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Antibiotics
Special Issues
Combination Therapy against Multidrug-Resistant Pathogens
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Combination Therapy against Multidrug-Resistant Pathogens

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Antibiotics Use and Antimicrobial Stewardship".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 7815

Special Issue Editors

Dr. Mao Hagihara

E-Mail Website
Guest Editor
Department of Molecular Epidemiology and Biomedical Sciences, Aichi Medical University, Aichi, Japan
Interests: pharmacokinetics; pharmacodynamics; antimicrobial; multi-drug resistant pathogen; therapeutic drug monitoring; in vivo study
Special Issues, Collections and Topics in MDPI journals
Dr. Hideo Kato

E-Mail Website
Guest Editor
1. Department of Pharmacy, Mie University Hospital, Mie 5148507, Japan
2. Department of Clinical Pharmaceutics, Mie University Graduate School of Medicine, Mie 5148507, Japan
3. Department of Clinical Infectious Diseases, Aichi Medical University, Aichi 4801195, Japan
Interests: infections and antibiotic use; efficacy and safety of antibiotics; antibiotic resistance; PK/PD study; animal infectious model; meta-analysis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Antibiotic combination therapy is often used to enhance and improve clinical efficacy in patients where a given therapy is thought to have limitations when used alone. The majority of the data evaluating combination therapy were determined using in vitro techniques or animal models with some types of infections. Through analyses of this information, coupled with the available clinical data, it is possible to identify a number of clinical situations where combination therapy can be supported. When used appropriately at optimal doses, combination therapy may offer an excellent opportunity to maximize clinical outcomes, particularly in the face of antibacterial resistance. Therefore, clinicians should evaluate carefully the risks and the potential benefits before adding additional antibiotics to standard single-drug therapies.

This Special Issue invites researchers interested in antibacterial combination therapy against antibacterial resistance pathogens, to optimize antibacterial use with special emphasis to help in the development of antibacterial treatment guidelines.

Dr. Mao Hagihara
Dr. Hideo Kato
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • combination therapy
  • multidrug-resistant pathogens
  • in vitro
  • in vivo
  • clinical study
  • pharmacokinetics
  • pharmacodynamics.

Published Papers (3 papers)

