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Antimicrobial Resistance and Therapy in Intensive Care Unit

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A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Antibiotic Therapy in Infectious Diseases".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 27192

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Special Issue Editors

Dr. Pablo Vidal-Cortés

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Guest Editor

Intensive Care Unit, Hospital Universitario de Ourense, Orense, Spain
Interests: sepsis; antibiotics

Dr. Borja Suberviola

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Guest Editor

Hospital Universitario Marqués de Valdecilla, Santander, Spain
Interests: infections in critically ill patient

Dr. David Andaluz-Ojeda

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Guest Editor

1. Complejo Asistencial Universitario, Palencia, Spain
2. Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
3. Fundación de Investigación HM, Madrid, Spain
Interests: sepsis; biomarkers; inflammation; personalized medicine; severe infection; COVID-19; critical care

Special Issue Information

Dear Colleagues,

In recent decades, antimicrobial resistance has become a global health problem. Despite the efforts and the money invested in the development of new antibiotics, bacteria are capable of developing resistance shortly after their commercialization. Patients admitted to intensive care units are at high risk of infection by multidrug-resistant bacteria and, when infected, need an appropriate treatment as soon as possible. This frequent situation is a challenge for doctors, who need to know the local microbiology, become familiar with the new methods of microbiological diagnosis, and have in-depth knowledge of the characteristics of antibiotics, both classic and those that have appeared in recent years. Today, we have a very varied antimicrobial arsenal, with antibiotics not only with a different spectrum and activity against resistance mechanisms, but also with fewer side effects than other molecules used to date due to the lack of alternatives. In addition, some of these antibiotics have peculiarities from the pharmacokinetic/pharmacodynamic point of view that can make a difference between therapeutic success or failure.

The objective of this Special Issue is to review the epidemiology and treatment of the key problem bacteria in intensive care units, trying to establish the best therapeutic scheme for each one of the most frequent resistance mechanisms. In addition, we will review new microbiological diagnostic methods and ways to optimize the performance of prescribed antibiotics.

Dr. Pablo Vidal-Cortés
Dr. Borja Suberviola
Dr. David Andaluz-Ojeda
Guest Editors

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Keywords

ICU
sepsis
antimicrobial
multidrug-resistant bacteria
sepsis
antimicrobial stewardship

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Published Papers (9 papers)

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Research

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15 pages, 522 KiB

Open AccessArticle

Antibiotic Resistance and Mortality in ICU Patients: A Retrospective Analysis of First Culture Growth Results

by Metin Kilinc

Antibiotics 2025, 14(3), 290; https://doi.org/10.3390/antibiotics14030290 - 11 Mar 2025

Cited by 1 | Viewed by 1539

Abstract

Objectives: This study aimed to analyze the antibiotic resistance patterns of microorganisms isolated from intensive care unit (ICU) patients and evaluate their impact on mortality and length of ICU stay. Given the increasing prevalence of multidrug-resistant (MDR) pathogens in critically ill patients, understanding their resistance profiles is crucial for optimizing empirical antibiotic therapy and improving patient outcomes. Methods: This retrospective study included 237 ICU patients admitted between 1 July 2022, and 1 January 2024. The initial culture growth results from blood and urine samples were analyzed. Microorganism identification was performed using VITEK 2 Compact and conventional bacteriological methods, while antibiotic susceptibility testing followed CLSI 2022 and EUCAST 2022 guidelines. Results: A total of 237 ICU patients were included in this study. The most frequently isolated microorganisms were Escherichia coli (E. coli) (44.3%), Klebsiella pneumoniae (K. pneumoniae) (35.0%), and Pseudomonas aeruginosa (P. aeruginosa) (25.3%), with Acinetobacter baumannii (A. baumannii) (31.2%) being the most resistant pathogen. Among Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA) (12.2%) and vancomycin-resistant enterococci (VRE) (21.5%) were the most frequently identified multidrug-resistant (MDR) pathogens. Regarding antimicrobial resistance, carbapenem resistance was highest in A. baumannii (55%), followed by P. aeruginosa (40%) and K. pneumoniae (30%). Additionally, ESBL-producing E. coli (43.2%) and K. pneumoniae (38.5%), as well as carbapenemase-producing K. pneumoniae (18.6%) and E. coli (9.2%), were identified as key resistance mechanisms impacting clinical outcomes. Patients with MDR infections had significantly longer ICU stays (p < 0.05) and higher mortality rates. The Kaplan–Meier survival analysis revealed that A. baumannii infections were associated with the highest mortality risk (HR: 4.6, p < 0.001), followed by MRSA (HR: 3.5, p = 0.005) and P. aeruginosa (HR: 2.8, p = 0.01). Among laboratory biomarkers, elevated procalcitonin (≥2 ng/mL, OR: 2.8, p = 0.008) and CRP (≥100 mg/L, OR: 2.2, p = 0.01) were significantly associated with ICU mortality. Additionally, patients who remained in the ICU for more than seven days had a 1.4-fold increased risk of mortality (p = 0.02), further emphasizing the impact of prolonged hospitalization on adverse outcomes. Conclusions: MDR pathogens, particularly A. baumannii, MRSA, P. aeruginosa, and K. pneumoniae, are associated with longer ICU stays and higher mortality rates. Carbapenem, cephalosporin, fluoroquinolone, and aminoglycoside resistance significantly impact clinical outcomes, emphasizing the urgent need for antimicrobial stewardship programs. ESBL, p-AmpC, and carbapenemase-producing Enterobacterales further worsen patient outcomes, highlighting the need for early infection control strategies and optimized empirical antibiotic selection. Biomarkers such as procalcitonin and CRP, alongside clinical severity scores, serve as valuable prognostic tools for ICU mortality. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Therapy in Intensive Care Unit)

