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Antibiotics Use and Therapy in Gram-Negative Bacterial Infection

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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: closed (29 February 2024) | Viewed by 28697

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Prof. Dr. Maria Helena Rigatto

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1. Internal Medicine Department, Federal University of Rio Grande do Sul Medical School, Porto Alegre, RS, Brazil
2. Medical Sciences Postgraduate Program, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
3. Infectious Disease Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
Interests: bacterial resistance; gram-negative infections; polymyxins

Special Issue Information

Dear Colleagues,

Gram-negative bacterial infections represent a major worldwide public health concern. The sharp rise in bacterial resistance and high mortality rates associated to these infections have placed these organisms on the World Health Organization Global priority list of antibiotic-resistant bacteria, in order to guide research, discovery, and the development of new antibiotics, with high priority given to carbapenem-resistant Gram-negative bacilli (GNB). New antimicrobials have been launched in the last decade to treat these infections—mostly combinations of new beta-lactams/beta-lactamase inhibitors. While significant improvement in patients’ outcomes have been reported with these new drugs, many therapeutic challenges remain. First, not all GNBs respond adequately to these new therapeutic options; in particular, Acinetobacter baumannii, some Pseudomonas aeruginosa and class B carbapenemase-producing Enterobaterales isolates, can be unaffected. Second, resistance to these new agents has increasingly been reported. Questions about the potential benefit of combination therapy, ideal antimicrobial dose and duration remain open. Finally, some of these new agents are either not available in low-income and developing countries, or their wide use may be cost-prohibitive in these localities. Therefore, the use of old antibiotics, such as polymyxins and aminoglycosides, which are related to high toxicity rates, have not been abandoned as part of the therapeutic armamentarium against these bacteria. This Special Issue seeks manuscript submissions that enhance our understanding of antimicrobial options to treat GNB infections. We especially encourage submissions evaluating treatment strategies in the challenging scenario of multi-drug resistant organisms.

Prof. Dr. Maria Helena Rigatto
Guest Editor

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Keywords

gram-negative infections
carbapenem resistance
combination therapy
therapy duration

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Published Papers (10 papers)

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Research

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13 pages, 267 KiB

Open AccessArticle

Phenotypic and Genotypic Characterization of Pan-Drug-Resistant Klebsiella pneumoniae Isolated in Qatar

by Mazen A. Sid Ahmed, Jemal M. Hamid, Ahmed M. M. Hassan, Sulieman Abu Jarir, Emad Bashir Ibrahim and Hamad Abdel Hadi

Antibiotics 2024, 13(3), 275; https://doi.org/10.3390/antibiotics13030275 - 19 Mar 2024

Cited by 1 | Viewed by 2087

Abstract

In secondary healthcare, carbapenem-resistant Enterobacterales (CREs), such as those observed in Klebsiella pneumoniae, are a global public health priority with significant clinical outcomes. In this study, we described the clinical, phenotypic, and genotypic characteristics of three pan-drug-resistant (PDR) isolates that demonstrated extended resistance to conventional and novel antimicrobials. All patients had risk factors for the acquisition of multidrug-resistant organisms, while microbiological susceptibility testing showed resistance to all conventional antimicrobials. Advanced susceptibility testing demonstrated resistance to broad agents, such as ceftazidime-avibactam, ceftolozane–tazobactam, and meropenem–vaborbactam. Nevertheless, all isolates were susceptible to cefiderocol, suggested as one of the novel antimicrobials that demonstrated potent in vitro activity against resistant Gram-negative bacteria, including CREs, pointing toward its potential therapeutic role for PDR pathogens. Expanded genomic studies revealed multiple antimicrobial-resistant genes (ARGs), including bla_NMD-5 and bla_OXA derivative types, as well as a mutated outer membrane porin protein (OmpK37). Full article

(This article belongs to the Special Issue Antibiotics Use and Therapy in Gram-Negative Bacterial Infection)

20 pages, 747 KiB

Open AccessFeature PaperArticle

Characterization of Antibiotic Treatment among Children Aged 0–59 Months Hospitalized for Acute Bacterial Gastroenteritis in Israel

by Muna Omar, Eias Kassem, Roula Abu-Jabal, Basher Mwassi, Dani Cohen and Khitam Muhsen

