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Antibiotics
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Combination Therapy of Antimicrobial
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Combination Therapy of Antimicrobial

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "The Global Need for Effective Antibiotics".

Deadline for manuscript submissions: closed (16 June 2022) | Viewed by 29594

Special Issue Editor

Dr. Andrew David Berti

E-Mail Website
Guest Editor
Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI, USA
Interests: combination therapy; mechanisms of antimicrobial resistance and tolerance; optimization of pharmacological interventions; Staphylococcus aureus
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Effective antimicrobial therapy has permitted entire fields of medicine to develop, including organ transplantation and highly intensive chemotherapy. However, treatment with a single antibiotic is not always sufficient in terms of antimicrobial potency or prevention of resistance development. Unlike treatments for HIV infection or tuberculosis, use of combination therapy remains controversial for many bacterial infections. This Special Issue seeks manuscript submissions that further our understanding of when combination therapy is appropriate, why combination therapy can be beneficial, and how best to administer antibiotic combinations. We propose topic prompts below, but manuscripts addressing other aspects of combination therapy are welcome:

  1. Appropriateness of empiric combination therapy in endovascular Staphylococcus aureus infection;
  2. Combination therapy as a resistance mitigation strategy;
  3. Genetic or physiological mechanisms of antimicrobial synergy;
  4. Clinical trial design to assess antimicrobial combinations;
  5. Antimicrobial combinations as salvage therapies;
  6. Appropriate endpoints to evaluate clinical effectiveness of combination therapy;
  7. Appropriate use criteria for initiation of combination therapy;
  8. Combination therapy in the context of resistance to one of the agents;
  9. Maintaining appropriate combination therapy across transitions of care.

Dr. Andrew David Berti
Guest Editor

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
  • Synergy
  • Antimicrobial Resistance

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Published Papers (8 papers)

