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Multi-Drug Resistant Gram-Negative Microorganisms: Epidemiology, Treatment and Alternative Approach

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A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 31688

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Dr. Maria Teresa Mascellino

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Department of Public Health and Infectious Diseases, Policlinico Umberto1 viale del Policlinico 155, Rome, Italy
Interests: bacterial antibiotic resistance; multidrug resistant microorganisms (MDR bacteria); probiotics; molecular laboratory methods; bacterial infections; biofilm and sonication; double carbapenem synergistic activity; association of antibiotics; enterobacterales; antimicrobial agents and resistance; relationship with the therapeutic approach; microbiota; Clostridium difficile infection; bacterial translocation and virulence factors; COVID 19 vaccines
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Dear Colleagues,

Infections caused by multidrug-resistant (MDR) Gram-negative bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae, especially carbapenem-resistant Klebsiella pneumoniae (CR-KP), constitute an important issue for establishing a correct and appropriate therapy. Outbreaks due to KPC (K. pneumoniae carbapenemase) have been detected in many countries around the world; indeed, these infections have become endemic not just in Europe but also in the United States, Israel, and China. KPC is an important mechanism of resistance for an increasingly wide range of Gram-negative bacteria. Reducing the spread of resistant pathogens, other than reducing the rate of resistance evolution, is a complex task to be achieved. Therapeutic regimens currently available are encountering several problems due to the diffusion of multidrug resistance. Old antibiotics such as colistin and fosphomycin in combination with other antibiotics should be evaluated. New antibiotics such as tigecycline, ceftolozane–tazobactam, aztreonam–avibactam, cefiderocol, ceftazidime–avibactam, meropenem–vaborbactam, eravacycline and plazomicin should be taken into account. It would be desirable to look for any alternative approach, specifically the use of antimicrobial peptides that interact with the anionic Gram-negative cell wall because of charge electrostatic or the use of medicinal oils, antibodies, common biocides, killing factors, drugs with antibacterial activity different from antibiotics and even phage therapy.

Dr. Maria Mascellino
Guest Editor

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Keywords

Multi-drug resistance
Enterobacteriaceae
Acinetobacter baumannii
Pseudomonas aeruginosa
Resistant clinical strains
Colistin
Antibiotics combination
Double carbapenem
New antimicobial agents
Innovative therapies
Phage therapy

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Published Papers (9 papers)

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Editorial

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3 pages, 172 KiB

Open AccessEditorial

Multi-Drug-Resistant Gram-Negative Microorganisms: Epidemiology, Treatment and Alternative Approach

by Maria Teresa Mascellino

Antibiotics 2022, 11(5), 678; https://doi.org/10.3390/antibiotics11050678 - 18 May 2022

Cited by 2 | Viewed by 2099

Abstract

The presence of enzymes such as Extended-Spectrum β-lactamase (ESBL) and carbapenemases (KPCs, Metallo β-lactamases and OXA) constitutes the principal resistance mechanism to antibiotics [...] Full article

(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Microorganisms: Epidemiology, Treatment and Alternative Approach)

Research

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13 pages, 768 KiB

Open AccessArticle

Clinical Outcomes and Adverse Effects in Septic Patients with Impaired Renal Function Who Received Different Dosages of Cefoperazone–Sulbactam

by Chien-Hsiang Tai, Hung-Jen Tang and Chen-Hsiang Lee

Antibiotics 2022, 11(4), 460; https://doi.org/10.3390/antibiotics11040460 - 29 Mar 2022

Cited by 1 | Viewed by 3552

Abstract

This study aimed to compare clinical outcomes and adverse effects in septic patients with impaired renal function who received different dosages of cefoperazone–sulbactam (CFP–SUL 1 g/1 g or 2 g/2 g every 12 h). The retrospective study was conducted using the Chang Gung Research Database to include adult patients who had renal insufficiency presented with septicemia caused by Gram-negative organisms and had received CFP–SUL for more than 1 week. A total of 265 patients (44 in the CFP–SUL 1 g/1 g group and 221 in the CFP–SUL 2 g/2 g group) were eligible to be included in this study. After 1:3 propensity score matching, 41 and 123 patients in the CFP–SUL 1 g/1 g and CFP–SUL 2 g/2 g groups, respectively, were included for analyses. There were no significant between-group differences in all-cause mortality rates and adverse effects, including prolonged prothrombin time. A logistic regression model showed that the Pitt bacteremia score was related to all-cause mortality rate and prolonged prothrombin time was associated with renal replacement therapy. The adverse effects of CFP–SUL did not increase in septic patients with impaired renal function receiving CFP–SUL 2 g/2 g Q12H. However, this study may be underpowered to reveal a difference in all-cause mortality. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Microorganisms: Epidemiology, Treatment and Alternative Approach)

