<p>An Evidence-Based Multidisciplinary Approach Focused at Creating Algorithms for Targeted Therapy of BSIs, cUTIs, and cIAIs Caused by <em>Enterobacterales</em> in Critically Ill Adult Patients</p>

Milo Gatti; Bruno Viaggi; Gian Maria Rossolini; Federico Pea; Pierluigi Viale

doi:10.2147/IDR.S314241

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Expert Opinion

An Evidence-Based Multidisciplinary Approach Focused at Creating Algorithms for Targeted Therapy of BSIs, cUTIs, and cIAIs Caused by Enterobacterales in Critically Ill Adult Patients

Authors Gatti M, Viaggi B, Rossolini GM , Pea F , Viale P

Received 4 April 2021

Accepted for publication 7 May 2021

Published 30 June 2021 Volume 2021:14 Pages 2461—2498

DOI https://doi.org/10.2147/IDR.S314241

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Héctor Mora-Montes

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Milo Gatti,^1,² Bruno Viaggi,³ Gian Maria Rossolini,^{4– 6} Federico Pea,^1,² Pierluigi Viale^1,⁷

¹Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy; ²SSD Clinical Pharmacology, IRCCS Azienda Ospedaliero Universitaria Sant’Orsola, Bologna, Italy; ³Neurointensive Care Unit, Department of Anesthesiology, Careggi, University Hospital, Florence, Italy; ⁴Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; ⁵Microbiology and Virology Unit, Florence Careggi University Hospital, Florence, Italy; ⁶IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy; ⁷Infectious Diseases Unit, IRCCS Azienda Ospedaliero Universitaria Sant’Orsola, Bologna, Italy

Correspondence: Federico Pea
Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Massarenti, 9, Bologna, 40138, Italy
Tel +39 051 214 3199
Email [email protected]

Abstract: Prompt implementation of appropriate targeted antibiotic therapy represents a valuable approach in improving clinical and ecological outcome in critically septic patients. This multidisciplinary opinion article focused at developing evidence-based algorithms for targeted antibiotic therapy of bloodstream (BSIs), complicated urinary tract (cUTIs), and complicated intrabdominal infections (cIAIs) caused by Enterobacterales. The aim was to provide a guidance for intensive care physicians either in appropriately placing novel antibiotics or in considering strategies for sparing the broadest-spectrum antibiotics. A multidisciplinary team of experts (one intensive care physician, one infectious disease consultant, one clinical microbiologist and one MD clinical pharmacologist), performed several rounds of assessment to reach agreement in developing six different algorithms according to the susceptibility pattern (one each for multi-susceptible, extended-spectrum beta-lactamase-producing, AmpC beta-lactamase-producing, Klebsiella pneumoniae carbapenemase (KPC)-producing, OXA-48-producing, and Metallo-beta-lactamase (MBL)-producing Enterobacterales). Whenever multiple therapeutic options were feasible, a hierarchical scale was established. Recommendations on antibiotic dosing optimization were also provided. In order to retrieve evidence-based support for the therapeutic choices proposed in the algorithms, a comprehensive literature search was performed by a researcher on PubMed-MEDLINE from inception until March 2021. Quality and strength of evidence was established according to a hierarchical scale of the study design. Only articles published in English were included. It is expected that these algorithms, by allowing prompt revision of antibiotic regimens whenever feasible, appropriate place in therapy of novel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and pharmacokinetic/pharmacodynamic optimization of antibiotic dosing regimens, may be helpful either in improving clinical outcome or in containing the spread of antimicrobial resistance.

Keywords: critically ill patients, targeted antibiotic therapy, antimicrobial stewardship, Enterobacterales, multidisciplinary taskforce, PK/PD dosing optimization

Introduction

Sepsis is a common occurrence in patients admitted to intensive care unit (ICU), accounting for high mortality and massive antibiotic consumption.^1–3 Bloodstream infections (BSIs), complicated intra abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs) are second only to pneumonia as sources of infections among ICU patients.^4,5 Enterobacterales account for the most frequently isolated pathogens.^5,6 Beta-lactams represent mainstay of treatment, and may have different roles according to the susceptibility pattern of clinical isolates. Previous antibiotic use, colonization by or ICU acquisition of MDR-Enterobacterales, prolonged hospitalisation, severity of acute illness are the major determinants of risk for developing infections caused by multidrug-resistant (MDR) Enterobacterales.^7–9 Six different susceptibility patterns to beta-lactams may be identified among Enterobacterales: multi-susceptible, extended-spectrum beta-lactamase (ESBL)-producing, AmpC beta-lactamase (AmpC)-producing, Klebsiella pneumoniae carbapenemase (KPC)-producing, OXA-48-producing, and metallo-beta-lactamase (MBL)- producing Enterobacterales.^7–9

