CRE Guideline

16. Hakeam HA, Alsahli H, Albabtain L, et al. August 2021. Effectiveness of ceftazidime-avibactam versus colistin in treating carbapenem-resistant Enterobacteriaceae bacteraemia. Clinical Microbiology Review. Multicentre Study Int J Infect Dis 2021 Aug;109:1-7.

Abstract:

Ceftazidime-avibactam was associated with a lower risk of 14-day mortality than colistin in patients with CRE bacteraemia.

17. Ikuta KS, Swetschinski LR, Aguilar GR, et al. November 2022. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet. DOI: https://doi.org/10.1016/S0140-6736(22)02185-7

18. Jean-François Timsit Antibiotics (Basel). Feb 2022. Treatment of Severe Infections Due to Metallo-Beta lactamases Enterobacterales in Critically Ill Patients. 11(2): 144. https://doi.org/10.3390%2Fantibiotics11020144

Abstract:

Metallo-beta-lactamases-producing (MBL) Enterobacterales is a growing problem worldwide. The optimization of antibiotic therapy is challenging. The pivotal available therapeutic options are either the combination of ceftazidime/avibactam and aztreonam or cefiderocol. Colistin, Fosfomycin, tetracyclines and aminoglycosides are also frequently effective in vitro, but are associated with less bactericidal activity or more toxicity. Prior to the availability of antibiotic susceptibility testing, severe infections should be treated with a combination therapy. A careful optimization of the pharmacokinetic/pharmacodynamic properties of antimicrobials is instrumental in severe infections. The rules of antibiotic therapy are also reported and discussed. To conclude, treatment of severe MBL infections in critically ill patients is difficult. It should be individualized with a close collaboration of intensivists with microbiologists, pharmacists and infection control practitioners.

19. Labuschagnea Q, Schellacka N, Gousa A, et al. COLISTIN: adult and paediatric guideline for South Africa. Southern African Journal of Infectious Diseases 2016; 31(1):3–7. http://dx.doi.org/10.1080/23120053.2016.1144285

Abstract:

Loading dosage

During life-threatening infections, it is important to achieve therapeutic concentrations of colistin (CMS) rapidly. Patients who are critically ill have capillary leakage, which increases their volume of distribution 4-15-fold. According to Landersdorfer & Nation (2015) CMS is converted to colistin slowly. This fact, combined with the long half-life of formed colistin, may result in a time interval of 2-3 days to reach an adequate therapeutic plasma concentration, in the absence of a loading dosage. Therefore, it is very important to initiate colistin (CMS) therapy with a loading dosage of 12 MU – regardless of kidney function – to reach therapeutic concentrations quicker. The high loading dosage does not affect the renal function; only the subsequent maintenance dosages would need to be adjusted.

20. Lasko MJ and Nicolau DP. 2020. Carbapenem-Resistant Enterobacterales: Considerations for Treatment in the Era of New Antimicrobials and Evolving Enzymology. Springer Science + Business Media.

Abstract:

Purpose of Review Gram-negative resistance is a growing concern globally. Enterobacterales, formerly Enterobacteriaceae, have developed resistance mechanisms to carbapenems that leave very few antimicrobial options in the clinician’s armamentarium. Recent Findings New antimicrobials like ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and plazomicin have the potential to overcome resistance mechanisms in Enterobacterales including different classes of carbapenemases. Summary Novel β-lactam/β-lactamase inhibitors, plazomicin, and cefiderocol give the clinician options that were once not available. Utilizing these options is of the utmost importance when treating carbapenem-resistant Enterobacterales

21. Lodise TP, Nicholas O’Donnell J, Raja S, et al. 2022. Safety of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase I, Open-Label Study in Healthy Adult Volunteers. American Society of Microbiology. DOI: https://doi.org/10.1128/aac.00935-22

Abstract:

This phase I study evaluated the safety of the optimal ceftazidime-avibactam (CZA) with aztreonam (ATM) regimens identified in hollow fiber infection models of MBL-producing Enterobacterales. Eligible healthy subjects aged 18 to 45 years were assigned to one of six cohorts: 2.5 g CZA over 2 h every 8 h (approved dose), CZA continuous infusion (CI) (7.5 g daily), 2 g ATM over 2 h every 6 h, ATM CI (8 g daily), CZA (approved dose) with 1.5 g ATM over 2 h every 6 h, and CZA (approved dose) with 2 g ATM over 2 h every 6 h. Study drug(s) were administered for 7 days. The most frequently observed adverse events (AEs) were hepatic aminotransferase (ALT/AST) elevations (n = 19 subjects). Seventeen of the 19 subjects with ALT/AST elevations received ATM alone or CZA-ATM. The incidence of ALT/AST elevations was comparable between the ATM-alone and CZA-ATM cohorts. Two subjects in the ATM CI cohort experienced severe ALT/AST elevation AEs. All subjects with ALT/AST elevations were asymptomatic with no other findings suggestive of liver injury. Most other AEs were of mild to moderate severity and were similar across cohorts, except for prolonged prothrombin time (more frequent in CZA-ATM cohorts). These results suggest that CZA-ATM administered as 2-h intermittent infusions is safe and that some caution should be exercised with the use of ATM CI at an ATM dose of 8 g daily. If CZA-ATM is prescribed, clinicians are advised to monitor liver function, hematologic, and coagulation parameters. Future controlled studies are required to better define the safety and efficacy of the CZA-ATM regimens evaluated in this phase I study.

22. Lodise TP, Nicholas O’Donnell J, Belavic S, et al. 2022. Pharmacokinetics of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase 1, Open-Label Study of Healthy Adults. DOI: https://doi.org/10.1128/aac.00936-22

Abstract:

Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations. Subjects (n = 48) were assigned to one of six cohorts (intermittent infusion [II] CZA, continuous infusion [CI] CZA, II ATM, CI ATM [8 g/daily], II CZA with II ATM [6 g/daily],

and II CZA with II ATM [8 g/daily]), and study product(s) were administered for 7 days. A total of 19 subjects (40%) had ALT/AST elevations, and most (89%) occurred in the ATM/CZA-ATM cohorts. Two subjects in the CI ATM cohort experienced severe ALT/AST elevations, which halted the study. All subjects with ALT/AST elevations were asymptomatic with no other signs of liver injury, and all ALT/AST elevations resolved without sequalae after cessation of dosing. In the population PK (PopPK) analyses, CZA-ATM administration reduced total ATM clearance by 16%, had a negligible effect on total ceftazidime clearance, and was not a covariate in the avibactam PopPK model. In the exposure-response analyses, coadministration of CZA-ATM was not found to augment ALT/AST elevations. Modest associations were observed between ATM exposure (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve [AUC]) and ALT/AST elevations in the analysis of subjects in the II ATM/CZA-ATM cohorts. The findings suggest that administration of CZA-ATM reduces ATM clearance but does not exacerbate AST/ALT elevations relative to ATM alone. The results also indicate that CI ATM should be used with caution.

23. Michael S. Niederman, et al. 2021. Initial antimicrobial management of sepsis. Critical Care. volume 25, Article number: 307.

Abstract:

Sepsis is a common consequence of infection, associated with a mortality rate > 25%. Although community-acquired sepsis is more common, hospital-acquired infection is more lethal. The most common site of infection is the lung, followed by abdominal infection, catheter-associated blood steam infection and urinary tract infection. Gram-negative sepsis is more common than gram-positive infection, but sepsis can also be due to fungal and viral pathogens. To reduce mortality, it is necessary to give immediate, empiric, broad-spectrum therapy to those with severe sepsis and/or shock, but this approach can drive antimicrobial overuse and resistance and should be accompanied by a commitment to de-escalation and antimicrobial stewardship. Biomarkers such a procalcitonin can provide decision support for antibiotic use, and may identify patients with a low likelihood of infection, and in some settings, can guide duration of antibiotic therapy. Sepsis can involve drug-resistant pathogens, and this often necessitates consideration of newer antimicrobial agent.

24. Paul M, Carrara E, Retamar P, et al. 2022. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clinical Microbiological Infection. 2022 Apr;28(4):521-547.