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9 pages, 1083 KiB

Open AccessArticle

Pharmacokinetic/Pharmacodynamic Analysis and Dose Optimization of Cefmetazole and Flomoxef against Extended-Spectrum β-Lactamase-Producing Enterobacterales in Patients with Invasive Urinary Tract Infection Considering Renal Function

by Yukihiro Hamada, Hidefumi Kasai, Moeko Suzuki-Ito, Yasufumi Matsumura, Yohei Doi and Kayoko Hayakawa

Antibiotics 2022, 11(4), 456; https://doi.org/10.3390/antibiotics11040456 - 28 Mar 2022

Cited by 4 | Viewed by 4146

Abstract

The optimal regimens of cefmetazole and flomoxef for the treatment of urinary tract infections caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacterales are not well defined. Our study found that the pharmacokinetic/pharmacodynamic targets for cefmetazole and flomoxef were 70% T > MIC, which is suggestive of bactericidal activity. A Monte Carlo simulation (MCS) was performed using the published data to calculate a new probability of target attainment (PTA ≥ 90%) for each renal function. The MCS was performed with 1000 replicates, and clinical breakpoints were calculated to attain PTA ≥ 90% for creatinine clearance (CCR) of 10, 30, 50, and 70 mL/min. The 90% ≥ PTA (70% T > MIC) of cefmetazole and flomoxef in patients who received a standard regimen (0.5 or 1 g, 1 h injection) for each renal function was calculated. Our results suggest that in patients with CCR of less than 30, 31–59, and more than 60 mL/min, the optimal dosage of cefmetazole would be 1 g q12 h, 1 g q8 h, and 1 g q6 h, respectively. Furthermore, in patients with CCR of less than 10, 10–50, and more than 50 mL/min, the optimal dosage of flomoxef would be 1 g q24 h, 1 g q8 h or 12 h, and 1 g q6 h, respectively. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Microorganisms: Epidemiology, Treatment and Alternative Approach)

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14 pages, 2393 KiB

Open AccessArticle

High Activity of N-Acetylcysteine in Combination with Beta-Lactams against Carbapenem-Resistant Klebsiella pneumoniae and Acinetobacter baumannii

by Massimiliano De Angelis, Maria T. Mascellino, Maria C. Miele, Dania Al Ismail, Marisa Colone, Annarita Stringaro, Vincenzo Vullo, Mario Venditti, Claudio M. Mastroianni and Alessandra Oliva

Antibiotics 2022, 11(2), 225; https://doi.org/10.3390/antibiotics11020225 - 10 Feb 2022

Cited by 11 | Viewed by 2727

Abstract

Aim: The aim of the study was to evaluate the in vitro activity of N-acetylcysteine (NAC), alone or in combination with beta-lactams, against carbapenem-resistant Klebsiella pneumoniae (CR-Kp) and Acinetobacter baumannii (CR-Ab). Methods: The antibacterial activity of each compound was tested by broth microdilution and the synergism was evaluated by the checkerboard method. Killing studies of NAC alone and in combination with beta-lactams were performed. Bacterial morphological changes were investigated with scanning electron microscopy (SEM). Results: Overall, 30 strains were included (15 CR-Kp and 15 CR-Ab). The NAC Minimal Inhibitory Concentrations (MIC)50/90 were 5/5 and 2.5/5 mg/mL for CR-Kp and CR-Ab, respectively. For both microorganisms, NAC, in addition to beta-lactams (meropenem for CR-Kp, meropenem and ampicillin/sulbactam for CR-Ab, respectively), was able to enhance their activity. The killing studies showed a rapid and concentration-dependent activity of NAC alone; the addition of NAC to meropenem or ampicillin/sulbactam at subinhibitory concentrations induced a fast and lasting bactericidal activity that persisted over time. The SEM analyses showed evident morphological alterations of the bacterial cells following incubation with NAC, alone and in combination with meropenem. Conclusions: NAC demonstrated a high in vitro activity against CR-Kp and CR-Ab and was able to enhance beta-lactams’ susceptibility in the tested strains. The preliminary data on the SEM analyses confirmed the in vitro results. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Microorganisms: Epidemiology, Treatment and Alternative Approach)

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20 pages, 8174 KiB

Open AccessArticle

Molecular Characterization of Carbapenem-Resistant Acinetobacter baumannii Isolated from the Intensive Care Unit in a Tertiary Teaching Hospital in Malaysia

by Jia Jie Woon, Cindy Shuan Ju Teh, Chun Wie Chong, Kartini Abdul Jabar, Sasheela Ponnampalavanar and Nuryana Idris

Antibiotics 2021, 10(11), 1340; https://doi.org/10.3390/antibiotics10111340 - 2 Nov 2021