Early and appropriate antimicrobial treatment represents a cornerstone in the management of critically septic patient.^10,11 The Surviving Sepsis Campaign guidelines recommend prompt implementation of targeted antibiotic therapy once that pathogen has been identified and antimicrobial susceptibility has been tested.¹² A multidisciplinary team composed of the intensive care physician, the infectious disease consultant, the clinical microbiologist, and the MD clinical pharmacologist (Figure 1), could be helpful to pursuit this aim. Prompt implementation of appropriate definitive therapy according to the “antimicrobial puzzle” concepts¹³ could play a key role in improving clinical and ecological outcome in critical settings.^14,15

Figure 1 Features of multidisciplinary taskforce involved in implementation of targeted antimicrobial therapy in critically ill patients.

Abbreviations: ID, infectious disease; PCR, polymerase chain reaction; PK/PD; pharmacokinetic/pharmacodynamic; TDM, therapeutic drug monitoring.

This multidisciplinary opinion article aims to develop evidence-based algorithms for targeted antibiotic therapy of BSIs, cIAIs, and cUTIs caused by Enterobacterales in critically ill adult patients.

The aim was to provide a useful guidance for intensive care physicians either in appropriately placing novel antimicrobial agents in lack of definitive evidence or in considering antimicrobial stewardship strategies for sparing the broadest-spectrum antibiotics.

Materials and Methods

A multidisciplinary team composed by one intensive care physician (B.V.), one infectious disease consultant (P.V.), one clinical microbiologist (G.M.R.), and one MD clinical pharmacologist (F.P.) met virtually on several occasions to reach agreement in developing algorithms and specific recommendations for targeted antimicrobial therapy of BSIs, cIAIs, and cUTIs caused by Enterobacterales in ICU critically ill patients. The definitive agreement for each therapeutic algorithm was reached by the multidisciplinary team after thoroughly discussion based on specific long-standing experience and on the specific expertise of each single member. The rationale for considering common algorithms for these infection sites is based on the fact that cIAIs and cUTIs were investigated together in the last pivotal trials concerning novel antibiotics.¹⁶ Additionally, bacteraemic and non-bacteraemic cUTIs and cIAIs are commonly considered as relatively benign infection sources showing no high-inoculum effect, differently from that occurs in severe nosocomial pneumonia.^17,18 Consequently, we believe that algorithms for targeted therapy of infection-related ventilator associated complications (IVACs) must be considered apart. Six different scenarios were structured according to the pattern of antibiotic susceptibility of the pathogens and/or of the genotype of resistance. Whenever multiple therapeutic options were feasible, a hierarchical scale was established. Recommendations on antibiotic dosing optimization were also provided.

Scientific evidence supporting the specific choices included in the algorithms was retrieved by means of a literature search conducted by a researcher (M.G.) on PubMed-MEDLINE (from inception until March 2021). Key terms for search included selected antibiotics, site of infections, and genotype of resistance and/or pattern of susceptibility of bacterial pathogens. Quality of evidence was established according to a hierarchical scale of the study design, as reported in the evidence pyramid:¹⁹ randomized controlled trials (RCTs); prospective observational studies; retrospective observational studies; case series; case reports; in vitro studies. International guidelines issued by the Infectious Disease Society of America and/or by the European Society of Clinical Microbiology and Infectious Diseases, systematic reviews and meta-analyses were also consulted. Consistence between retrieved studies was also considered, by assessing the concordance in clinical outcome of the included studies at each level of the evidence pyramid. Only articles published in English were included, and search was focused mainly on the last ten years in order to provide an up-to-date overview on the scientific evidence that may support the therapeutic algorithms.

Targeted Treatment of BSIs, cUTIs, and cIAIs Caused by Enterobacterales in Critically Ill Adult Patients

Six different algorithms for targeted treatment of BSIs, cUTIs, cIAIs are depicted in Figure 2, one each for infections caused by multi-susceptible, ESBL-, AmpC-, KPC-, OXA-48-, and MBL-producing Enterobacterales.

Figure 2 Algorithms for targeted treatment of BSI, cUTI and cIAI, caused by Enterobacterales with different pattern of susceptibility in the ICU setting. *if MIC for cefepime ≤1 mg/L. ** ESCPM group includes: Enterobacter (E. cloacae complex, E. aerogenes), Serratia marcescens, Citrobacter freundii, Providencia stuartii, and Morganella morganii.

Abbreviations: CI, continuous infusion; MIC, minimum inhibitory concentration.