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15 pages, 580 KiB

Open AccessArticle

Challenges Facing Two Outbreaks of Carbapenem-Resistant Acinetobacter baumannii: From Cefiderocol Susceptibility Testing to the Emergence of Cefiderocol-Resistant Mutants

by Montserrat Rodríguez-Aguirregabiria, Fernando Lázaro-Perona, Juana Begoña Cacho-Calvo, Mª Soledad Arellano-Serrano, Juan Carlos Ramos-Ramos, Eduardo Rubio-Mora, Mariana Díaz-Almirón and Mª José Asensio-Martín

Antibiotics 2024, 13(8), 784; https://doi.org/10.3390/antibiotics13080784 - 21 Aug 2024

Cited by 6 | Viewed by 1875

Abstract

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are associated with poor outcomes depending on patient’s conditions, clinical severity and type of infection, and treatment is challenging given the limited therapeutic options available. The aim of this study was to describe the clinical and microbiological characteristics of two outbreaks caused by CRAB in an intensive care unit (ICU). In addition, the mechanisms of resistance detected in these strains and the treatment chosen according to the available therapeutic options were analyzed. Overall, 28 patients were included. Ten patients (35.71%) had ventilator-associated pneumonia (VAP), ten (35.71%) had a bloodstream infection (BSI), and eight (28.57%) were only colonized. Recurrent infection occurred in 25% (5/20) of infected patients. Two different strains of A. baumannii were isolated from the index patient of the first outbreak. The first strain belonged to the ST85 and carried the bla_NDM-1 carbapenemase gene, while the second belonged to the ST2 and carried bla_OXA-23, and bla_OXA-66 carbapenemase genes. The phylogenetic analysis revealed that the ST2 strain was the cause of the major outbreak, and mutations in the AmpC gene were related to progressive increasing minimum inhibitory concentration (MIC) and finally, cefiderocol-resistance in one strain. The CRAB isolates from the second outbreak were also identified as ST2. Cefiderocol-resistant strains tests identified by the disc diffusion method were involved in 24% (6/25) of nosocomial infections. Using broth microdilution (BMD) ComASP^® only, 33.3% (2/6) of these strains were cefiderocol-resistant. All-cause ICU mortality was 21.4%. Conclusions: Cefiderocol is the first approved siderophore cephalosporin for the treatment of CRAB infections. Cefiderocol-resistant strains were related with bla_NDM-1 carbapenemase and mutations in the AmpC gene. Cefiderocol-resistant strains or that cannot be properly interpreted by disk diffusion, should be retested using BMD for definitive categorization. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Therapy in Intensive Care Unit)

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16 pages, 2774 KiB

Open AccessArticle

Optimizing Antibiotic Therapy for Stenotrophomonas maltophilia Infections in Critically Ill Patients: A Pharmacokinetic/Pharmacodynamic Approach

by Helena Barrasa, Miguel Angel Morán, Leire Fernández-Ciriza, Arantxa Isla, María Ángeles Solinís, Andrés Canut-Blasco and Alicia Rodríguez-Gascón

Antibiotics 2024, 13(6), 553; https://doi.org/10.3390/antibiotics13060553 - 13 Jun 2024