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Research

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13 pages, 2508 KiB  
Article
Activity of the Lactate Dehydrogenase Inhibitor Oxamic Acid against the Fermentative Bacterium Streptococcus mitis/oralis: Bactericidal Effects and Prevention of Daptomycin Resistance In Vitro and in an Ex Vivo Model
by Razieh Kebriaei, Arnold S. Bayer, Christian K. Lapitan, Michael J. Rybak, Greg A. Somerville and Nagendra N. Mishra
Antibiotics 2022, 11(10), 1409; https://doi.org/10.3390/antibiotics11101409 - 13 Oct 2022
Cited by 3 | Viewed by 1969
Abstract
Streptococcus mitis/oralis is a fermentative bacterium that relies on lactate dehydrogenase to balance its redox poise and keep glycolysis active. Metabolomic analysis of an in vitro–derived daptomycin-resistant (DAP-R) S. mitis/oralis strain (351-D10) revealed differences in glucose catabolism relative to its DAP-susceptible (DAP-S) parental [...] Read more.
Streptococcus mitis/oralis is a fermentative bacterium that relies on lactate dehydrogenase to balance its redox poise and keep glycolysis active. Metabolomic analysis of an in vitro–derived daptomycin-resistant (DAP-R) S. mitis/oralis strain (351-D10) revealed differences in glucose catabolism relative to its DAP-susceptible (DAP-S) parental strain, 351. Metabolic changes associated with the transition to this DAP-R phenotype suggested that inhibiting glycolysis could alter DAP susceptibility. In addition, the strong reliance of S. mitis/oralis on glycolysis for energy and biosynthetic intermediates suggested that inhibiting glycolysis would adversely affect growth and biomass accumulation. To test these hypotheses, we used the lactate dehydrogenase inhibitor oxamic acid (OXA) to assess its efficacy against DAP-S S. mitis/oralis strain 351 during DAP exposures in vitro and ex vivo. As expected, OXA was growth inhibitory to S. mitis/oralis in a dose-dependent manner in vitro; however, it did not alter in vitro DAP susceptibility profiles. In contrast, OXA did prevent the emergence of DAP-R in an ex vivo model of simulated endocardial vegetations. These data suggest that metabolic inhibitors directed against this fermentative bacterium with limited metabolic capabilities could enhance killing and potentially forestall the emergence of DAP resistance. Full article
(This article belongs to the Special Issue Combination Therapy of Antimicrobial)
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16 pages, 3119 KiB  
Article
Enhancing Dissolution Rate and Antibacterial Efficiency of Azithromycin through Drug-Drug Cocrystals with Paracetamol
by Noor Ul Islam, Ezzat Khan, Muhammad Naveed Umar, Attaullah Shah, Muhammad Zahoor, Riaz Ullah and Ahmed Bari
Antibiotics 2021, 10(8), 939; https://doi.org/10.3390/antibiotics10080939 - 4 Aug 2021
Cited by 16 | Viewed by 5823
Abstract
Cocrystallization is a promising approach to alter physicochemical properties of active pharmaceutical ingredients (hereafter abbreviated as APIs) bearing poor profile. Nowadays pharmaceutical industries are focused on preparing drug-drug cocrystals of APIs that are often prescribed in combination therapies by physicians. Physicians normally prescribe [...] Read more.
Cocrystallization is a promising approach to alter physicochemical properties of active pharmaceutical ingredients (hereafter abbreviated as APIs) bearing poor profile. Nowadays pharmaceutical industries are focused on preparing drug-drug cocrystals of APIs that are often prescribed in combination therapies by physicians. Physicians normally prescribe antibiotic with an analgesic/antipyretic drug to combat several ailments in a better and more efficient way. In this work, azithromycin (AZT) and paracetamol (PCM) cocrystals were prepared in 1:1 molar ratio using slow solvent evaporation method. The cocrystals were characterized by Fourier transform infrared (FTIR), Raman spectroscopy, powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), thermo gravimetric analysis (TGA) and high-performance liquid chromatography (HPLC). Vibrational spectroscopy and DSC confirmed that both APIs interact physically and showed chemical compatibility, while PXRD pattern of the starting material and products revealed that cocrystal have in a unique crystalline phase. The degree of hydration was confirmed by TGA analysis and result indicates monohydrate cocrystal formation. The HPLC analysis confirmed equimolar ratio of AZT:PCM in the cocrystal. The in vitro dissolution rate, saturation solubility, and antimicrobial activity were evaluated for AZT dihydrate and the resulting cocrystals. The cocrystals exhibited better dissolution rate, solubility and enhanced biological activities. Full article
(This article belongs to the Special Issue Combination Therapy of Antimicrobial)
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7 pages, 608 KiB  
Article
Biofilm Time-Kill Curves to Assess the Bactericidal Activity of Daptomycin Combinations against Biofilm-Producing Vancomycin-Resistant Enterococcus faecium and faecalis
by Katie E. Barber, Zade Shammout, Jordan R. Smith, Razieh Kebriaei, Taylor Morrisette and Michael J. Rybak
Antibiotics 2021, 10(8), 897; https://doi.org/10.3390/antibiotics10080897 - 23 Jul 2021
Cited by 10 | Viewed by 3445
Abstract
Introduction: E. faecium and E. faecalis are responsible for 13.9% of hospital-acquired infections with frequent resistance to vancomycin (82.6% of E. faecium, 9.5% of E. faecalis). Medical device infections secondary to enterococci often require combination therapy due to impaired activity against [...] Read more.
