Antimicrobial Resistance and Antimicrobial Therapy of Clinically Relevant Bacteria

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Mechanism and Evolution of Antibiotic Resistance".

Deadline for manuscript submissions: closed (29 February 2024) | Viewed by 14401

Special Issue Editors


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Guest Editor
Department of Microbiology, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
Interests: antibiotic resistance mechanisms; phenotypic and molecular methods for antibiotic resistance detection; Klebsiella pneumoniae; Pseudomonas aeruginosa; Acinetobacter baumannii; SARS-CoV-2; clinical microbiology

E-Mail Website
Guest Editor
Department of Microbiology, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
Interests: nosocomial infections; antimicrobial resistance mechanisms; HIV immunology; SARS-CoV-2 infection
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Microbiology, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
Interests: antibiotic resistance mechanisms; phenotypic and molecular methods for antibiotic resistance detection; Klebsiella pneumoniae; Pseudomonas aeruginosa; Acinetobacter baumannii; SARS-CoV-2; clinical microbiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Antimicrobial resistance is a public health problem of major importance, and the World Health Organization (WHO) has warned that the current antibiotic armamentarium is not sufficient to face future challenges. The antibiotic pipeline is not providing new compounds at a sufficient speed for various reasons, and thus few novel drugs have reached clinical practice lately and old, formerly abandoned antimicrobials are increasingly used as last-resort treatment options. At this pace, untreatable infections could emerge on a large scale, and the world may experience in some cases dramatic situations of the pre-antibiotic era. Already, clinicians in endemic areas routinely encounter patients with infections that do not respond to available treatments, and laboratories often report multidrug-resistant (MDR) or even pan-drug-resistant (PDR) bacteria. In this context, continuous monitoring of the resistance mechanisms’ epidemiology as well as knowledge regarding treatment options for clinically relevant bacteria are of great interest to health-care professionals. This Special Issue seeks manuscript submissions that further our understanding of antimicrobial resistance in clinically relevant bacteria, improvements in the detection of these mechanisms in laboratory practice as well as treatment solutions and observations. Submissions on the development of new antibiotic compounds or the in-vitro susceptibility of relevant bacteria to these compounds are especially encouraged.

Dr. Georgios Meletis
Dr. Lemonia Skoura
Dr. Efthymia Protonotariou
Guest Editors

Manuscript Submission Information

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Keywords

  • antimicrobial resistance mechanisms
  • antimicrobial resistance detection
  • antimicrobial resistance epidemiology
  • antimicrobial treatment
  • new antibiotics
  • MDR
  • Klebsiella pneumoniae
  • Acinetobacter baumannii
  • Pseudomonas aeruginosa
  • MRSA

Published Papers (8 papers)