Multi-Susceptible Enterobacterales

Recommendations are depicted in Figure 2, panel A.1. Ampicillin-sulbactam [3g q6h over 6h by continuous infusion (CI) after 3g loading dose [LD]] or ceftriaxone (2g q24h) are recommended for BSIs, cUTIs, and cIAIs caused by multi-susceptible Enterobacterales. Evidences supporting these choices are summarized in Table 1. Both the European²⁰ and the American²¹ guidelines recommended the use of ampicillin-sulbactam or ceftriaxone for the management of mild-to-moderate cIAIs/peritonitis. In regard to ampicillin-sulbactam, an RCT²² found no significant difference in clinical response rate between ampicillin-sulbactam and cefoxitin (86% vs 78%) in patients affected by cIAIs mainly due to Escherichia coli, although features concerning infection severity were not provided. A retrospective observational study found comparable clinical response rate between ampicillin-sulbactam and ticarcillin-clavulanate (84.3% vs 77.5%) among hospitalized patients with infections including cIAIs and cUTIs.²³ Data on ICU admission and severity of infection were unavailable.

Table 1 Summary of the Studies Investigating the Treatment of Full-Sensitive Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Ampicillin or Ceftriaxone

In regard to ceftriaxone, an RCT comparing ceftriaxone plus tobramycin versus ceftazidime in the treatment of severe hospital-acquired Gram-negative infections (including BSIs and cUTIs) showed no significant difference in clinical response rate among patients who required ICU admission in 43.3% of cases.²⁴ Several RCTs^25–28 showed no significant difference in terms of microbiological response rate between ceftriaxone and ertapenem for the management of cUTIs caused mainly by E. coli and K. pneumoniae. Almost 40% of patients had severe infection and relapse rate was <10%. cUTI were bacteraemic in 5.9–33.6% of cases may provide, and this may support the efficacy of ceftriaxone in BSIs as well.

Extended-Spectrum Beta-Lactamase (ESBL)-Producing Enterobacterales

Recommentations are depicted in Figure 2, panel A.2. Piperacillin-tazobactam (18g CI after 6.75g LD) is recommended for the management of infections caused by ESBL-producing Enterobacterales with a piperacillin-tazobactam MIC ≤8 mg/L (according to the EUCAST breakpoint) tested by broth microdilution (the reference method for piperacillin-tazobactam susceptibility testing). Conversely, meropenem (0.5–1g q6h over 6h CI after 2g LD) should be preferred whenever piperacillin/tazobactam MIC is >8 mg/L. Ceftolozane-tazobactam (1.5g LD followed by 4.5g CI) and ceftazidime-avibactam (2.5g LD followed by 2.5g q8h over 8h CI) may represent alternative options when focusing at a “carbapenem-sparing” approach.²⁹ In settings with high prevalence of carbapenem-resistant Enterobacterales (CRE), ceftazidime-avibactam should be reserved for CRE treatment to avoid epidemiological shift of carbapenemase producers to metallo-beta-lactamases (MBLs).^29,30 Evidences supporting these choices are summarized in Table 2. Several studies compared piperacillin-tazobactam with carbapenems in the treatment of BSIs, cUTIs, and cIAIs caused by ESBL-producing Enterobacterales. Overall, an inconsistence emerged from the available evidence. The MERINO trial³¹ was the first large RCT that assessed the efficacy of a carbapenem-sparing strategy by comparing piperacillin-tazobactam vs meropenem in the treatment of ceftriaxone-resistant Escherichia coli or Klebsiella pneumoniae BSIs. Non-inferiority was not achieved in the piperacillin-tazobactam arm, as an overall 30-day all-cause mortality rate 3-fold higher than in the meropenem arm was observed (12.3% vs 3.7%, p=0.90). This arose concerns regarding the use of piperacillin-tazobactam as empirical or definitive therapy of ESBL-producing Enterobacterales BSIs.¹⁷ Indeed, it should be mentioned that a number of issues affected trial conclusions.^17,32 The low mortality rate in the meropenem group was an unexpected finding; the primary source of BSI was imbalanced between arms (higher UTIs rate in the meropenem group); the number of neutropenic and immunocompromised patients was higher in the piperacillin-tazobactam group; sample size calculation was suboptimal; there was a high prevalence of bla_OXA-1 genes (67%) strictly associated with high MICs for piperacillin-tazobactam (8–16 mg/L);³³ pharmacokinetic/pharmacodynamic (PK/PD) properties of piperacillin-tazobactam were not maximized (administration by intermittent rather than by prolonged infusion). Conversely, a large body of evidence coming from well-design observational studies and systematic review^34–46 showed no significant difference in efficacy and mortality rate between piperacillin-tazobactam and carbapenems among patients with ESBL-producing primary or secondary BSI in settings with ICU admission rate up to 40%. An RCT of piperacillin-tazobactam vs ertapenem found no significant difference in clinical cure and mortality rate among patients with bacteraemic cUTIs.⁴⁷ Two studies showed a lower occurrence of MDR bacterial or fungal infections at 30-day from treatment with piperacillin-tazobactam compared to carbapenems (7.4% vs 24.6%; p=0.01),³⁹ and a trend toward lower CRE isolation rate (2% vs 8%; p=0.09).⁴⁶ Conversely, two other observational studies showed significantly lower mortality rate in patients treated with carbapenems compared to piperacillin-tazobactam.^48,49 However, in one of this⁴⁸ some limits must be recognized, as 61% of patients received lower-than-desirable dosage of piperacillin-tazobactam (3.375g q6h) by intermittent infusion, and 60% of Enterobacterales isolates had piperacillin-tazobactam MIC ≥8 mg/L. Overall, the available literature may provide support for considering piperacillin-tazobactam a valuable carbapenem-sparing agent in the management of ESBL-related infections when dealing with fully susceptible pathogens (MIC ≤8 mg/L). Notably, CI of high-dose piperacillin-tazobactam (18g) should be strongly recommended to achieve optimal PK/PD target in critically ill patients affected by ESBL-producing Enterobacterales infections, especially when dealing with isolates exhibiting high MIC values.^50,51 Evidence supporting ceftolozane-tazobactam and/or ceftazidime-avibactam as carbapenem-sparing options for the treatment of for BSIs, cUTIs, and cIAIs caused by ESBL-producing Enterobacterales came from the non-inferiority showed vs carbapenems in pivotal Phase III trials.^52–57 Indeed, it should be recognized that the overall proportion of ESBL-producing isolates was 100% only in one study that enrolled exclusively patients with documented ceftazidime-resistant infections,⁵⁷ whereas it was <20% in all of the others.