Antibiotics 2024, 13(1), 64; https://doi.org/10.3390/antibiotics13010064 - 8 Jan 2024

Cited by 1 | Viewed by 2946

Abstract

Background: We examined the extent and correlates of appropriate antibiotic use among children hospitalized with bacterial acute gastroenteritis (AGE) in Israel, a high-income country setting. Methods: Data were collected from children aged 0–59 months who participated in active hospital-based surveillance of AGE undertaken during 2007–2015. Bacterial AGE was defined as having a positive stool culture for Salmonella, Shigella, Campylobacter, or dysentery. Appropriate antibiotic use was defined as the administration of ciprofloxacin, azithromycin, or third-generation cephalosporins during hospitalization or at discharge. Results: Overall, 550 children had bacterial AGE; of those, 369 (67.1% [95% CI 63.1–70.9]) received antibiotics, mostly azithromycin (61.8%) and third-generation cephalosporins (37.9%). Appropriate antibiotic treatment was given to 318/550 (57.8% [95% CI 53.7–61.9]). Children aged 0–11 months vs. 24–49 months were more likely to receive appropriate antibiotic treatment (OR = 1.90 [95% CI 1.09–3.33]). Having dysentery (OR = 5.30 [95% CI 3.35–8.39]), performing blood culture (OR = 1.59 [95% CI 1.02–2.48]), and C-reactive protein (CRP) levels (OR = 1.01 [95% CI 1.01–1.02]) were positively associated with receiving appropriate antibiotic treatment. Conclusions: Most children with bacterial AGE received appropriate antibiotic treatment, which correlated with young age, dysentery, CRP level, and performing blood culture, suggesting more severe illness, thus supporting the clinical decisions of physicians. Full article

(This article belongs to the Special Issue Antibiotics Use and Therapy in Gram-Negative Bacterial Infection)

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19 pages, 4545 KiB

Open AccessEditor’s ChoiceArticle

Exploring Structure–Activity Relationships of Niclosamide-Based Colistin Potentiators in Colistin-Resistant Gram-Negative Bacteria

by Liam Berry, Quinn Neale, Rajat Arora, Danyel Ramirez, Marc Brizuela, Ronald Domalaon, Gilbert Arthur and Frank Schweizer

Antibiotics 2024, 13(1), 43; https://doi.org/10.3390/antibiotics13010043 - 3 Jan 2024

Cited by 3 | Viewed by 2061

Abstract

Colistin is primarily used as a last resort antibiotic against highly resistant Gram-negative bacteria (GNB). Rising rates of colistin resistance, however, may limit future use of this agent. The anthelmintic drug niclosamide has been shown to enhance colistin activity in combination therapy, but a detailed structure–activity relationship (SAR) for niclosamide against GNB has yet to be studied. A series of niclosamide analogs were synthesized to perform an SAR, leading to the discovery of a lead compound that displayed comparable colistin-potentiating activity to niclosamide with reduced cytotoxicity. Overall, this work provides important insights into synthetic strategies for the future development of new niclosamide derivatives and demonstrates that toxicity to mammalian cells can be reduced while maintaining colistin potentiation. Full article

(This article belongs to the Special Issue Antibiotics Use and Therapy in Gram-Negative Bacterial Infection)

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13 pages, 2260 KiB

Open AccessArticle

Comparative Meropenem Pharmacodynamics and Emergence of Resistance against Carbapenem-Susceptible Non-Carbapenemase-Producing and Carbapenemase-Producing Enterobacterales: A Pharmacodynamic Study in a Hollow-Fiber Infection Model

by Maria V. Golikova, Kamilla N. Alieva, Elena N. Strukova, Daria A. Kondratieva, Nika F. Petrova, Mayya A. Petrova and Stephen H. Zinner

Antibiotics 2023, 12(12), 1717; https://doi.org/10.3390/antibiotics12121717 - 12 Dec 2023