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Research

13 pages, 1630 KiB  
Article
Competition between H4PteGlu and H2PtePAS Confers para-Aminosalicylic Acid Resistance in Mycobacterium tuberculosis
by Ji-Fang Yu, Jin-Tian Xu, Ao Feng, Bao-Ling Qi, Jing Gu, Jiao-Yu Deng and Xian-En Zhang
Antibiotics 2024, 13(1), 13; https://doi.org/10.3390/antibiotics13010013 (registering DOI) - 21 Dec 2023
Viewed by 990
Abstract
Tuberculosis remains a serious challenge to human health worldwide. para-Aminosalicylic acid (PAS) is an important anti-tuberculosis drug, which requires sequential activation by Mycobacterium tuberculosis (M. tuberculosis) dihydropteroate synthase and dihydrofolate synthase (DHFS, FolC). Previous studies showed that loss of function [...] Read more.
Tuberculosis remains a serious challenge to human health worldwide. para-Aminosalicylic acid (PAS) is an important anti-tuberculosis drug, which requires sequential activation by Mycobacterium tuberculosis (M. tuberculosis) dihydropteroate synthase and dihydrofolate synthase (DHFS, FolC). Previous studies showed that loss of function mutations of a thymidylate synthase coding gene thyA caused PAS resistance in M. tuberculosis, but the mechanism is unclear. Here we showed that deleting thyA in M. tuberculosis resulted in increased content of tetrahydrofolate (H4PteGlu) in bacterial cells as they rely on the other thymidylate synthase ThyX to synthesize thymidylate, which produces H4PteGlu during the process. Subsequently, data of in vitro enzymatic activity experiments showed that H4PteGlu hinders PAS activation by competing with hydroxy dihydropteroate (H2PtePAS) for FolC catalysis. Meanwhile, over-expressing folC in ΔthyA strain and a PAS resistant clinical isolate with known thyA mutation partially restored PAS sensitivity, which relieved the competition between H4PteGlu and H2PtePAS. Thus, loss of function mutations in thyA led to increased H4PteGlu content in bacterial cells, which competed with H2PtePAS for catalysis by FolC and hence hindered the activation of PAS, leading to decreased production of hydroxyl dihydrofolate (H2PtePAS-Glu) and finally caused PAS resistance. On the other hand, functional deficiency of thyA in M. tuberculosis pushes the bacterium switch to an unidentified dihydrofolate reductase for H4PteGlu biosynthesis, which might also contribute to the PAS resistance phenotype. Our study revealed how thyA mutations confer PAS resistance in M. tuberculosis and provided new insights into studies on the folate metabolism of the bacterium. Full article
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11 pages, 792 KiB  
Article
Neonatal Bloodstream Infection with Ceftazidime-Avibactam-Resistant blaKPC-2-Producing Klebsiella pneumoniae Carrying blaVEB-25
by Charalampos Zarras, Elias Iosifidis, Maria Simitsopoulou, Styliani Pappa, Angeliki Kontou, Emmanuel Roilides and Anna Papa
Antibiotics 2023, 12(8), 1290; https://doi.org/10.3390/antibiotics12081290 - 05 Aug 2023
Viewed by 1243
Abstract
Background: Although ceftazidime/avibactam (CAZ/AVI) has become an important option for treating adults and children, no data or recommendations exist for neonates. We report a neonatal sepsis case due to CAZ/AVI-resistant blaKPC-2-harboring Klebsiella pneumoniae carrying blaVEB-25 and the use of a [...] Read more.
Background: Although ceftazidime/avibactam (CAZ/AVI) has become an important option for treating adults and children, no data or recommendations exist for neonates. We report a neonatal sepsis case due to CAZ/AVI-resistant blaKPC-2-harboring Klebsiella pneumoniae carrying blaVEB-25 and the use of a customized active surveillance program in conjunction with enhanced infection control measures. Methods: The index case was an extremely premature neonate hospitalized for 110 days that had been previously treated with multiple antibiotics. Customized molecular surveillance was implemented at hospital level and enhanced infection control measures were taken for early recognition and prevention of outbreak. Detection and identification of blaVEB-25 was performed using next-generation sequencing. Results: This was the first case of a bloodstream infection caused by KPC-producing K. pneumoniae that was resistant to CAZ/AVI without the presence of a metalo-β-lactamase in the multiplex PCR platform in a neonate. All 36 additional patients tested (12 in the same NICU and 24 from other hospital departments) carried wild-type blaVEB-1 but they did not harbor blaVEB-25. Conclusion: The emergence of blaVEB-25 is signal for the horizontal transfer of plasmids at hospital facilities and it is of greatest concern for maintaining a sharp vigilance for the surveillance of novel resistance mechanisms. Molecular diagnostics can guide appropriate antimicrobial therapy and the early implementation of infection control measures against antimicrobial resistance. Full article