Table 2 Summary of the Studies Investigating the Treatment of Extended Spectrum Beta-Lactamase (ESBL)-Producing Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Carbapenems Compared to Piperacillin-Tazobactam or Novel Beta-Lactam/Beta-Lactamase Inhibitors (BL/BLIs)

AmpC Beta-Lactamase-Producing Enterobacterales

Recommendations are depicted in Figure 2, panel A.3. Meropenem (0.5–1g q6h over 6h CI after 2g LD) is recommended as first-line treatment for BSIs, cUTIs, and cIAIs caused by AmpC-producing Enterobacterales. Cefepime (6g CI after 2g LD) may be a “carbapenem-sparing” alternative option if the MIC is ≤1 mg/L. AmpC beta-lactamases belong to the class C of the Ambler’s classification, and genes encoding for them are usually located in the chromosome of bacteria belonging to the so-called ESCPM group (namely Enterobacter cloacae complex, Enterobacter aerogenes, Serratia marcescens, Citrobacter freundii, Providencia stuartii, and Morganella morganii),⁵⁸ but can also be carried on transferable plasmids and found in isolates of other species (eg, E. coli, K. pneumoniae, P. mirabilis). AmpC may hydrolyse all the penicillins, the 1^st, 2^nd and 3^rd cephalosporins, and the monobactam aztreonam, but not the 4^th generation cephalosporins and the carbapenems. Furthermore, beta-lactamase inhibitors (tazobactam, sulbactam, clavulanate) exhibit no activity against AmpC-producing isolates. Evidences coming from comparative studies between carbapenems and cefepime in the treatment of BSIs, cUTIs, and cIAIs caused by AmpC-producing Enterobacterales is provided in Table 3. Overall, a large body of evidence obtained from well-design prospective and retrospective observational studies and from systematic reviews showed no significant difference in terms of clinical cure and mortality rate between cefepime and carbapenems in settings characterized by ICU admission up to 60%.^59–66 However, it should not be overlooked that cefepime was less effective against strains with an MIC ≥2 mg/L. One study showed significantly higher mortality rate in patients affected by cefepime-susceptible dose dependent (SDD) isolates (MIC 4–8 mg/L) who were treated with cefepime compared to those treated with carbapenems (71.4% vs 18.2%; p=0.045), even if a full-dose cefepime (6g/day) was administered only in 38.6% of cases.⁶⁵ Likewise, higher rate of persistent bacteraemia was shown among patients affected with cefepime-SDD isolates who were treated with cefepime.⁶² However, only 16% of patients received full-dose cefepime.