Viewed by 1945

Abstract

Resistance to carbapenems has become a problem due to Klebsiella pneumoniae (K. pneumoniae), harboring carbapenemases. Among them, there are isolates that are recognized as carbapenem-susceptible; however, these carbapenemase-producing strains with low meropenem minimal inhibitory concentrations (MICs) may pose a threat to public health. We aimed to investigate the impact of the ability to produce carbapenemases by a bacterial isolate on the effectiveness of meropenem in the hollow-fiber infection model. K. pneumoniae and Escherichia coli (E. coli) strains with equal meropenem MICs but differing in their ability to produce carbapenemases were used in pharmacodynamic simulations with meropenem. In addition to standard MIC determination, we assessed the MICs against tested strains at high inoculum density to test if the inoculum effect occurs. According to pharmacodynamic data, the carbapenemase-producing strains were characterized with a relatively decreased meropenem effectiveness compared to non-producers. Meanwhile, the effect of meropenem perfectly correlated with the meropenem exposure expressed as the DOSE/MIC ratio when high-inoculum (HI) MICs but not standard-inoculum (SI) MICs were used for regression analysis. It could be concluded that meropenem-susceptible carbapenemase-producing strains may not respond to meropenem therapy; the antibiotic inoculum effect (IE) may have a prognostic value to reveal the meropenem-susceptible Enterobacterales that harbor carbapenemase genes. Full article

(This article belongs to the Special Issue Antibiotics Use and Therapy in Gram-Negative Bacterial Infection)

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12 pages, 827 KiB

Open AccessFeature PaperArticle

Comparison between Colistin and Polymyxin B in the Treatment of Bloodstream Infections Caused by Carbapenem-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii-calcoaceticus Complex

by Rebeca Carvalho Lacerda Garcia, Rodrigo Douglas Rodrigues, Ester Carvalho Lacerda Garcia and Maria Helena Rigatto

Antibiotics 2023, 12(8), 1317; https://doi.org/10.3390/antibiotics12081317 - 15 Aug 2023

Cited by 5 | Viewed by 3515

Abstract

Polymyxins are still widely used for the treatment of carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa bloodstream infections (BSIs). This study seeks to evaluate the impact of polymyxin B versus colistin on mortality and nephrotoxicity in BSI caused by these bacteria. We conducted a retrospective cohort study from 2014 to 2021 in Porto Alegre, Brazil. We included patients aged ≥18 years and excluded patients with polymicrobial infection or treatment for ≤48 h. The 30-day mortality was the primary outcome evaluated through Cox regression. We included 259 patients with BSI episodes: 78.8% caused by A. baumannii and 21.2% caused by P. aeruginosa. Polymyxin B did not impact mortality compared to colistin (adjusted hazard ratio (aHR), 0.82; 95% confidence interval (CI), 0.52–1.30; p = 0.40 (when adjusted for COVID-19 comorbidity, p = 0.05), Pitt bacteremia score, p < 0.01; Charlson comorbidity index, p < 0.001; time to start active antimicrobial therapy, p = 0.02). Results were maintained in the subgroups of BSI caused by A. baumannii (aHR, 0.92; 95% CI, 0.55–1.54; p = 0.74), P. aeruginosa (aHR, 0.47; 95% CI, 0.17–1.32; p = 0.15) and critical care patients (aHR, 0.77; 95% CI, 0.47–1.26; p = 0.30). Treatment with polymyxin B or colistin did not impact 30-day mortality in patients with carbapenem-resistant A. baumannii or P. aeruginosa BSI. Full article

(This article belongs to the Special Issue Antibiotics Use and Therapy in Gram-Negative Bacterial Infection)

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16 pages, 4890 KiB

Open AccessArticle

Fluorescence Microscopy: Determination of Meropenem Activity against Klebsiella pneumoniae

by Kamilla N. Alieva, Maria V. Golikova, Anastasia A. Kuznetsova and Stephen H. Zinner

Antibiotics 2023, 12(7), 1170; https://doi.org/10.3390/antibiotics12071170 - 10 Jul 2023

Cited by 2 | Viewed by 1680

Abstract

The development and implementation of diagnostic methods that allow rapid assessment of antibiotic activity against pathogenic microorganisms is an important step towards antibiotic therapy optimization and increase in the likelihood of successful treatment outcome. To determine whether fluorescence microscopy with acridine orange can be used for rapid assessment (≤8 h) of the meropenem activity against Klebsiella pneumoniae, six isolates including three OXA-48-carbapenemase-producers were exposed to meropenem at different levels of its concentration (0.5 × MIC, 1 × MIC, 8 or 16 µg/mL) and the changes in the viable counts within 24 h were evaluated using fluorescence microscopy and a control culture method. The approach was to capture the regrowth of bacteria as early as possible. Within the first 8 h fluorescence microscopy allowed to categorize 5 out of 6 K. pneumoniae strains by their meropenem susceptibility (based on the MIC breakpoint of 8 mg/L), but meropenem activity against three isolates, two of which were OXA-48-producers, could not be accurately determined at 8 h. The method proposed in our study requires improvement in terms of accelerating the bacterial growth and regrowth for early meropenem MIC determination. Volume-dependent elevation in meropenem MICs against OXA-48-producers was found and this phenomenon should be studied further. Full article