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10 pages, 2304 KiB  
Article
Prevalence of Carbapenemases in Carbapenem-Resistant Acinetobacter baumannii Isolates from the Kingdom of Bahrain
by Nouf Al-Rashed, Khalid M. Bindayna, Mohammad Shahid, Nermin Kamal Saeed, Abdullah Darwish, Ronni Mol Joji and Ali Al-Mahmeed
Antibiotics 2023, 12(7), 1198; https://doi.org/10.3390/antibiotics12071198 - 17 Jul 2023
Cited by 2 | Viewed by 1486
Abstract
Background: Acinetobacter baumannii is regarded as a significant cause of death in hospitals. The WHO recently added carbapenem-resistant Acinetobacter baumannii (CRAB) to its global pathogen priority list. There is a dearth of information on CRAB from our region. Methods: Fifty CRAB isolates were [...] Read more.
Background: Acinetobacter baumannii is regarded as a significant cause of death in hospitals. The WHO recently added carbapenem-resistant Acinetobacter baumannii (CRAB) to its global pathogen priority list. There is a dearth of information on CRAB from our region. Methods: Fifty CRAB isolates were collected from four main hospitals in Bahrain for this study. Bacterial identification and antibiotic susceptibility tests were carried out using the BD PhoenixTM and VITEK-2 compact, respectively. Using conventional PCR, these isolates were further screened for carbapenem resistance markers (blaOXA-51, blaOXA-23, blaOXA-24, blaOXA-40, blaIMP, blaNDM, blaVIM, and blaKPC). Results: All of the isolates were resistant to imipenem (100%), meropenem (98%), and cephalosporins (96–98%), followed by other commonly used antibiotics. All these isolates were least resistant to gentamicin (64%). The detection of resistance determinants showed that the majority harbored blaOXA-51 (100%) and blaIMP (94%), followed by blaOXA-23 (82%), blaOXA-24 (46%), blaOXA-40 (14%), blaNDM (6%), blaVIM (2%), and blaKPC (2%). Conclusion: The study isolates showed a high level of antibiotic resistance. Class D carbapenemases were more prevalent in our CRAB isolate collection. The resistance genes were found in various combinations. This study emphasizes the importance of strengthening surveillance and stringent infection control measures in clinical settings to prevent the emergence and further spread of such isolates. Full article
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14 pages, 2168 KiB  
Article
Evaluation of Five Host Inflammatory Biomarkers in Early Diagnosis of Ventilator-Associated Pneumonia in Critically Ill Children: A Prospective Single Center Cohort Study
by Maria Sdougka, Maria Simitsopoulou, Elena Volakli, Asimina Violaki, Vivian Georgopoulou, Argiro Ftergioti, Emmanuel Roilides and Elias Iosifidis
Antibiotics 2023, 12(5), 921; https://doi.org/10.3390/antibiotics12050921 - 17 May 2023
Cited by 1 | Viewed by 1425
Abstract
Background: Early diagnosis of ventilator-associated pneumonia (VAP) remains a challenge due to subjective clinical criteria and the low discriminative power of diagnostic tests. We assessed whether rapid molecular diagnostics in combination with Clinically Pulmonary Index Score (CPIS) scoring, microbiological surveillance and biomarker measurements [...] Read more.
Background: Early diagnosis of ventilator-associated pneumonia (VAP) remains a challenge due to subjective clinical criteria and the low discriminative power of diagnostic tests. We assessed whether rapid molecular diagnostics in combination with Clinically Pulmonary Index Score (CPIS) scoring, microbiological surveillance and biomarker measurements of PTX-3, SP-D, s-TREM, PTX-3, IL-1β and IL-8 in the blood or lung could improve the accuracy of VAP diagnosis and follow-up in critically ill children. Methods: A prospective pragmatic study in a Pediatric Intensive Care Unit (PICU) was conducted on ventilated critically ill children divided into two groups: high and low suspicion of VAP according to modified Clinically Pulmonary Index Score (mCPIS). Blood and bronchial samples were collected on days 1, 3, 6 and 12 after event onset. Rapid diagnostics were used for pathogen identification and ELISA for PTX-3, SP-D, s-TREM, IL-1β and IL-8 measurements. Results: Among 20 enrolled patients, 12 had a high suspicion (mCPIS > 6), and 8 had a low suspicion of VAP (mCPIS < 6); 65% were male; and 35% had chronic disease. IL-1β levels at day 1 correlated significantly with the number of mechanical ventilation days (rs = 0.67, p < 0.001) and the PICU stay (r = 0.66; p < 0.002). No significant differences were found in the levels of the other biomarkers between the two groups. Mortality was recorded in two patients with high VAP suspicion. Conclusions: PTX-3, SP-D, s-TREM, IL-1β and IL-8 biomarkers could not discriminate patients with a high or low suspicion of VAP diagnosis. Full article
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11 pages, 1836 KiB  