Table 3 Summary of the Studies Investigating the Treatment of AmpC-Producing Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Carbapenems and Cefepime

Klebsiella Pneumoniae Carbapenemase (KPC)-Producing Enterobacterales

Recommentations are depicted in Figure 2, panel A.4. Ceftazidime-avibactam (2.5g LD followed by 2.5g q8h over 8h CI) is recommended as first-line therapy for the management of BSIs, cIAIs, and cUTIs caused by KPC-producing Enterobacterales. Meropenem-vaborbactam (2g/2g q8h over 8h CI after 2g/2g LD), imipenem-relebactam (0.5g/0.25g q6h over 3h), and cefiderocol (2g LD followed by 2g q8h over 8h CI) could be alternative options, and are listed in a hierarchical scale. A summary of scientific evidences is provided in Table 4. One prospective and eight retrospective observational studies support the role of ceftazidime-avibactam in the management of KPC-producing BSIs, cIAIs, and cUTIs in settings with an ICU admission up to 60%.^67–75 Van Duin et al assessed prospectively 137 carbapenemase-producing Enterobacterales (CPE) infections (38 treated with ceftazidime-avibactam vs 99 with colistin-based regimens).⁶⁷ Ceftazidime-avibactam showed a better adjusted probability of favourable outcome (64%; p=0.0012), and a 3.5-fold lower all-cause mortality rate than colistin-based regimens (8% vs 33%; p=0.001). Caston et al analysed retrospectively 31 CPE infections among hematologic patients (8 treated with CAZ-AVI vs 23 treated with other antibiotic combinations, mainly carbapenems and aminoglycosides).⁶⁸ Patients treated with ceftazidime-avibactam showed significantly higher clinical cure rate (85.7% vs 34.8%; p=0.03). Tumbarello et al analysed 208 patients with KPC-producing Klebsiella pneumoniae BSIs (104 treated with ceftazidime-avibactam as second line therapy vs 104 treated with different rescue mono- or combo-treatments).⁶⁹ Patients treated with ceftazidime-avibactam showed significantly lower 30-day mortality rate (36.5% vs 55.8%; p=0.005), and ceftazidime-avibactam was the only independent predictor of survival at multivariate analysis. Shields et al analysed 109 CPE infections, 13 of whom treated with ceftazidime-avibactam and the other 96 with other antimicrobials (mainly colistin, aminoglycosides and carbapenems).⁷⁰ Patients receiving ceftazidime-avibactam showed significantly lower 30-day mortality rate (8% vs 31.3%; p=0.01) and higher clinical success rate (85% vs 40.6%; p=0.006). Very recently, Tumbarello et al analysed 577 patients with KPC-producing Klebsiella pneumoniae infections (67.8% with BSIs) treated with ceftazidime-avibactam.⁷⁵ No difference in mortality rate was found between ceftazidime-avibactam monotherapy vs combination therapy (26.1% vs 25.0%; p=0.79). Notably, ceftazidime-avibactam prolonged infusion resulted protective against mortality at multivariate analysis (p=0.006). In regard to meropenem-vaborbactam, it should be mentioned that vaborbactam was specifically developed to restore the activity of meropenem against KPCs.⁷⁶ A phase III RCT (TANGO II) assessed 47 patients affected by KPC-producing Enterobacterales infections, 32 of whom were treated with meropenem-vaborbactam and the other 15 with best-available therapy (including mono/combination therapy with colistin, carbapenems, aminoglycosides, tigecycline, or ceftazidime-avibactam alone). Meropenem-vaborbactam showed better clinical cure rate (65.6% vs 33.3%; p=0.03) and a trend toward lower mortality rate (15.6% vs 33.3%; p=0.20) compared to best available therapy.⁷⁷ However, it should be recognized that patients enrolled in this RCT required ICU admission only in 15.6% of cases. More attractive evidence for meropenem-vaborbactam as targeted therapy for KPC-producing Enterobacterales infections in critically ill patients came from observational studies, in which ICU admission ranged from 65.4% to 70%.^78–80 Clinical cure rate ranged 65–70%, and mortality rate 10–22.5%. Relapse rate of CPE infections ranged 11.5–15%, and in up to 5% of patients was reported resistance development to meropenem-vaborbactam. One retrospective study⁷⁸ reported no significant difference between 26 patients receiving meropenem-vaborbactam and 105 receiving ceftazidime-avibactam in terms of clinical cure rate (69.2 vs 61.9%) and mortality rate (11.5 vs 19.1%). In regard to imipenem-relebactam, it’s worth mentioning that relebactam was combined to imipenem-cilastatin in order to restore activity against carbapenemase producing Enterobacterales and Pseudomonas aeruginosa.⁷⁶ In a phase III RCT of patients with severe Gram-negative infections, imipenem-relebactam demonstrated significantly better clinical cure rate compared to imipenem plus colistin (71.4% vs 40%; p<0.05).⁸¹ However, infection by KPC-producing Enterobacterales was documented in only 4 out of the 21 patients enrolled in the imipenem-relebactam group. In regard to cefiderocol, in a phase III RCT 150 patients affected by carbapenem-resistant Gram-negative infections were randomized to cefiderocol (n=101) or best available therapy (including combination of aminoglycoside, carbapenems, colistin, fosfomycin or tigecycline) (n=49).⁸² Clinical and microbiological cure rates between groups did not significantly differ. However, the number of documented KPC-producing Enterobacterales infections was quite limited.