Abstract:

Scope: These ESCMID guidelines address the targeted antibiotic treatment of third-generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant Gram-negative bacteria, focusing on the effectiveness of individual antibiotics and on combination versus monotherapy. Methods: An expert panel was convened by ESCMID. A systematic review was performed including randomized controlled trials and observational studies, examining different antibiotic treatment regimens for the targeted treatment of infections caused by the 3GCephRE, carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii. Treatments were classified as head-to-head comparisons between individual antibiotics and between monotherapy and combination therapy regimens, including defined monotherapy and combination regimens only. The primary outcome was all-cause mortality, preferably at 30 days and secondary outcomes included clinical

failure, microbiological failure, development of resistance, relapse/ recurrence, adverse events and length of hospital stay. The last search of all databases was conducted in December 2019, followed by a focused search for relevant studies up until ECCMID 2021. Data were summarized narratively. The certainty of the evidence for each comparison between antibiotics and between monotherapy and combination therapy regimens was classified by the GRADE recommendations. The strength of the recommendations for or against treatments was classified as strong or conditional (weak). Recommendations: The guideline panel reviewed the evidence per pathogen, preferably per site of infection, critically appraising the existing studies. Many of the comparisons were addressed in small observational studies at high risk of bias only. Notably, there was very little evidence on the effects of the new, recently approved, b-lactam/b-lactamase inhibitors on infections caused by carbapenem-resistant Gram-negative bacteria. Most recommendations are based on very-low- and low-certainty evidence. A high value was placed on antibiotic stewardship considerations in all recommendations, searching for carbapenem-sparing options for 3GCephRE and limiting the recommendations of the new antibiotics for severe infections, as defined by the sepsis-3 criteria. Research needs are addressed.

25. Pranita D Tamma, et al. Sept 2022. Infectious Diseases Society of America Guidance on the Treatment of AmpC β-Lactamase-Producing Enterobacterales, Carbapenem-Resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia Infections. Clinical Infectious Diseases. 1:ciac698. doi: 10.1093/cid/ciac698.

Abstract:

Here, guidance is provided for treating AmpC β-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia infections. A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated questions about the treatment of AmpC-E, CRAB, and S. maltophilia infections. Answers are presented as suggested approaches and corresponding rationales. In contrast to guidance in the previous document, published data on the optimal treatment of AmpC-E, CRAB, and S. maltophilia infections are limited. As such, guidance in this document is provided as “suggested approaches” based on clinical experience, expert opinion, and a review of the available literature. Because of differences in the epidemiology of resistance and availability of specific anti-infectives internationally, this document focuses on the treatment of infections in the United States.

26. Tabah A, Lipman J, Barbier F, et al. Review Use of Antimicrobials for Bloodstream Infections in the Intensive Care Unit, a Clinically Oriented Review. Antibiotics 2022. 11(3), 362; https://doi.org/10.3390/antibiotics11030362.

Abstract:

Bloodstream infections (BSIs) in critically ill patients are associated with significant mortality. For patients with septic shock, antibiotics should be administered within the hour. Probabilistic treatment should be targeted to the most likely pathogens, considering the source and risk factors for bacterial resistance including local epidemiology. Source control is a critical component of the management. Sending blood cultures (BCs) and other specimens before antibiotic administration, without delaying them, is key to microbiological diagnosis and subsequent opportunities for antimicrobial stewardship. Molecular rapid diagnostic testing may provide faster identification of pathogens and specific resistance patterns from the initial positive BC. Results allow for antibiotic optimisation, targeting the causative pathogen with

escalation or de-escalation as required. Through this clinically oriented narrative review, we provide expert commentary for empirical and targeted antibiotic choice, including a review of the evidence and recommendations for the treatments of extended-spectrum β-lactamase-producing, AmpC-hyperproducing and carbapenem-resistant Enterobacterales; carbapenem-resistant Acinetobacter baumannii; and Staphylococcus aureus. In order to improve clinical outcomes, dosing recommendations and pharmacokinetics/pharmacodynamics specific to ICU patients must be followed, alongside therapeutic drug monitoring.

27. Tamma PD, Aitken SL, Bonomo RA, et al. 19 April 2022. 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. Clinical Infectious Diseases. 268. doi: 10.1093/cid/ciac268.