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Research

15 pages, 1706 KiB  
Article
Combination of Amphiphilic Cyclic Peptide [R4W4] and Levofloxacin against Multidrug-Resistant Bacteria
by Muhammad Imran Sajid, Sandeep Lohan, Shun Kato and Rakesh Kumar Tiwari
Antibiotics 2022, 11(3), 416; https://doi.org/10.3390/antibiotics11030416 - 20 Mar 2022
Cited by 6 | Viewed by 2873
Abstract
Bacterial resistance is a growing global concern necessitating the discovery and development of antibiotics effective against the drug-resistant bacterial strain. Previously, we reported a cyclic antimicrobial peptide [R4W4] containing arginine (R) and tryptophan (W) with a MIC of 2.67 [...] Read more.
Bacterial resistance is a growing global concern necessitating the discovery and development of antibiotics effective against the drug-resistant bacterial strain. Previously, we reported a cyclic antimicrobial peptide [R4W4] containing arginine (R) and tryptophan (W) with a MIC of 2.67 µg/mL (1.95 µM) against methicillin-resistant Staphylococcus aureus (MRSA). Herein, we investigated the cyclic peptides [R4W4] or linear (R4W4) and their conjugates (covalent or noncovalent) with levofloxacin (Levo) with the intent to improve their potency to target drug-resistant bacteria. The physical mixture of the Levo with the cyclic [R4W4] proved to be significantly effective against all strains of bacteria used in the study as compared to covalent conjugation. Furthermore, the checkerboard assay revealed the significant synergistic effect of the peptides against all studied strains except for the wild type S. aureus, in which the partial synergy was observed. The hemolysis assay revealed less cytotoxicity of the physical mixture of the Levo with [R4W4] (22%) as compared to [R4W4] alone (80%). The linear peptide (R4W4) and the cyclic [R4W4] demonstrated ~90% and 85% cell viability at 300 µg/mL in the triple-negative breast cancer cells (MDA-MB-231) and the normal kidney cells (HEK-293), respectively. Similar trends were also observed in the cell viability of Levo-conjugates on these cell lines. Furthermore, the time-kill kinetic study of the combination of [R4W4] and Levo demonstrate rapid killing action at 4 h for MRSA (ATCC BAA-1556) and 12 h for E. coli (ATCC BAA-2452), P. aeruginosa (ATCC BAA-1744), and K. pneumoniae (ATCC BAA-1705). These results provide the effectiveness of a combination of Levo with cyclic [R4W4] peptide, which may provide an opportunity to solve the intriguing puzzle of treating bacterial resistance. Full article
(This article belongs to the Special Issue Combination Therapy against Multidrug-Resistant Pathogens)
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10 pages, 922 KiB  
Article
In Vitro Efficacy of Antibiotic Combinations with Carbapenems and Other Agents against Anaerobic Bacteria
by Takumi Umemura, Mao Hagihara, Takeshi Mori and Hiroshige Mikamo
Antibiotics 2022, 11(3), 292; https://doi.org/10.3390/antibiotics11030292 - 22 Feb 2022
Viewed by 1497
Abstract
We investigated the in vitro efficacy of combinations of carbapenems with clindamycin (CLDM) and minocycline (MINO) against Bacteroides fragilis and Peptostreptococcus species. We selected the carbapenems imipenem, meropenem, panipenem, doripenem, and biapenem. To evaluate the antibiotic efficacy of these combination regimens, the fractional [...] Read more.
We investigated the in vitro efficacy of combinations of carbapenems with clindamycin (CLDM) and minocycline (MINO) against Bacteroides fragilis and Peptostreptococcus species. We selected the carbapenems imipenem, meropenem, panipenem, doripenem, and biapenem. To evaluate the antibiotic efficacy of these combination regimens, the fractional inhibitory concentration index (FICI) was calculated against clinical isolates. Consequently, combination regimens of each carbapenem with CLDM or MINO showed synergistic or additive effects against 83.3–100.0% and no antagonistic effects against P. anaerobius isolates. However, against the B. fragilis group (B. fragilis, B. thetaiotaomicron, and Parabacteroides distasonis), although the combination with other carbapenems and CLDM or MINO did not show remarkable synergistic effects, the combination regimen of IPM with CLDM or MINO indicated mainly additive antibiotic efficacies (FICIs: >0.5 to ≤1.0) to B. fragilis groups. Then, antagonistic effects were admitted in only 5.6% of B. fragilis groups. The effectiveness of antibiotic combination therapy against pathogenic anaerobes has remained unclear. Then, our results can provide new insights to explore the effective combination regimens against multidrug-resistant anaerobic bacteria as empirical and definitive therapies, while this study used only carbapenem susceptible isolates. Hence, further studies are needed to use highly antibiotic-resistant anaerobic isolates to carbapenems. Full article
(This article belongs to the Special Issue Combination Therapy against Multidrug-Resistant Pathogens)
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11 pages, 2105 KiB  
Article
In Vivo Pharmacodynamics of β-Lactams/Nacubactam against Carbapenem-Resistant and/or Carbapenemase-Producing Enterobacter cloacae and Klebsiella pneumoniae in Murine Pneumonia Model
by Mao Hagihara, Hideo Kato, Toshie Sugano, Hayato Okade, Nobuo Sato, Yuichi Shibata, Daisuke Sakanashi, Jun Hirai, Nobuhiro Asai, Hiroyuki Suematsu, Yuka Yamagishi and Hiroshige Mikamo
Antibiotics 2021, 10(10), 1179; https://doi.org/10.3390/antibiotics10101179 - 28 Sep 2021
Cited by 4 | Viewed by 2468
Abstract
Carbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE) have become global threats. CRE− and CPE− derived infections have been associated with high mortality due to limited treatment options. Nacubactam is a β-lactamase inhibitor and belongs to the new class of diazabicyclooctane. The agent has [...] Read more.
Carbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE) have become global threats. CRE− and CPE− derived infections have been associated with high mortality due to limited treatment options. Nacubactam is a β-lactamase inhibitor and belongs to the new class of diazabicyclooctane. The agent has an in vitro antimicrobial activity against several classes of β-lactamase-producing Enterobacterales. This study evaluated antimicrobial activity of combination therapies including β-lactams (aztreonam, cefepime, and meropenem) and nacubactam against four Enterobacter cloacae and six Klebsiella pneumoniae isolates with murine pneumonia model. Based on changes in bacterial quantity, antimicrobial activities of some regimens were assessed. Combination therapies including β-lactams (aztreonam, cefepime, and meropenem) with nacubactam showed enhanced antimicrobial activity against CRE E. cloacae (−3.70 to −2.08 Δlog10 CFU/lungs) and K. pneumoniae (−4.24 to 1.47 Δlog10 CFU/lungs) with IMP-1, IMP-6, or KPC genes, compared with aztreonam, cefepime, meropenem, and nacubactam monotherapies. Most combination therapies showed bacteriostatic (−3.0 to 0 Δlog10 CFU/lungs) to bactericidal (<−3.0 Δlog10 CFU/lungs) activities against CRE isolates. This study revealed that combination regimens with β-lactams (aztreonam, cefepime, and meropenem) and nacubactam are preferable candidates to treat pneumonia due to CRE and CPE. Full article
(This article belongs to the Special Issue Combination Therapy against Multidrug-Resistant Pathogens)
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