Cited by 2 | Viewed by 5314

Abstract

Stenotrophomonas maltophilia is an opportunistic, multidrug-resistant non-fermentative Gram-negative bacillus, posing a significant challenge in clinical treatment due to its numerous intrinsic and acquired resistance mechanisms. This study aimed to evaluate the adequacy of antibiotics used for the treatment of S. maltophilia infections in critically ill patients using a pharmacokinetic/pharmacodynamic (PK/PD) approach. The antibiotics studied included cotrimoxazole, levofloxacin, minocycline, tigecycline, cefiderocol, and the new combination aztreonam/avibactam, which is not yet approved. By Monte Carlo simulations, the probability of target attainment (PTA), the PK/PD breakpoints, and the cumulative fraction of response (CFR) were estimated. PK parameters and MIC distributions were sourced from the literature, the European Committee on Antimicrobial Susceptibility Testing (EUCAST), and the SENTRY Antimicrobial Surveillance Program collection. Cefiderocol 2 g q8h, minocycline 200 mg q12h, tigecycline 100 mg q12h, and aztreonam/avibactam 1500/500 mg q6h were the best options to treat empirically infections due to S. maltophilia. Cotrimoxazole provided a higher probability of treatment success for the U.S. isolates than for European isolates. For all antibiotics, discrepancies between the PK/PD breakpoints and the clinical breakpoints defined by EUCAST (or the ECOFF) and CLSI were detected. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Therapy in Intensive Care Unit)

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13 pages, 293 KiB

Open AccessArticle

Catastrophic Streptococcus pyogenes Disease: A Personalized Approach Based on Phenotypes and Treatable Traits

by Juan Carlos Ruiz-Rodríguez, Luis Chiscano-Camón, Carolina Maldonado, Adolf Ruiz-Sanmartin, Laura Martin, Ivan Bajaña, Juliana Bastidas, Rocio Lopez-Martinez, Clara Franco-Jarava, Juan José González-López, Vicent Ribas, Nieves Larrosa, Jordi Riera, Xavier Nuvials-Casals and Ricard Ferrer

Antibiotics 2024, 13(2), 187; https://doi.org/10.3390/antibiotics13020187 - 15 Feb 2024

Cited by 4 | Viewed by 2930

Abstract

Streptococcal toxic shock syndrome (STTS) is a critical medical emergency marked by high morbidity and mortality, necessitating swift awareness, targeted treatment, and early source control due to its rapid symptom manifestation. This report focuses on a cohort of 13 patients admitted to Vall d’Hebron University Hospital Intensive Care Unit, Barcelona, from November 2022 to March 2023, exhibiting invasive Streptococcus pyogenes infections and meeting institutional sepsis code activation criteria. The primary infections were community-acquired pneumonia (61.5%) and skin/soft tissue infection (30.8%). All patients received prompt antibiotic treatment, with clinical source control through thoracic drainage (30.8%) or surgical means (23.1%). Organ support involved invasive mechanical ventilation, vasopressors, and continuous renal replacement therapy as per guidelines. Of note, 76.9% of patients experienced septic cardiomyopathy, and 53.8% required extracorporeal membrane oxygenation (ECMO). The study identified three distinct phenotypic profiles—hyperinflammatory, low perfusion, and hypogammaglobulinemic—which could guide personalized therapeutic approaches. STTS, with a mean SOFA score of 17 (5.7) and a 53.8% requiring ECMO, underscores the need for precision medicine-based rescue therapies and sepsis phenotype identification. Integrating these strategies with prompt antibiotics and efficient source control offers a potential avenue to mitigate organ failure, enhancing patient survival and recovery in the face of this severe clinical condition. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Therapy in Intensive Care Unit)

11 pages, 1357 KiB

Open AccessArticle

Extended Versus Intermittent Meropenem Infusion in the Treatment of Nosocomial Pneumonia: A Retrospective Single-Center Study

by Dong-gon Hyun, Jarim Seo, Su Yeon Lee, Jee Hwan Ahn, Sang-Bum Hong, Chae-Man Lim, Younsuck Koh and Jin Won Huh

Antibiotics 2023, 12(10), 1542; https://doi.org/10.3390/antibiotics12101542 - 15 Oct 2023