Introduction: E. faecium and E. faecalis are responsible for 13.9% of hospital-acquired infections with frequent resistance to vancomycin (82.6% of E. faecium, 9.5% of E. faecalis). Medical device infections secondary to enterococci often require combination therapy due to impaired activity against biofilm embedded cells. In vitro data demonstrate synergistic activity of daptomycin combinations. Using a novel, biofilm time-kill approach, we evaluated whether daptomycin combinations maintained synergy against biofilm-producing E. faecium and E. faecalis. Methods: Broth microdilution (BMD) and biofilm MIC (bMIC) values for daptomycin, ampicillin, ceftriaxone, fosfomycin, and rifampin were determined against biofilm-producing E. faecium and E. faecalis. Daptomycin combination bMIC values were determined in the presence of biologic concentrations of other antimicrobials. Synergy was evaluated against two E. faecalis (R6981, R7808) and two E. faecium (5938 and 8019) using a previously described biofilm time-kill method. Synergy was defined as ≥2 log10 CFU/cm2 reduction over the most active agent alone. Bactericidal activity was defined as ≥3 log10 CFU/cm2 reduction. Results: Daptomycin bMICs were 2–8-fold higher than BMD. In the presence of other antimicrobials, daptomycin bMICs were reduced ≥ two-fold in dilutions. Ceftriaxone and ampicillin demonstrated the most potent combinations with daptomycin, yielding synergy against three of four strains. Daptomycin plus rifampin was synergistic against E. faecium 5938 and E. faecalis 6981 and produced bactericidal kill. The combination of daptomycin plus fosfomycin displayed synergy solely against E. faecalis 6981. Conclusions: Daptomycin combinations with beta-lactams demonstrated promising synergistic activity against both E. faecium and E. faecalis. While daptomycin plus rifampin yielded bactericidal results, the effect was not seen across all organisms. These combinations warrant further evaluation to determine the optimal dose and response. Full article
(This article belongs to the Special Issue Combination Therapy of Antimicrobial)
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11 pages, 622 KiB  
Article
In Vitro Synergy of Colistin in Combination with Meropenem or Tigecycline against Carbapenem-Resistant Acinetobacter baumannii
by Jacinda C. Abdul-Mutakabbir, Juwon Yim, Logan Nguyen, Philip T. Maassen, Kyle Stamper, Zain Shiekh, Razieh Kebriaei, Ryan K. Shields, Mariana Castanheira, Keith S. Kaye and Michael J. Rybak
Antibiotics 2021, 10(7), 880; https://doi.org/10.3390/antibiotics10070880 - 20 Jul 2021
Cited by 18 | Viewed by 3639
Abstract
Acinetobacter baumannii is currently classified as one of six pathogens that contribute to increased patient mortality. Thus, exploratory studies navigating alternative treatment strategies are of supreme interest. Herein, we completed minimum inhibitory concentration (MIC) testing, and time-kill analyses (TKA) on 50 carbapenem-resistant Acinetobacter [...] Read more.
Acinetobacter baumannii is currently classified as one of six pathogens that contribute to increased patient mortality. Thus, exploratory studies navigating alternative treatment strategies are of supreme interest. Herein, we completed minimum inhibitory concentration (MIC) testing, and time-kill analyses (TKA) on 50 carbapenem-resistant Acinetobacterbaumannii isolates including 28 colistin-resistant isolates. Upon testing of MEM or TGC in the presence of sub-inhibitory COL against the 50 isolates, there was a median 2-fold reduction in MEM and TGC MICs. In the TKAs, the COL+MEM combination was synergistic in 45 (90%) isolates and bactericidal in 43 (86%) isolates at 24 hours, whereas the COL+TGC combination TKAs demonstrated synergy in 32 (64%) isolates and bactericidal activity was shown in 28 (56%) isolates. Additionally, sulbactam (SUL) and TGC were added to the COL+MEM dual therapy regimen to assess the possible utility of a triple therapy regimen against five non-responsive isolates. The COL+MEM+SUL and COL+MEM+TGC regimens effectively restored synergy in (5/5) 100% of the isolates. The results of this study demonstrate the potential utility of COL combinations in the treatment of carbapenem-resistant isolates. Full article
(This article belongs to the Special Issue Combination Therapy of Antimicrobial)
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12 pages, 714 KiB  
Article
Impact of Cardiovascular Failure in Intensive Care Unit-Acquired Pneumonia: A Single-Center, Prospective Study
by Ignacio Martin-Loeches, Adrian Ceccato, Marco Carbonara, Gianluigi li Bassi, Pierluigi di Natale, Stefano Nogas, Otavio Ranzani, Carla Speziale, Tarek Senussi, Francesco Idone, Anna Motos, Miquel Ferrer and Antoni Torres
Antibiotics 2021, 10(7), 798; https://doi.org/10.3390/antibiotics10070798 - 30 Jun 2021
Cited by 2 | Viewed by 1950
Abstract
Background: Cardiovascular failure (CVF) may complicate intensive care unit-acquired pneumonia (ICUAP) and radically alters the empirical treatment of this condition. The aim of this study was to determine the impact of CVF on outcome in patients with ICUAP. Methods: A prospective, single-center, observational [...] Read more.
Background: Cardiovascular failure (CVF) may complicate intensive care unit-acquired pneumonia (ICUAP) and radically alters the empirical treatment of this condition. The aim of this study was to determine the impact of CVF on outcome in patients with ICUAP. Methods: A prospective, single-center, observational study was conducted in six medical and surgical ICUs at a University Hospital. CVS was defined as a score of 3 or more on the cardiovascular component of the Sequential Organ Failure Assessment (SOFA) score. At the onset of ICUAP, CVF was reported as absent, transient (if lasting ≤ 3 days) or persistent (>3 days). The primary outcome was 90-day mortality modelled through a Cox regression analysis. Secondary outcomes were 28-day mortality, hospital mortality, ICU length of stay (LOS) and hospital LOS. Results: 358 patients were enrolled: 203 (57%) without CVF, 82 (23%) with transient CVF, and 73 (20%) with persistent CVF. Patients with transient and persistent CVF were more severely ill and presented higher inflammatory response than those without CVF. Despite having similar severity and aetiology, the persistent CVF group more frequently received inadequate initial antibiotic treatment and presented more treatment failures than the transient CVF group. In the persistent CVF group, at day 3, a bacterial superinfection was more frequently detected. The 90-day mortality was significantly higher in the persistent CVF group (62%). The 28-day mortality rates for patients without CVF, with transient and with persistent CVF were 19, 35 and 41% respectively and ICU mortality was 60, 38 and 19% respectively. In the multivariate analysis chronic pulmonary conditions, lack of Pa02/FiO2 improvement at day 3, pulmonary superinfection at day 3 and persistent CVF were independently associated with 90-day mortality in ICUAP patients. Conclusions: Persistent CVF has a significant impact on the outcome of patients with ICUAP. Patients at risk from persistent CVF should be promptly recognized to optimize treatment and outcomes. Full article
(This article belongs to the Special Issue Combination Therapy of Antimicrobial)
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Review