(This article belongs to the Special Issue Antibiotics Use and Therapy in Gram-Negative Bacterial Infection)

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11 pages, 832 KiB

Open AccessEditor’s ChoiceArticle

Comparison of Cefepime with Piperacillin/Tazobactam Treatment in Patients with Hospital-Acquired Pneumonia

by Bo-Guen Kim, Danbee Kang, Kyung Hoon Min, Juhee Cho and Kyeongman Jeon

Antibiotics 2023, 12(6), 984; https://doi.org/10.3390/antibiotics12060984 - 30 May 2023

Cited by 3 | Viewed by 7764

Abstract

Although cefepime and piperacillin/tazobactam are commonly prescribed for the treatment of hospital-acquired pneumonia (HAP), which one is the superior therapy remains unclear. Using Korean National Health Insurance Service data from January 2018 to December 2018, we compared the clinical outcomes of patients with HAP who were treated with cefepime and those treated with piperacillin/tazobactam. Data from 9955 adult patients with HAP, of whom 1502 (15%) received cefepime and 8453 (85%) received piperacillin/tazobactam, were retrieved for primary analysis. Tube feeding, suctioning, positioning care, and intensive care unit admission were more common among patients who received piperacillin/tazobactam. Treatment outcomes, including rates of in-hospital mortality, pneumonia-related readmission, and all-cause mortality within 6 months after discharge, were comparable between the two groups. In a subgroup analysis of data from patients who required tube feeding, the risk for in-hospital mortality was significantly higher among those who received cefepime (fully adjusted odds ratio, 1.43; 95% confidence interval, 1.04–1.97; p = 0.042). Treatment outcomes did not differ between patients who received cefepime and those who received piperacillin/tazobactam treatment, but among patients who were at risk for aspiration, such as those receiving tube feeding, those who received piperacillin/tazobactam had lower rates of in-hospital mortality. Full article

(This article belongs to the Special Issue Antibiotics Use and Therapy in Gram-Negative Bacterial Infection)

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14 pages, 1493 KiB

Open AccessArticle

Inverse Association between the Existence of CRISPR/Cas Systems with Antibiotic Resistance, Extended Spectrum β-Lactamase and Carbapenemase Production in Multidrug, Extensive Drug and Pandrug-Resistant Klebsiella pneumoniae

by Noor A. Jwair, Mushtak T. S. Al-Ouqaili and Farah Al-Marzooq

Antibiotics 2023, 12(6), 980; https://doi.org/10.3390/antibiotics12060980 - 29 May 2023

Cited by 19 | Viewed by 2568

Abstract

Antimicrobial resistance, with the production of extended-spectrum β-lactamases (ESBL) and carbapenemases, is common in the opportunistic pathogen, Klebsiella pneumoniae. This organism has a genome that can contain clustered regularly interspaced short palindromic repeats (CRISPRs), which operate as a defense mechanism against external invaders such as plasmids and viruses. This study aims to determine the association of the CRISPR/Cas systems with antibiotic resistance in K. pneumoniae isolates from Iraqi patients. A total of 100 K. pneumoniae isolates were collected and characterized according to their susceptibility to different antimicrobial agents. The CRISPR/Cas systems were detected via PCR. The phenotypic detection of ESBLs and carbapenemases was performed. The production of ESBL was detected in 71% of the isolates. Carbapenem-resistance was detected in 15% of the isolates, while only 14% were susceptible to all antimicrobial agents. Furthermore, the bacteria were classified into multidrug (77%), extensively drug-resistant (11.0%) and pandrug-resistant (4.0%). There was an inverse association between the presence of the CRISPR/Cas systems and antibiotic resistance, as resistance was higher in the absence of the CRISPR/Cas system. Multidrug resistance in ESBL-producing and carbapenem-resistant K. pneumoniae occurred more frequently in strains negative for the CRISPR/Cas system. Thus, we conclude that genes for exogenous antibiotic resistance can be acquired in the absence of the CRISPR/Cas modules that can protect the bacteria against acquiring foreign DNA. Full article