Abstract:

The Infectious Diseases Society of America (IDSA) is committed to providing up to-date guidance on the treatment of antimicrobial-resistant infections. The initial guidance document on infections caused by extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa) was published on September 17th, 2020. Over the past year, there have been a number of important publications furthering our understanding of the management of ESBL-E, CRE, and DTR-P. aeruginosa infections, prompting a rereview of the literature and this updated guidance document. Methods: A panel of six infectious diseases specialists with expertise in managing antimicrobial-resistant infections reviewed, updated, and expanded previously developed questions and recommendations about the treatment of ESBL-E, CRE, and DTR-P. aeruginosa infections. Because of differences in the epidemiology of resistance and availability of specific anti-infectives internationally, this document focuses on the treatment of infections in the United States. Results: Preferred and alternative treatment recommendations are provided with accompanying rationales, assuming the causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment, duration of therapy, and other management considerations are also discussed briefly. Recommendations apply for both adult and paediatric populations. Conclusions: The field of antimicrobial resistance is highly dynamic. Consultation with an infectious diseases specialist is recommended for the treatment of antimicrobial-resistant infections. This document is current as of October 24th, 2021. The most current versions of IDSA documents, including dates of publication, are available at www.idsociety.org/practiceguideline/amr-guidance/

28. Tan X, Kim HS, Baugh K. Feb 2021. Therapeutic Options for Metallo-β-Lactamase-Producing

Enterobacterales. Infection and Drug Resistance. Volume 14: 595-596.

Abstract:

The spread of metallo-β-lactamase (MBL)-producing Enterobacterales worldwide without the simultaneous increase in active antibiotics makes these organisms an urgent public health threat. This review summarizes recent advancements in diagnostic and treatment strategies for infections caused by MBL-producing Enterobacterales. Adequate treatment of patients infected with MBL-producing Enterobacterales relies on detection of the β-lactamase in the clinic. There are several molecular platforms that are currently available to identify clinically relevant MBLs as well as other important serine-β-lactamases. Once detected, there are several antibiotics that have historically been used for the treatment of MBL-producing Enterobacterales. Antimicrobials

such as aminoglycosides, tetracyclines, Fosfomycin, and polymyxins often show promising in vitro activity though clinical data are currently lacking to support their widespread use. Ceftazidime-avibactam combined with aztreonam is promising for treatment of infections caused by MBL-producing Enterobacterales and currently has the most clinical data of any available antibiotic to support its use. While cefiderocol has displayed promising activity against MBL-producing Enterobacterales in vitro and in preliminary clinical studies, further clinical studies will better shed light on its place in treatment. Lastly, there are several promising MBL inhibitors in the pipeline, which may further improve the treatment of MBL-producing Enterobacterales.

29. Tan X, Kim HS, Baugh K, et al. 2021. Therapeutic Options for Metallo-β-Lactamase producing Enterobacterales. Infection and Drug Resistance 2021:14 125–142.

Abstract:

The spread of metallo-β-lactamase (MBL)-producing Enterobacterales worldwide without the simultaneous increase in active antibiotics makes these organisms an urgent public health threat. This review summarizes recent advancements in diagnostic and treatment strategies for infections caused by MBL-producing Enterobacterales. Adequate treatment of patients infected with MBL-producing Enterobacterales relies on detection of the β-lactamase in the clinic. There are several molecular platforms that are currently available to identify clinically relevant MBLs as well as other important serine-β-lactamases. Once detected, there are several antibiotics that have historically been used for the treatment of MBL-producing Enterobacterales. Antimicrobials such as aminoglycosides, tetracyclines, Fosfomycin, and polymyxins often show promising in vitro activity though clinical data are currently lacking to support their widespread use. Ceftazidime-avibactam combined with aztreonam is promising for treatment of infections caused by MBL-producing Enterobacterales and currently has the most clinical data of any available antibiotic to support its use. While cefiderocol has displayed promising activity against MBL-producing Enterobacterales in vitro and in preliminary clinical studies, further clinical studies will better shed light on its place in treatment. Lastly, there are several promising MBL inhibitors in the pipeline, which may further improve the treatment of MBL-producing Enterobacterales.