Cited by 2 | Viewed by 3767

Abstract

The efficacy of extended meropenem infusions in patients with nosocomial pneumonia is not well defined. Therefore, we compared the clinical outcomes of extended versus intermittent meropenem infusions in the treatment of nosocomial pneumonia. We performed a retrospective analysis of extended versus intermittent meropenem infusions in adult patients who had been treated for nosocomial pneumonia at a medical ICU between 1 May 2018 and 30 April 2020. The primary outcome was mortality at 14 days. Overall, 64 patients who underwent an extended infusion and 97 with an intermittent infusion were included in this study. At 14 days, 10 (15.6%) patients in the extended group and 22 (22.7%) in the intermittent group had died (adjusted hazard ratio (HR), 0.55; 95% confidence interval (CI): 0.23–1.31; p = 0.174). In the subgroup analysis, significant differences in mortality at day 14 were observed in patients following empirical treatment with meropenem (adjusted HR, 0.17; 95% CI: 0.03–0.96; p = 0.045) and in Gram-negative pathogens identified by blood or sputum cultures (adjusted HR, 0.01; 95% CI: 0.01–0.83; p = 0.033). Extended infusion of meropenem compared with intermittent infusion as a treatment option for nosocomial pneumonia may have a potential advantage in specific populations. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Therapy in Intensive Care Unit)

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12 pages, 276 KiB

Open AccessArticle

Real-Time TDM-Based Expert Clinical Pharmacological Advice Program for Attaining Aggressive Pharmacokinetic/Pharmacodynamic Target of Continuous Infusion Meropenem in the Treatment of Critically Ill Patients with Documented Gram-Negative Infections Undergoing Continuous Veno-Venous Hemodiafiltration

by Milo Gatti, Matteo Rinaldi, Tommaso Tonetti, Antonio Siniscalchi, Pierluigi Viale and Federico Pea

Antibiotics 2023, 12(10), 1524; https://doi.org/10.3390/antibiotics12101524 - 10 Oct 2023

Cited by 3 | Viewed by 1829

Abstract

(1) Objectives: to describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of continuous infusion (CI) meropenem in critical patients with documented Gram-negative infections undergoing continuous veno-venous hemodiafiltration (CVVHDF) and to assess the relationship with microbiological outcome. (2) Methods: Data were retrospectively retrieved for patients admitted to the general and the post-transplant intensive care units in the period October 2022–May 2023 who underwent CVVHDF during treatment with CI meropenem optimized by means of a real-time therapeutic drug monitoring (TDM)-based expert clinical pharmacological advice (ECPA) program for documented Gram-negative infections. Steady-state meropenem plasma concentrations were measured, and the free fractions (fC_ss) were calculated. Meropenem total clearance (CL_tot) was calculated at each TDM assessment, and the impact of CVVHDF dose intensity and of residual diuresis on CL_tot was investigated by means of linear regression. Optimal meropenem PK/PD target attainment was defined as an fC_ss/MIC ratio > 4. The relationship between meropenem PK/PD target attainment and microbiological outcome was assessed. (3) Results: A total of 24 critical patients (median age 68 years; male 62.5%) with documented Gram-negative infections were included. Median (IQR) meropenem fC_ss was 19.9 mg/L (17.4–28.0 mg/L). Median (IQR) CL_tot was 3.89 L/h (3.28–5.29 L/h), and median (IQR) CVVHDF dose intensity was 37.4 mL/kg/h (33.8–44.6 mL/kg/h). Meropenem dosing adjustments were provided in 20 out of 24 first TDM assessments (83.3%, all decreases) and overall in 26 out of the 51 total ECPA cases (51.0%). Meropenem PK/PD target attainment was always optimal, and microbiological eradication was achieved in 90.5% of assessable cases. (4) Conclusion: the real-time TDM-guided ECPA program was useful in attaining aggressive PK/PD targeting with CI meropenem in critically ill patients undergoing high-intensity CVVHDF and allowed microbiological eradication in most cases with dosing regimens ranging between 125 and 500 mg q6h over 6 h. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Therapy in Intensive Care Unit)

Review

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36 pages, 1291 KiB

Open AccessReview

Difficult-to-Treat Pseudomonas aeruginosa Infections in Critically Ill Patients: A Comprehensive Review and Treatment Proposal

by Pablo Vidal-Cortés, Sandra Campos-Fernández, Elena Cuenca-Fito, Lorena del Río-Carbajo, Paula Fernández-Ugidos, Víctor J. López-Ciudad, Jorge Nieto-del Olmo, Ana Rodríguez-Vázquez and Ana I. Tizón-Varela

Antibiotics 2025, 14(2), 178; https://doi.org/10.3390/antibiotics14020178 - 11 Feb 2025

Viewed by 2986

Abstract

The management of infections caused by difficult-to-treat Pseudomonas aeruginosa in critically ill patients poses a significant challenge. Optimal antibiotic therapy is crucial for patient prognosis, yet the numerous resistance mechanisms of P. aeruginosa, which may even combine, complicate the selection of an appropriate antibiotic. In this review, we examine the epidemiology, resistance mechanisms, risk factors, and available and future therapeutic options, as well as strategies for treatment optimization. Finally, we propose a treatment algorithm to facilitate decision making based on the resistance patterns specific to each Intensive Care Unit. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Therapy in Intensive Care Unit)