Article
Replacement of the Double Meropenem Disc Test with a Lateral Flow Assay for the Detection of Carbapenemase-Producing Enterobacterales and Pseudomonas aeruginosa in Clinical Laboratory Practice
by Areti Tychala, Georgios Meletis, Paraskevi Mantzana, Angeliki Kassomenaki, Charikleia Katsanou, Aikaterini Daviti, Lydia Kouroudi, Lemonia Skoura and Efthymia Protonotariou
Antibiotics 2023, 12(4), 771; https://doi.org/10.3390/antibiotics12040771 - 17 Apr 2023
Viewed by 1626
Abstract
The prompt detection of carbapenemases among Gram-negative bacteria isolated from patients’ clinical infection samples and surveillance cultures is important for the implementation of infection control measures. In this context, we evaluated the effectiveness of replacing phenotypic tests for the detection of carbapenemase producers [...] Read more.
The prompt detection of carbapenemases among Gram-negative bacteria isolated from patients’ clinical infection samples and surveillance cultures is important for the implementation of infection control measures. In this context, we evaluated the effectiveness of replacing phenotypic tests for the detection of carbapenemase producers with the immunochromatographic Carbapenem-Resistant K.N.I.V.O. Detection K-Set lateral flow assay (LFA). In total, 178 carbapenem-resistant Enterobacterales and 32 carbapenem-resistant Pseudomonas aeruginosa isolated in our hospital were tested with both our established phenotypic and molecular testing procedures and the LFA. The Kappa coefficient of agreement for Enterobacterales was 0.85 (p < 0.001) and 0.6 (p < 0.001) for P. aeruginosa. No major disagreements were observed and notably, in many cases, the LFA detected more carbapenemases than the double meropenem disc test, especially regarding OXA-48 in Enterobacterales and VIM in P. aeruginosa. Overall, the Carbapenem-Resistant K.N.I.V.O. Detection K-Set was very effective and at least equivalent to the standard procedures used in our lab. However, it was much faster as it provided results in 15 min compared to a minimum of 18–24 h for the phenotypic tests. Full article
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17 pages, 5755 KiB  
Article
Identification of Efflux Pump Mutations in Pseudomonas aeruginosa from Clinical Samples
by Sonia Quddus, Zainab Liaqat, Sadiq Azam, Mahboob Ul Haq, Sajjad Ahmad, Metab Alharbi and Ibrar Khan
Antibiotics 2023, 12(3), 486; https://doi.org/10.3390/antibiotics12030486 - 01 Mar 2023
Cited by 1 | Viewed by 1722
Abstract
Efflux pumps are a specialized tool of antibiotic resistance used by Pseudomonas aeruginosa to expel antibiotics. The current study was therefore conducted to examine the expression of MexAB-OprM and MexCD-OprJ efflux pump genes. In this study, 200 samples were collected from Khyber Teaching [...] Read more.
Efflux pumps are a specialized tool of antibiotic resistance used by Pseudomonas aeruginosa to expel antibiotics. The current study was therefore conducted to examine the expression of MexAB-OprM and MexCD-OprJ efflux pump genes. In this study, 200 samples were collected from Khyber Teaching Hospital (KTH) and Hayatabad Medical Complex (HMC) in Peshawar, Pakistan. All the isolates were biochemically identified by an Analytical Profile Index kit and at the molecular level by Polymerase Chain Reaction (PCR) utilizing specific primers for the OprL gene. A total of 26 antibiotics were tested in the current study using the guidelines of the Clinical and Laboratory Standard Institute (CLSI) and high-level resistance was shown to amoxicillin-clavulanic acid (89%) and low-level to chloramphenicol (1%) by the isolates. The antibiotic-resistant efflux pump genes MexA, MexB, OprM, MexR, MexC, MexD, OprJ, and NfxB were detected in 178 amoxicillin-clavulanic acid-resistant isolates. Mutations were detected in MexA, MexB, and OprM genes but no mutation was found in the MexR gene as analyzed by I-Mutant software. Statistical analysis determined the association of antibiotics susceptibility patterns by ANOVA: Single Factor p = 0.05. The in silico mutation impact on the protein structure stability was determined via the Dynamut server, which revealed the mutations might increase the structural stability of the mutants. The docking analysis reported that MexA wild protein showed a binding energy value of −6.1 kcal/mol with meropenem and the mexA mutant (E178K) value is −6.5 kcal/mol. The mexB wild and mutant binding energy value was −5.7 kcal/mol and −8.0 kcal/mol, respectively. Efflux pumps provide resistance against a wide range of antibiotics. Determining the molecular mechanisms of resistance in P. aeruginosa regularly will contribute to the efforts against the spread of antibiotic resistance globally. Full article
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12 pages, 859 KiB  
Article