Cited by 6 | Viewed by 3183

Abstract

The emergence of carbapenem-resistant Acinetobacter baumannii (CRAB) has now become a global sentinel event. CRAB infections often instigate severe clinical complications and are potentially fatal, especially for debilitated patients. The present study aimed to conduct molecular characterization on CRAB isolated from patients in the intensive care unit from 2015 to 2016 and determine the risk factors associated with patients’ mortality. One hundred CRAB isolates were retrospectively selected and included in this study. Antimicrobial susceptibility testing showed that all isolates remained susceptible to colistin, even though 62% of them conferred resistance to all other classes of antibiotics tested. OXA carbapenemase gene was found to be the predominant carbapenemase gene, with 99% of the isolates coharbouring bla_OXA-23-like and bla_OXA-51-like carbapenemase genes. All isolates were carrying intact CarO genes, with the presence of various degree of nucleotide insertion, deletion and substitution. Overall, PFGE subtyped the isolates into 13 distinct pulsotypes, with the presence of 2 predominant pulsotypes. Univariate analysis implied that age, infection/colonization by CRAB, ethnicity, comorbidity and CRAB specimen source were significantly associated with in-hospital mortality. Multivariate analysis identified a higher risk of mortality for patients who are of Chinese ethnicity with diabetes as an underlying disease. As CRAB infection could lead to high rate of mortality, comprehensive infection control measures are needed to minimize the spread of this pathogen. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Microorganisms: Epidemiology, Treatment and Alternative Approach)

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20 pages, 1088 KiB

Open AccessArticle

Effective Antimicrobial Solutions for Eradicating Multi-Resistant and β-Lactamase-Producing Nosocomial Gram-Negative Pathogens

by Elaine Meade, Micheal Savage and Mary Garvey

Antibiotics 2021, 10(11), 1283; https://doi.org/10.3390/antibiotics10111283 - 21 Oct 2021

Cited by 12 | Viewed by 3227

Abstract

Antimicrobial resistance (AMR) remains one of the greatest public health-perturbing crises of the 21st century, where species have evolved a myriad of defence strategies to resist conventional therapy. The production of extended-spectrum β-lactamase (ESBL), AmpC and carbapenemases in Gram-negative bacteria (GNB) is one such mechanism that currently poses a significant threat to the continuity of first-line and last-line β-lactam agents, where multi-drug-resistant GNB currently warrant a pandemic on their own merit. The World Health Organisation (WHO) has long recognised the need for an improved and coordinated global effort to contain these pathogens, where two factors in particular, international travel and exposure to antimicrobials, play an important role in the emergence and dissemination of antibiotic-resistant genes. Studies described herein assess the resistance patterns of isolated nosocomial pathogens, where levels of resistance were detected using recognised in vitro methods. Additionally, studies conducted extensively investigated alternative biocide (namely peracetic acid, triameen and benzalkonium chloride) and therapeutic options (specifically 1,10-phenanthroline-5,6-dione), where the levels of induced endotoxin from E. coli were also studied for the latter. Antibiotic susceptibility testing revealed there was a significant association between multi-drug resistance and ESBL production, where the WHO critical-priority pathogens, namely E. coli, K. pneumoniae, A. baumannii and P. aeruginosa, exhibited among the greatest levels of multi-drug resistance. Novel compound 1,10-phenanthroline-5,6-dione (phendione) shows promising antimicrobial activity, with MICs determined for all bacterial species, where levels of induced endotoxin varied depending on the concentration used. Tested biocide agents show potential to act as intermediate-level disinfectants in hospital settings, where all tested clinical isolates were susceptible to treatment. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Microorganisms: Epidemiology, Treatment and Alternative Approach)

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10 pages, 772 KiB

Open AccessArticle

Multi-Drug Resistant Organisms Infection Impact on Patients Length of Stay in Respiratory Care Ward

by Yi-Ping Chen, Xian-Wen Tasi, Ko Chang, Xuan-Di Cao, Jung-Ren Chen and Chien-Sen Liao

Antibiotics 2021, 10(5), 608; https://doi.org/10.3390/antibiotics10050608 - 20 May 2021

Cited by 5 | Viewed by 3110

Abstract

This study aimed to investigate the effects of multi-drug-resistant organism (MDRO) infection and other factors on the length of hospital stay (LOS) of patients in the respiratory care ward (RCW) of a regional hospital in Taiwan. In this retrospective study, we collected cases from MDRO-infected patients in the RCW from January 2016 to March 2020. The RCW comprises 13 beds in total. There were 106 infected patients, of which 42 were in the case group (infected with MDROs) and 64 were in the control group (not infected with MDROs). Clinical specimens were inoculated in a selective medium to isolate the pathogenic bacteria by standard procedures. The results showed the main factors affecting the LOS were: patients with MDRO infection, patients discharged from the RCW, and patients who underwent catheterization. The LOS of patients infected with MDROs was significantly longer than that of patients without MDRO infection (β = 0.55, 95% CI = 0.02–1.09), with the case group and the control group being 479.8 ± 546.5 and 307.3 ± 436.2 days, respectively. Infection with carbapenem-resistant Pseudomonas aeruginosa (CRPA) was associated with a longer LOS than other MDRO strains. These findings have important implications for infection control in RCW and in better tracking the health of patients. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Microorganisms: Epidemiology, Treatment and Alternative Approach)