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20 pages, 310 KiB  
Review
Losing the Battle but Winning the War: Can Defeated Antibacterials Form Alliances to Combat Drug-Resistant Pathogens?
by Song Oh, Raymond Chau, Anh T. Nguyen and Justin R. Lenhard
Antibiotics 2021, 10(6), 646; https://doi.org/10.3390/antibiotics10060646 - 28 May 2021
Cited by 4 | Viewed by 3024
Abstract
Despite the recent development of antibacterials that are active against multidrug-resistant pathogens, drug combinations are often necessary to optimize the killing of difficult-to-treat organisms. Antimicrobial combinations typically are composed of multiple agents that are active against the target organism; however, many studies have [...] Read more.
Despite the recent development of antibacterials that are active against multidrug-resistant pathogens, drug combinations are often necessary to optimize the killing of difficult-to-treat organisms. Antimicrobial combinations typically are composed of multiple agents that are active against the target organism; however, many studies have investigated the potential utility of combinations that consist of one or more antibacterials that individually are incapable of killing the relevant pathogen. The current review summarizes in vitro, in vivo, and clinical studies that evaluate combinations that include at least one drug that is not active individually against Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, or Staphylococcus aureus. Polymyxins were often included in combinations against all three of the Gram-negative pathogens, and carbapenems were commonly incorporated into combinations against K. pneumoniae and A. baumannii. Minocycline, sulbactam, and rifampin were also frequently investigated in combinations against A. baumannii, whereas the addition of ceftaroline or another β-lactam to vancomycin or daptomycin showed promise against S. aureus with reduced susceptibility to vancomycin or daptomycin. Although additional clinical studies are needed to define the optimal combination against specific drug-resistant pathogens, the large amount of in vitro and in vivo studies available in the literature may provide some guidance on the rational design of antibacterial combinations. Full article
(This article belongs to the Special Issue Combination Therapy of Antimicrobial)
15 pages, 355 KiB  
Review
Potential Application of Combined Therapy with Lectins as a Therapeutic Strategy for the Treatment of Bacterial Infections
by João Victor de Oliveira Santos, Ana Lúcia Figueiredo Porto and Isabella Macário Ferro Cavalcanti
Antibiotics 2021, 10(5), 520; https://doi.org/10.3390/antibiotics10050520 - 2 May 2021
Cited by 9 | Viewed by 2957
Abstract
Antibiotic monotherapy may become obsolete mainly due to the continuous emergence of resistance to available antimicrobials, which represents a major uncertainty to human health. Taking into account that natural products have been an inexhaustible source of new compounds with clinical application, lectins are [...] Read more.
Antibiotic monotherapy may become obsolete mainly due to the continuous emergence of resistance to available antimicrobials, which represents a major uncertainty to human health. Taking into account that natural products have been an inexhaustible source of new compounds with clinical application, lectins are certainly one of the most versatile groups of proteins used in biological processes, emerging as a promising alternative for therapy. The ability of lectins to recognize carbohydrates present on the cell surface allowed for the discovery of a wide range of activities. Currently the number of antimicrobials in research and development does not match the rate at which resistance mechanisms emerge to an effective antibiotic monotherapy. A promising therapeutic alternative is the combined therapy of antibiotics with lectins to enhance its spectrum of action, minimize adverse effects, and reduce resistance to treatments. Thus, this review provides an update on the experimental application of antibiotic therapies based on the synergic combination with lectins to treat infections specifically caused by multidrug-resistant and biofilm-producing Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We also briefly discuss current strategies involving the modulation of the gut microbiota, its implications for antimicrobial resistance, and highlight the potential of lectins to modulate the host immune response against oxidative stress. Full article
(This article belongs to the Special Issue Combination Therapy of Antimicrobial)

