Sepsis Forum 2022: Sepsis treatment in an era of multi-resistance

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The emergence and spread of multi-resistant organisms is one of the biggest challenges in dealing with sepsis, not only in Brazil but around the world. Concepts of treating sepsis in connection with resistance were discussed in one of the plenary sessions of the XVIII International Sepsis Forum, which dealt with aspects of infections with Gram-negative and Gram-positive bacteria.

See some of the highlights!

sepsis and microbial multidrug resistance

Sepsis and multiresistance

Initially, some definitions regarding the classification of multi-resistance:

Classification Definition
MDR Resistance to at least 1 drug out of 3 or more classes of antibiotics
XDR Resistance to at least 1 drug per class, present in all classes, except a maximum of 2 classes
PanDR or PDR Resistance to all substances of all classes
  • For the treatment of gram-negative bacteria with multi-resistance, the most important investments are in the use of new combinations of beta-lactams / beta-lactamase inhibitors. Although several options have been developed and approved in recent years, few are available in Brazil so far.
  • Ceftazidime / avibactam (CAZ-AVI) is one of these new combinations that is most used in the Brazilian context when available. Studies with real data support its use in the treatment of carbapenem-resistant enterobacterial infections. A study conducted at a North American hospital showed better clinical success rates with the use of CAZ-AVI in the treatment of bacterial bacteremia. Klebsiella pneumoniae resistant to carbanapenem compared to other treatment regimens (including aminoglycosides or polymyxin in combination with carbapenems, among other regimens such as monotherapy or in combination).
  • Another retrospective study evaluating KPC bacteremias found no difference in mortality using CAZ-AVI alone compared to its use as part of combination therapy. The mortality rate for all causes after 30 days was 25%. Independent risk factors for death found in the study included septic shock, neutropenia, pneumonia, and CAZ-AVI dose adjustment for renal function.
  • An interesting result of this study is that administration of CAZ-AVI in prolonged infusion was associated with lower mortality.
  • For other gram-negative organisms, experience with CAZ-AVI is still limited. A retrospective multicenter study with data from 13 Italian hospitals showed generally positive results. Most of the included patients had nosocomial pneumonia or bacteremia, and the main drugs were Pseudomonas aeruginosa and ESBL-producing Enterobacteriaceae. The clinical cure rate was 90.2% (90% in patients with nosocomial pneumonia and 86% in patients with primary bacteremia). Stratification of the results after pathogen, the cure rates were 100% for polymicrobial and ESBL infections and 87.8% for those caused by ESBL. P. aeruginosa.
  • Metallo-beta-lactamases (MBL) remain one of the major concerns in terms of resistance mechanisms, with few therapeutic options and associated with high mortality. One option that has been investigated is the combination of CAZ-AVI with aztreonam. A multicenter observational study showed lower 30-day mortality in patients with bacteremia documented by MBL-producing organisms compared to other regimens.
  • Gram-positive bacteria are a problem in intensive care units, especially in connection with infections related to deep venous access. For infections associated with Staphylococcus aureus, there is a recommendation for focus control (removal of access) and investigation of complications, especially endocarditis. The first lines of treatment are antistaphylococcal penicillins or first-generation cephalosporins in the case of MSSA and vancomycin or dpatomicin for MRSA.
  • The recommended treatment time is 14 days for uncomplicated infections and 4 to 6 weeks for complicated ones. In order for a S. aureus infection to be considered uncomplicated, all of the following criteria must be present:
    • Control blood cultures (after catheter removal) negative
    • Use of first-line treatment
    • Rapid response to therapy
    • Absence of intravascular devices such as prosthetic valves or endovascular grafts
    • No signs of metastatic infections
    • Exclusion of endocarditis by echocardiogram
  • For cases of persistent infection, rescue treatment options found in the literature include association of vancomycin and beta-lactams, combination of daptomycin and beta-lactams, high dose daptomycin, linezolid and sulfamethoxazole tripetoprim. However, data are still very limited and mainly refer to MRSA infections.

More from the Sepsis 2022 forum:

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#Shields RK, et al. Ceftazidime-Avibactam is superior to other carbapenem-resistant treatment regimens Klebsiella pneumoniae Bacteria. Antimicrobial agents Kemother. 2017 Jul 25; 61 (8): e00883-17. doi: 10.1128 / AAC.00883-17. #Tumbarello M, et al. Ceftazidime-Avibactam Use for Klebsiella pneumoniae Carbapenemase-producing K. pneumoniae infections: A retrospective observational multicenter study. Clin Infect Dis. 2021 Nov 2; 73 (9): 1664-1676. doi: 10.1093 / cid / ciab176. #Vena A, et al. Clinical experience with Ceftazidime-Avibactam for the treatment of infections due to multiresistant gram-negative bacteria other than carbapenem-resistant Enterobacterales. Antibiotics (Basel). February 9, 2020; 9 (2): 71. doi: 10.3390 / antibiotika9020071. #Falcone M, et al. Efficacy of Ceftazidime-avibactam Plus Aztreonam in patients with circulatory infections caused by metallo-β-lactamase-producing Enterobacterales. Clin Infect Dis. 2021 Jun 1; 72 (11): 1871-1878. doi: 10.1093 / cid / ciaa586. #Kullar R, et al. When Sepsis Continues: A Review of MRSA Bacteriaemia Rescue Therapy. J Antimicrob Chemother. 2016 Mar; 71 (3): 576-86. doi: 10.1093 / jac / dkv368. Epub 2015 12. nov. PMID: 26565015.

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