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Review

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26 pages, 7831 KiB

Open AccessReview

Mutational Diversity in the Quinolone Resistance-Determining Regions of Type-II Topoisomerases of Salmonella Serovars

by Aqsa Shaheen, Anam Tariq, Mazhar Iqbal, Osman Mirza, Abdul Haque, Thomas Walz and Moazur Rahman

Antibiotics 2021, 10(12), 1455; https://doi.org/10.3390/antibiotics10121455 - 26 Nov 2021

Cited by 21 | Viewed by 3936

Abstract

Quinolone resistance in bacterial pathogens has primarily been associated with mutations in the quinolone resistance-determining regions (QRDRs) of bacterial type-II topoisomerases, which are DNA gyrase and topoisomerase IV. Depending on the position and type of the mutation (s) in the QRDRs, bacteria either become partially or completely resistant to quinolone. QRDR mutations have been identified and characterized in Salmonella enterica isolates from around the globe, particularly during the last decade, and efforts have been made to understand the propensity of different serovars to carry such mutations. Because there is currently no thorough analysis of the available literature on QRDR mutations in different Salmonella serovars, this review aims to provide a comprehensive picture of the mutational diversity in QRDRs of Salmonella serovars, summarizing the literature related to both typhoidal and non-typhoidal Salmonella serovars with a special emphasis on recent findings. This review will also discuss plasmid-mediated quinolone-resistance determinants with respect to their additive or synergistic contributions with QRDR mutations in imparting elevated quinolone resistance. Finally, the review will assess the contribution of membrane transporter-mediated quinolone efflux to quinolone resistance in strains carrying QRDR mutations. This information should be helpful to guide the routine surveillance of foodborne Salmonella serovars, especially with respect to their spread across countries, as well as to improve laboratory diagnosis of quinolone-resistant Salmonella strains. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Microorganisms: Epidemiology, Treatment and Alternative Approach)

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Other

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9 pages, 409 KiB

Open AccessCase Report

Meropenem/Vaborbactam Plus Aztreonam as a Possible Treatment Strategy for Bloodstream Infections Caused by Ceftazidime/Avibactam-Resistant Klebsiella pneumoniae: A Retrospective Case Series and Literature Review

by Alessandra Belati, Davide Fiore Bavaro, Lucia Diella, Nicolò De Gennaro, Francesco Di Gennaro and Annalisa Saracino

Antibiotics 2022, 11(3), 373; https://doi.org/10.3390/antibiotics11030373 - 10 Mar 2022

Cited by 18 | Viewed by 3777

Abstract

Objectives: The aim of this study was to describe our experience of a combination treatment including meropenem/vaborbactam (M/V) plus aztreonam (ATM) for bloodstream infections (BSIs) due to ceftazidime/avibactam-resistant Klebsiella pneumoniae (CAZ/AVI-R-Kp), for which gene typing was not available at the time the blood culture (BC) results were obtained. Methods: Between 20 July and 22 August 2021, in our hospital laboratory, the molecular test for carbapenemase gene typing was not available. All Gram-negative bloodstream infections were recorded, and characteristics of patients were analysed. Among them, three patients had positive BCs for CAZ/AVI-R-Kp, and the empirical therapy was switched to M/V plus ATM pending phenotypic testing of sensitivity to M/V. Therapy was subsequently targeted on the basis of the results of this test. Results: KPC and NDM represent the most prevalent carbapenemases in our polyclinic. Three patients with CAZ/AVI-R-Kp sepsis were treated with M/V plus ATM not knowing the carbapenemase gene. Two had an NDM-Kp infection for which, upon obtaining the result of sensitivity to M/V, combination therapy was maintained. The third had KPC-Kp infection for which ATM was discontinued, after the acquisition of an antibiogram reporting full sensitivity to M/V (MIC = 0.25 mg/L). One patient with NDM-Kp infection died due to complications of the underlying disease for which he was hospitalised. Conclusions: Meropenem/vaborbactam plus ATM and subsequent de-escalation could represent a possible therapeutic strategy in severe CAZ/AVI-R-Kp infections when carbapenemase gene typing is not rapidly available. Full article

(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Microorganisms: Epidemiology, Treatment and Alternative Approach)

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