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16 pages, 342 KiB

Open AccessReview

Stenotrophomonas maltophilia: The Landscape in Critically Ill Patients and Optimising Management Approaches

by Nieves Carbonell, María Rosa Oltra and María Ángeles Clari

Antibiotics 2024, 13(7), 577; https://doi.org/10.3390/antibiotics13070577 - 22 Jun 2024

Cited by 1 | Viewed by 3413

Abstract

The aim of this review is to synthesise the key aspects of the epidemiology, current microbiological diagnostic challenges, antibiotic resistance rates, optimal antimicrobial management, and most effective prevention strategies for Stenotrophomonas maltophilia (SM) in the intensive care unit (ICU) population. In recent years, resistance surveillance data indicate that SM accounts for less than 3% of all healthcare-associated infection strains, a percentage that doubles in the case of ventilator-associated pneumonia (VAP). Interestingly, SM ranks as the third most isolated non-glucose fermenter Gram-negative bacilli (NFGNB). Although this NFGNB genus has usually been considered a bystander and colonising strain, recently published data warn about its potential role as a causative pathogen of severe infections, particularly pneumonia and bloodstream infections (BSI), not only for the classical immunocompromised susceptible host patients but also for critically ill ones even without overt immunosuppression. Indeed, it has been associated with crude 28-day mortality as high as 54.8%, despite initial response following targeted therapy. Additionally, alongside its intrinsic resistance to a wide range of common antimicrobials, various worldwide and local surveillance studies raise concerns about an increase in ICU settings regarding resistance to first-line drugs such as cotrimoxazole or tigecycline. This scenario alerts ICU physicians to the need to reconsider the best stewardship approach when SM is isolated in obtained samples from critically ill patients. Despite the coverage of this multidrug-resistant bacterium (MDRB) provided by some traditional and a non-negligible number of current pipeline antimicrobials, an ecological and cost-effective strategy is needed in the present era. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Therapy in Intensive Care Unit)

Other

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14 pages, 1750 KiB

Open AccessSystematic Review

Cefiderocol Versus Best Available Therapy in the Treatment of Critically Ill Patients with Severe Infections Due to Resistant Gram-Negative Bacteria: A Systematic Review and Meta-Analysis

by Carlos Risco-Risco, César Henriquez-Camacho, Marta Herrera-Rueda, José Barberán and David Andaluz-Ojeda

Antibiotics 2024, 13(11), 1048; https://doi.org/10.3390/antibiotics13111048 - 5 Nov 2024

Cited by 2 | Viewed by 2370

Abstract

Background: This study aims to assess the effectiveness and safety of cefiderocol in treating severe infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) in critically ill patients, particularly those in intensive care units (ICUs). Methods: A meta-analysis of studies, including randomized clinical trials and observational studies in adult patients, was performed. Studies with at least 50% of critically ill patients were included. Studies with small sample size or without comparison groups were excluded. Sources included PubMed, Scopus, or Google Scholar, up to 14 August 2024. Risk of bias was assessed according to the Cochrane tool. The main outcome examined was 30-day mortality, while secondary outcomes assessed included clinical cure rates and adverse effects. Results were expressed with odds ratios. No funding was received for this study. It was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with reference CRD42024563041. Results: eight studies, with 1339 patients were included in the meta-analysis. Cefiderocol treatment was associated with a lower 30-day mortality rate than other available therapies (pooled OR 0.47; 95% CI: 0.23–0.97, p = 0.04), particularly in cases of carbapenem-resistant A. baumannii infections (pooled OR 0.29; 95% CI: 0.14–0.60, p < 0.001). Although there was a non-significant trend toward higher clinical cure rates in the cefiderocol group (OR 1.59; 95% CI: 0.96–2.62, p = 0.07), the drug demonstrated at least non-inferiority when compared to other treatment options. Study limitations included moderate heterogeneity between studies, and a high risk of bias in non-RCT studies. (Five cohort studies were included). Another limitation is that five of the eight studies compared cefiderocol versus colistine, an antibiotic with known toxicity. Conclusions: The findings suggest that cefiderocol is a promising therapeutic option for managing severe MDR-GNB infections in critically ill patients, offering a potential global benefit on mortality and at least non-inferiority in the cure rate when compared with other therapies. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Therapy in Intensive Care Unit)

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