(This article belongs to the Special Issue Antibiotics Use and Therapy in Gram-Negative Bacterial Infection)

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12 pages, 297 KiB

Open AccessArticle

In Vitro Activity of Cefiderocol against Clinical Gram-Negative Isolates Originating from Germany in 2016/17

by Esther Wohlfarth, Michael Kresken, Fabian Deuchert, Sören G. Gatermann, Yvonne Pfeifer, Niels Pfennigwerth, Harald Seifert, Paul G. Higgins, Guido Werner and Study Group ‘Antimicrobial Resistance‘ of the Paul Ehrlich Society for Infection Therapy

Antibiotics 2023, 12(5), 864; https://doi.org/10.3390/antibiotics12050864 - 6 May 2023

Cited by 1 | Viewed by 2068

Abstract

Antimicrobial resistance poses a global threat to public health. Of great concern are Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales with resistance to carbapenems or third-generation cephalosporins. The aim of the present study was to investigate the in vitro activity of the novel siderophore cephaloporin cefiderocol (CID) and four comparator β-lactam-β-lactamase-inhibitor combinations and to give insights into the genetic background of CID-resistant isolates. In total, 301 clinical Enterobacterales and non-fermenting bacterial isolates were selected for this study, including randomly chosen isolates (set I, n = 195) and challenge isolates (set II, n = 106; enriched with ESBL and carbapenemase producers, as well as colistin-resistant isolates). Isolates displayed CID MIC_50/90 values of 0.12/0.5 mg/L (set I) and 0.5/1 mg/L (set II). Overall, the CID activity was superior to the comparators against A. baumannii, Stenotrophomonas maltophilia and set II isolates of P. aeruginosa. There were eight CID-resistant isolates detected (MIC > 2 mg/L): A. baumannii (n = 1), E. cloacae complex (n = 5) and P. aeruginosa (n = 2). Sequencing analyses of these isolates detected the acquired β-lactamase (bla) genes bla_NDM-1, bla_SHV-12 and naturally occurring bla_OXA-396, bla_ACT-type and bla_CMH-3. In conclusion, CID revealed potent activity against clinically relevant organisms of multidrug-resistant Enterobacterales and non-fermenters. Full article

(This article belongs to the Special Issue Antibiotics Use and Therapy in Gram-Negative Bacterial Infection)

Review

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21 pages, 1644 KiB

Open AccessReview

Relevance of the Adjuvant Effect between Cellular Homeostasis and Resistance to Antibiotics in Gram-Negative Bacteria with Pathogenic Capacity: A Study of Klebsiella pneumoniae

by Mildred Azucena Rivera-Galindo, Félix Aguirre-Garrido, Ulises Garza-Ramos, José Geiser Villavicencio-Pulido, Francisco José Fernández Perrino and Marcos López-Pérez

Antibiotics 2024, 13(6), 490; https://doi.org/10.3390/antibiotics13060490 - 26 May 2024

Cited by 2 | Viewed by 1302

Abstract

Antibiotic resistance has become a global issue. The most significant risk is the acquisition of these mechanisms by pathogenic bacteria, which can have a severe clinical impact and pose a public health risk. This problem assumes that bacterial fitness is a constant phenomenon and should be approached from an evolutionary perspective to develop the most appropriate and effective strategies to contain the emergence of strains with pathogenic potential. Resistance mechanisms can be understood as adaptive processes to stressful conditions. This review examines the relevance of homeostatic regulatory mechanisms in antimicrobial resistance mechanisms. We focus on the interactions in the cellular physiology of pathogenic bacteria, particularly Gram-negative bacteria, and specifically Klebsiella pneumoniae. From a clinical research perspective, understanding these interactions is crucial for comprehensively understanding the phenomenon of resistance and developing more effective drugs and treatments to limit or attenuate bacterial sepsis, since the most conserved adjuvant phenomena in bacterial physiology has turned out to be more optimized and, therefore, more susceptible to alterations due to pharmacological action. Full article

(This article belongs to the Special Issue Antibiotics Use and Therapy in Gram-Negative Bacterial Infection)

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