Table 4 Summary of the Studies Investigating the Treatment of Klebsiella pneumoniae Carbapenemase (KPC)-Producing Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Ceftazidime-Avibactam, Meropenem-Vaborbactam, Imipenem-Relebactam and Cefiderocol

OXA-48-Producing Enterobacterales

Recommendations are depicted in Figure 2, panel A.5. Ceftazidime-avibactam (2.5g LD followed by 2.5g q8h over 8h CI) is recommended as first-line therapy for the management of BSIs, cIAIs, and cUTIs caused by OXA-48 and OXA-48-like-producing Enterobacterales. (avibactam inhibits OXA-48, and ceftazidime is stable to this enzyme).⁸³ Cefiderocol (2g LD followed by 2g q8h over 8h CI) could be an alternative option. A summary of the studies evaluating the efficacy of ceftazidime-avibactam and cefiderocol in this setting is provided in Table 5. Alraddadi et al⁸⁴ compared retrospectively 10 patients treated with ceftazidime-avibactam with 28 treated with other mono- or combo-therapy (colistin, carbapenems, aminoglycosides, tigecycline, quinolone, cotrimoxazole, and aztreonam) for the management of CPE. After restricting analysis to OXA-48 infections, no difference in clinical cure (75% vs 40%; p=0.21) and in mortality rate (37.5% vs 50%; p=0.69) were reported. In two observational studies concerning the treatment with ceftazidime-avibactam of infections caused by OXA-48-producing Enterobacterales,^85,86 the clinical cure rate and mortality rate were similar to those found in other studies where it was used for the treatment of KPC infections [59–62]. Conversely, in one retrospective study assessing ceftazidime-avibactam as salvage therapy for infections caused by carbapenem-resistant organisms,⁷¹ among the 13 patients who were affected by OXA-48 infections a trend toward lower microbiological cure (25% vs 75%; p=0.07) and survival to hospital discharge (22.7% vs 77.3%; p=0.07) compared to the 23 who had KPC infections was found. In regard to cefiderocol, there is only one case⁸⁷ that reported its use for the management of a secondary BSI caused by carbapenem-resistant K. pneumoniae co-producing OXA-48-like and New Delhi metallo-beta-lactamase-1 (NDM-1). Microbiological cure was proven, and the patient died because of an ischaemic colitis secondary to Clostridium difficile infection. Besides, several in vitro studies^88–91 support the good activity of cefiderocol against OXA-48 producing Enterobacterales, with MIC₅₀ and MIC₉₀ ranging 0.25–0.5 mg/L, and 0.5–4 mg/L, respectively.

Table 5 Summary of the Studies Investigating the Treatment of OXA-48 Producing Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Ceftazidime-Avibactam and Cefiderocol