In Vitro Synergistic Activity of Antimicrobial Combinations against Carbapenem- and Colistin-Resistant Acinetobacter baumannii and Klebsiella pneumoniae
by Paraskevi Mantzana, Efthymia Protonotariou, Angeliki Kassomenaki, Georgios Meletis, Areti Tychala, Eirini Keskilidou, Maria Arhonti, Charikleia Katsanou, Aikaterini Daviti, Olga Vasilaki, Georgia Kagkalou and Lemonia Skoura
Antibiotics 2023, 12(1), 93; https://doi.org/10.3390/antibiotics12010093 - 05 Jan 2023
Cited by 9 | Viewed by 2588
Abstract
Polymyxins are commonly used as the last resort for the treatment of MDR Acinetobacter baumannii and Klebsiella pneumoniae nosocomial infections; however, apart from the already known toxicity issues, resistance to these agents is emerging. In the present study, we assessed the in vitro [...] Read more.
Polymyxins are commonly used as the last resort for the treatment of MDR Acinetobacter baumannii and Klebsiella pneumoniae nosocomial infections; however, apart from the already known toxicity issues, resistance to these agents is emerging. In the present study, we assessed the in vitro synergistic activity of antimicrobial combinations against carbapenem-resistant and colistin-resistant A. baumannii and K. pneumoniae in an effort to provide more options for their treatment. Two hundred A. baumannii and one hundred and six K. pneumoniae single clinical isolates with resistance to carbapenems and colistin, recovered between 1 January 2021 and 31 July 2022,were included. A. baumannii were tested by the MIC test strip fixed-ratio method for combinations of colistin with either meropenem or rifampicin or daptomycin. K. pneumoniae were tested for the combinations of colistin with meropenem and ceftazidime/avibactam with aztreonam. Synergy was observed at: 98.99% for colistin and meropenem against A. baumannii; 91.52% for colistin and rifampicin; and 100% for colistin and daptomycin. Synergy was also observed at: 73.56% for colistin and meropenem against K. pneumoniae and; and 93% for ceftazidime/avibactam with aztreonam. The tested antimicrobial combinations presented high synergy rates, rendering them valuable options against A. baumannii and K. pneumoniae infections. Full article
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13 pages, 1513 KiB  
Article
Curcumin Stimulates the Overexpression of Virulence Factors in Salmonella enterica Serovar Typhimurium: In Vitro and Animal Model Studies
by Martin Zermeño-Ruiz, Itzia A. Rangel-Castañeda, Daniel Osmar Suárez-Rico, Leonardo Hernández-Hernández, Rafael Cortés-Zárate, José M. Hernández-Hernández, Gabriela Camargo-Hernández and Araceli Castillo-Romero
Antibiotics 2022, 11(9), 1230; https://doi.org/10.3390/antibiotics11091230 - 10 Sep 2022
Cited by 2 | Viewed by 2152
Abstract
Salmonella spp. is one of the most common food poisoning pathogens and the main cause of diarrheal diseases in humans in developing countries. The increased Salmonella resistance to antimicrobials has led to the search for new alternatives, including natural compounds such as curcumin, [...] Read more.
Salmonella spp. is one of the most common food poisoning pathogens and the main cause of diarrheal diseases in humans in developing countries. The increased Salmonella resistance to antimicrobials has led to the search for new alternatives, including natural compounds such as curcumin, which has already demonstrated a bactericidal effect; however, in Gram-negatives, there is much controversy about this effect, as it is highly variable. In this study, we aimed to verify the antibacterial activity of curcumin against the Salmonella enterica serovar Typhimurium growth rate, virulence, and pathogenicity. The strain was exposed to 110, 220 or 330 µg/mL curcumin, and by complementary methods (spectrophotometric, pour plate and MTT assays), we determined its antibacterial activity. To elucidate whether curcumin regulates the expression of virulence genes, Salmonella invA, fliC and siiE genes were investigated by quantitative real-time reverse transcription (qRT-PCR). Furthermore, to explore the effect of curcumin on the pathogenesis process in vivo, a Caenorhabditis elegans infection model was employed. No antibacterial activity was observed, even at higher concentrations of curcumin. All concentrations of curcumin caused overgrowth (35–69%) and increased the pathogenicity of the bacterial strain through the overexpression of virulence factors. The latter coincided with a significant reduction in both the lifespan and survival time of C. elegans when fed with curcumin-treated bacteria. Our data provide relevant information that may support the selective antibacterial effects of curcumin to reconsider the indiscriminate use of this phytochemical, especially in outbreaks of pathogenic Gram-negative bacteria. Full article
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