconstriction and no outcome/survival benefit.

Emergence of Resistance to Novel β-lactams

Despite antimicrobial stewardship efforts, resistance has been documented in some of the newest agents available. Currently, ceftolozane-avibactam and ceftazidime-avibactam are the most concerning. One of the potential factors is that ceftazidime-avibactam was the first FDA-approved novel β-lactam for CRE, which led to its extensive use before other medications became available. However, resistance will begin to develop more with other treatments the longer they are used.

To illustrate this, ceftazidime-avibactam has been shown to have 20% resistance after clinical exposure to CRE.8 Additionally, ceftolozane-avibactam has shown up to 50% resistance after clinical exposure to DTR-PA. There has also been documented resistance to ceftazidime-avibactam (80%) after exposure to ceftolozane-avi- bactam in isolates previously susceptible to both medications without exposure to ceftazidime-avibactam.9

Approaches to prevent or delay resistance to the novel β-lactams have been suggested. First, prevention of infection and source control has been shown to be effective across all types of infections. Next, the use of susceptibility testing and repeating as needed is recommended to guide therapy. Pharmacists can play an influential role by providing recommendations to maintain the effectiveness of these agents, whether their role is focused on infectious disease or not.

Conclusion

AMR will continue to challenge healthcare providers for years to come. This will require diligence to stay up to date on the evidenced-based guidance and expert opinion to direct treatment plans. Combining the current evidence, the use of susceptibility testing, and preserving the most effective agents, pharmacists can play a vital role in reducing antibiotic resistance rates to improve patient outcomes.

Author: Joseph T. Martinez, PharmD, is a PGY1 Community-Based Pharmacy Resident at Walgreens Pharmacy and an Adjunct Clinical Instructor at Campbell University in Buies Creek, NC. jmartinez@campbell.edu

References

1. New report calls for urgent action to avert antimicrobial resistance crisis. World Health Organization. Apr 29 2019.

2. Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of America 2022 Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Clin Infect Dis. 2022 Aug 25;75(2):187-212.

3. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2019, 2019.

4. Villegas MV, Esparza G, Reyes J. Should ceftriaxone-resistant Enterobacterales be tested for ESBLs? A PRO/CON debate. JAC Antimicrob Resist. 2021 May 7;3(2):dlab035.

5. Tamma PD, Humphries RM. PRO: Testing for ESBL production is necessary for ceftriaxone-non-susceptible Enterobacterales: perfect should not be the enemy of progress. JAC Antimicrob Resist. 2021 May 7;3(2):dlab019.

6. Lexicomp Online, Lexi-Drugs Online. Waltham, MA: UpToDate, Inc. https://online.lexi.com. Accessed May 5, 2023.

7. Gupta K, Hooton TM, Naber KG, et al. Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011 Mar 1;52(5):e10320.

8. Karaiskos I, Daikos GL, Gkoufa A, et al. Hellenic Ceftazidime/Avibactam Registry Study Group. Ceftazidime/ avibactam in the era of carbapenemase-producing Klebsiella pneumoniae: experience from a national registry study. J Antimicrob Chemother. 2021 Feb 11;76(3):775-783.

9. Rubio AM, Kline EG, Jones CE, et al. In Vitro Susceptibility of MultidrugResistant Pseudomonas aeruginosa following Treatment-Emergent Resistance to Ceftolozane-Tazobactam. Antimicrob Agents Chemother. 2021 May 18;65(6):e00084-21.