Metallo-Beta-Lactamase (MBL)-Positive Enterobacterales

Recommendations are depicted in Figure 2, panel A.6. Ceftazidime-avibactam (2.5g LD followed by 2.5g q8h over 8h CI) plus aztreonam (2g q8h over 8h CI after 2g LD) is the recommended first-line therapy for the management of BSIs, cIAIs, and cUTIs caused by New-Delhi metallo beta-lactamases (NDM)-producing Enterobacterales. Cefiderocol (2g LD followed by 2g q8h over 8h CI) is recommended for the treatment of infections caused by Verona Integron-encoded metallo-beta-lactamase (VIM)-producing and/or imipenemase (IMP)-producing Enterobacterales. Fosfomycin (6g LD followed by 16g CI) plus high-dose meropenem (1.5–2g q6h over 6h CI after 2g LD) could be an alternative option for both NDM-producing and VIM-IMP-producing Enterobacterales. MBLs are associated with extremely-drug-resistant (XDR) phenotypes, as they may hydrolyse the vast majority of currently available beta-lactams.⁹² A summary of the studies evaluating the efficacy of these antibiotics in the setting is provided in Table 6. One prospective observational study, two case series and five case reports suggest the efficacy of the combination therapy ceftazidime-avibactam plus aztreonam in the treatment of critically ill patients affected by NDM infections (mainly expressed by Klebsiella pneumoniae).^93–100 Falcone et al⁹³ compared in a prospective observational study 52 patients receiving the combination ceftazidime-avibactam plus aztreonam with 50 subjects receiving other active antibiotics in the management of BSIs due to NDM-producing and/or VIM-producing Enterobacterales. Patients treated with ceftazidime-avibactam plus aztreonam showed significantly lower mortality rate (19.2% vs 44%; p=0.007) and clinical failure rate (25% vs 52%; p=0.005). Shaw et al⁹⁴ reported a case series of ceftazidime-avibactam plus aztreonam for the treatment of an outbreak caused by NDM-1/OXA-48-producing Klebsiella pneumoniae strain. Among 10 treated patients, 4 were solid organ transplant recipients, and half had bacteraemic infections (including cUTIs and cIAIs). Overall clinical cure rate at 30-day was 60%, and three patients died. Cairns et al¹⁰¹ reported a case series of four immunocompromised patients affected by IMP-4-producing Enterobacter cloacae infections successfully treated with ceftazidime-avibactam plus aztreonam, and relapse occurred only in one case. In regard to cefiderocol, only one case reported its role in the management of a secondary BSI caused by carbapenem-resistant K. pneumoniae co-producing NDM-1 and OXA-48-like beta-lactamases.⁸⁷ However, several in vitro studies support the good activity of cefiderocol against NDM-producing Enterobacterales (MIC₅₀: 1–4 mg/L and MIC₉₀: 4–8 mg/L, susceptibility rate of 41–72.1%), and IMP-VIM-positive isolates (MIC₅₀ 1 mg/L, MIC₉₀ 4 mg/L, susceptibility rate of 80.9–95.7%).^88,89,102 In regard to the combination of fosfomycin with high-dose meropenem, only one case documented the efficacy of this combo in a kidney transplant recipient affected by bacteraemic cUTI due to NDM-1-producing Morganella morganii.¹⁰³ An in vitro study showed the synergistic effect of this combination against 10 NDM-producing Klebsiella pneumoniae strains (including five isolates co-producing OXA-48 carbapenemases).¹⁰⁴

Table 6 Summary of the Studies Investigating the Treatment of Metallo-Beta-Lactamase (MBL) Producing Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Aztreonam-Avibactam, Cefiderocol and Combination Therapy with Meropenem and Fosfomycin

Overview of Recommendations

The widespread diffusion of CRE isolates and the different genotypes of resistance of Enterobacterales requires careful attention for the right place in therapy of novel beta-lactams and the prompt adoption of strategies for sparing the broadest-spectrum antibiotics whenever possible. Ampicillin-sulbactam and ceftriaxone still represent the first-choice treatment of BSIs, cIAIs, or cUTIs caused by multi-susceptible Enterobacterales. Piperacillin-tazobactam should be recommended for the treatment of BSIs, cIAIs, or cUTIs caused by ESBL-producing Enterobacterales with an MIC ≤8 mg/L, especially in low-risk patients.¹⁰⁵ In this scenario, altered dosing strategies based on high-doses administered by CI may maximize clinical efficacy of piperacillin-tazobactam against ESBL isolates, and this approach has been recently suggested by the EUCAST as well.¹⁰⁵ Ertapenem was not recommended for the treatment of ESBL-producing infections in critically ill patients, as some studies^106,107 showed that among patients affected by septic shock treatment with ertapenem was associated with higher mortality rate compared to other carbapenems. Cefepime may represent an effective “carbapenem-sparing” strategy for the treatment of infections caused by AmpC-producing Enterobacterales with an MIC ≤1 mg/L.¹⁰⁸ Hopefully, some ongoing studies (namely MERINO-2, MERINO-3, PETERPEN, and FOREST studies) could better clarify the role of old and novel BL/BLIs in the management of critically ill patients affected by ESBL-producing Enterobacterales infections. Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, and cefiderocol may represent first-line choices for the management of critically ill patients affected by CRE infections expressing class A (eg, KPC) or D (eg, OXA-48) beta-lactamases.⁷⁶ These agents should be administered in prolonged or continuous infusion as well to maximize efficacy and clinical outcome.^75,109 Monotherapy with novel BL and BL/BLIs should always be pursued in these settings considering that comparative studies showed no significant advantage in efficacy of combination therapy vs monotherapy.^110,111 Against MBL-producers, the use of ceftazidime-avibactam plus aztreonam may represent an effective strategy for the management of NDM-producing Enterobacterales infections, whereas cefiderocol should be reserved mainly to VIM- or IMP-producing Enterobacterales infections.⁷⁶ This latter recommendations is justified by the fact that the overall susceptibility rate of cefiderocol against NDM-producing Enterobacterales is <70%, and MIC₅₀/MIC₉₀ are 2–4-fold higher compared to VIM- or IMP-producing strains.^{89,102,112,113} Fosfomycin combined with high-dose meropenem could represent a valuable alternative against both types of MBL-producing Enterobacterales infections.