30. Timsit J, Paul M, Shields RK, et al. Cefiderocol for the Treatment of Infections due to Metallo-Beta-Lactamase-Producing Pathogens in the CREDIBLE-CR And APEKS-NP Phase 3 Randomized Studies. Clinical Infectious Diseases (2022 Feb 11). DOI: 10.1093/cid/ciac078.

Abstract:

In the CREDIBLE-CR and APEKS-NP studies, cefiderocol treatment was effective against Gram-negative bacteria producing metallo-beta-lactamases; rates of clinical cure (70.8% [17/24]), microbiological eradication (58.3% [14/24]), and Day-28 all-cause mortality (12.5% [3/24]) compared favourably with comparators of best available therapy and high-dose meropenem (40.0% [4/10]; 30.0% [3/10]; 50.0% [5/10]), respectively.

31. Yaghoubi S, Zekiy AO, Krutova M, et al. 2022. Tigecycline antibacterial activity, clinical effectiveness, and mechanisms and epidemiology of resistance: narrative review. European Journal of Clinical Microbiology & Infectious Diseases (2022) 41:1003–1022.

Tigecycline is unique glycylcycline class of semisynthetic antimicrobial agents developed for the treatment of polymicrobial infections caused by multidrug-resistant Gram-positive and Gram-negative pathogens. Tigecycline evades the main tetracycline resistance genetic mechanisms, such as tetracycline-specific efflux pump acquisition and ribosomal protection, via the addition of a glycyclamide moiety to the 9-position of minocycline. The use of the parenteral form of tigecycline is approved for complicated skin and skin structure infections (excluding diabetes foot infection), complicated intra-abdominal infections, and community acquired bacterial pneumonia in adults. New evidence also suggests the effectiveness of tigecycline for the treatment of severe Clostridioides difficile infections. Tigecycline showed in vitro susceptibility to Coxiella spp., Rickettsia spp., and multidrug resistant Neisseria gonnorrhoeae strains which indicate the possible use of tigecycline in the treatment of infections caused by these pathogens. Except for intrinsic, or often reported resistance in some Gram-negatives, tigecycline is effective against a wide range of multidrug-resistant nosocomial pathogens. Herein, we summarize the currently available data on tigecycline pharmacokinetics and pharmacodynamics, its mechanism of action, the epidemiology of tigecycline resistance, and its clinical effectiveness.

32. Yahiya Y. Syed. (2021). Cefderocol: A Review in Serious Gram Negative Bacterial Infections. Drugs. 81:1559–1571. https://doi.org/10.1007/s40265-021-01580-4

Abstract:

Infections caused by carbapenem-resistant (CR) Enterobacterales and non-fermenters (such as Pseudomonas, Acinetobacter, Stenotrophomonas, Burkholderia) are a major global health threat. Cefderocol, a cephalosporin with activity against CR Enterobacterales and non-fermenters, uses the bacteria’s own iron uptake system to gain cell entry, like a Trojan horse. Once inside, the drug disrupts the formation of the bacterial cell wall, killing the bacteria. Cefderocol is approved for the treatment of serious Gram-negative bacterial infections. In clinical trials, Cefderocol was effective versus carbapenems or best available therapy for complicated urinary tract infections, nosocomial pneumonia and bloodstream infections/sepsis, including those caused by CR bacteria. The drug had a good tolerability and safety profile. Thus, cefiderocol is a useful addition to the current treatment options for adults with cefiderocol-susceptible Gram-negative bacterial infections for whom there are limited treatment options.

33. Zhanel GG, Golden AR, Zelenitsky S, et al. Feb 2019. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs. 79(3):271-289. doi: 10.1007/s40265-019-1055-2.

Abstract:

Cefiderocol is an injectable siderophore cephalosporin discovered and being developed by Shionogi & Co., Ltd., Japan. As with other β-lactam antibiotics, the principal antibacterial/bactericidal activity of cefiderocol occurs by inhibition of Gram-negative bacterial cell wall synthesis by binding to penicillin binding proteins; however, it is unique in that it enters the bacterial periplasmic space as a result of its siderophore-like property and has enhanced stability to β-lactamases. The chemical structure of cefiderocol is similar to both ceftazidime and cefepime, which are third- and fourth-generation cephalosporins, respectively, but with high stability to a variety of β-lactamases, including AmpC and extended-spectrum β-lactamases (ESBLs).