Other

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22 pages, 954 KiB  
Systematic Review
The Efficacy of Using Combination Therapy against Multi-Drug and Extensively Drug-Resistant Pseudomonas aeruginosa in Clinical Settings
by Frank Jones, Yanmin Hu and Anthony Coates
Antibiotics 2022, 11(3), 323; https://doi.org/10.3390/antibiotics11030323 - 28 Feb 2022
Cited by 19 | Viewed by 5430
Abstract
Pseudomonas aeruginosa is a Gram-negative bacterium which is capable of developing a high level of antibiotic resistance. It has been placed on the WHO’s critical priority pathogen list and it is commonly found in ventilator-associated pneumonia infections, blood stream infections and other largely [...] Read more.
Pseudomonas aeruginosa is a Gram-negative bacterium which is capable of developing a high level of antibiotic resistance. It has been placed on the WHO’s critical priority pathogen list and it is commonly found in ventilator-associated pneumonia infections, blood stream infections and other largely hospital-acquired illnesses. These infections are difficult to effectively treat due to their increasing antibiotic resistance and as such patients are often treated with antibiotic combination regimens. Methods: We conducted a systematic search with screening criteria using the Ovid search engine and the Embase, Ovid Medline, and APA PsycInfo databases. Results: It was found that in many cases the combination therapies were able to match or outperform the monotherapies and none performed noticeably worse than the monotherapies. However, the clinical studies were mostly small, only a few were prospective randomized clinical trials and statistical significance was lacking. Conclusions: It was concluded that combination therapies have a place in the treatment of these highly resistant bacteria and, in some cases, there is some evidence to suggest that they provide a more effective treatment than monotherapies. Full article
(This article belongs to the Special Issue Combination Therapy of Antimicrobial)
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