Overall, altered dosing strategies of beta-lactams based on CI administration are strongly recommended for attaining very aggressive PK/PD target of 100% fT_>4-8xMIC.^51,105 This approach may both maximize clinical efficacy and prevent the development of resistance.¹⁰⁵ CI is feasible with a unique daily solution infused over 24 hours for those drugs that are stable in aqueous solution at room temperature for ≥ 1 day (eg, piperacillin-tazobactam, ceftolozane-tazobactam). Otherwise, for those drugs that are stable in aqueous solution at room temperature for 6–12h, CI may be granted through reconstitution of the aqueous solution every 6–8h and infusion over 6–8h (eg, meropenem, ampicillin/sulbactam, ceftazidime/avibactam).

Clinicians must be aware that the antibiotic dosing regimens that we recommended throughout the manuscript are focused only on treatment of patients with normal renal function. It should not be overlooked that the pharmacokinetics of hydrophilic antimicrobial agents, namely beta-lactams and fosfomycin, may be affected among critically ill patients by several pathophysiological conditions that may alter volume of distribution and/or renal clearance. Consequently, dose adjustments are needed in critically ill renal patients, especially among those with transient acute kidney injury, augmented renal clearance, and/or undergoing renal replacement therapy.¹¹⁴ Finally, it should be mentioned that for the treatment of patients with well-documented life-threatening beta-lactam allergies, alternative agents s should be considered. Fluoroquinolones, aminoglycosides and colistin could be helpful in these cases depending on the susceptibility pattern of the isolated Enterobacterales.

Conclusions

In an era characterized by the widespread diffusion of MDR Gram-negative pathogens and by the incremental spread of antibiotic resistance, implementation of a multidisciplinary approach focused at targeted therapy in critically ill patients has become a real necessity. This could simultaneously allow to promptly revise inappropriate/unnecessary antibiotic regimens, to implement “carbapenem-sparing” strategies based on monotherapy with traditional and/or novel beta-lactams and, whenever applicable, to optimize antibiotic exposure in each single patient by means of real-time TDM guided approach. It is expected that these strategies could be helpful either in improving clinical outcome or in containing the spread of antimicrobial resistance in the ICU setting. It should be noted that the availability of rapid diagnostic technologies, based on molecular methods, that can reveal the presence of clinically-relevant resistance determinants such as the main ESBL and carbapenemase genes can be very useful to shorten the time for revision of empiric therapy according to the proposed algorithms.

Disclosure

B. Viaggi participated in advisory boards and in speaker’s bureau for, and received research contracts, contributions and study events from Abbott, Accelerate Diagnostics, Ada, Alifax, Angelini, Becton Dickinson, Bellco, Biomerieux, Biotest, Cepheid, Correvio, Gilead, Menarini, MSD Italia, Nordic Pharma, Pfizer, Shionogi, Thermo Fisher Scientific; G.M. Rossolini participated in advisory boards and speaker’s bureau for, and received research contracts, contributions and travel grants from Accelerate, Angelini, Arrow, Beckman Biomedical Service, Coulter, Becton-Dickinson, bioMérieux, Cepheid, Hain Life Sciences, Menarini, Meridian, MSD, Nordic Pharma, Pfizer, Qiagen, Q-linea, Qpex, Quidel, Qvella, Roche, Seegene, Set-Lance, Shionogi, Symcel, ThermoFisher, VenatorX, Zambon; F. Pea participated in speaker bureau for Angelini, Basilea Pharmaceutica, Gilead, Hikma, Merck Sharp & Dohme, Nordic Pharma, Pfizer, and Sanofi Aventis, and in advisory board for Angelini, Basilea Pharmaceutica, Correvio, Gilead, Merck Sharp & Dohme, Nordic Pharma, Novartis, Pfizer, and Thermo-Fisher. P. Viale has served as a consultant for Biomerieux, Gilead, Merck Sharp & Dohme, Nabriva, Nordic Pharma, Pfizer, Thermo-Fisher, and Venatorx, and received payment for serving on the speaker’s bureau for Correvio, Gilead, Merck Sharp & Dohme, Nordic Pharma and Pfizer. The authors report no other conflicts of interest in this work.

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