Antimicrobial Combination Therapy to Treat Difficult-to-Treat Infections: From Bench to the Bedside

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Antibiotic Therapy in Infectious Diseases".

Deadline for manuscript submissions: 15 August 2024 | Viewed by 38013

Special Issue Editors


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Guest Editor
Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
Interests: biofilm-related infections; antimicrobial resistance; nosocomial infections; anti-biofilm antibiotics
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands
Interests: surgical site infection; prosthetic and foreign-material-related infection; diagnostic microbiology; antimicrobial stewardship
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Infectious Disease and Infection Control Unit, IRCCS-ISMETT, UPMC, Palermo, Italy
Interests: antifungal stewardship; appropriate use of antifungals; Invasive fungal infection; solid organ transplant

Special Issue Information

Dear Colleagues,

Antimicrobial combinations have been traditionally used in order to achieve synergy between molecules or for the treatment of difficult-to-treat infections.

In recent years, the combination of new or already known antimicrobial substances (either antibiotics or non-antibiotic therapeutic adjuvants able to increase antibiotic efficacy) has been exploited to overcome the increasing problem of multidrug resistance. In this setting, definite evidence of the optimal indications of combination therapy or its superiority over monotherapy is still lacking, and represents an area of debate.

Several patient and/or disease conditions may lean towards preferring antimicrobial combinations over monotherapy. Furthermore, whether an ideal partner for a combination therapeutic strategy exists is still a matter of debate.

Studies are needed to understand whether combination therapy can be used and show satisfactory efficacy. Clinical microbiology studies and susceptibility tests are needed to investigate in vitro synergisms. Pharmacokinetic/pharmacodynamic (either animal or human) studies are needed to understand whether the target attainment can be reached. Clearly, clinical studies, either observational or randomized control trials, are needed to investigate the efficacy of combination therapy.

In this Special Issue of Antibiotics, we welcome the submission of original research and review articles. Pharmacokinetic/pharmacodynamic studies may also be considered. We welcome fundamental science, animal studies, clinical trials, and observational studies. We are particularly interested in new antibiotics or molecules used to treat multidrug-resistant microorganisms.

Dr. Alessandra Oliva
Dr. Erlangga Yusuf
Dr. Alessandra Mularoni
Guest Editors

Manuscript Submission Information

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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 treatment
  • synergy
  • critically ill patients
  • difficult-to-treat microorganisms
  • fosfomycin
  • multi-drug resistance
  • multi-drug resistant gram negatives
  • sepsis and septic shock
  • endocarditis
  • methicillin-resistant staphylococcus aureus
  • PK/PD

Published Papers (8 papers)

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Research

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22 pages, 852 KiB  
Article
Antimicrobial Treatment Challenges in the Management of Infective Spondylodiscitis Associated with Hemodialysis: A Comprehensive Review of Literature and Case Series Analysis
by Ioana A. Ratiu, Corina F. Moisa, Laura Țiburcă, Edy Hagi-Islai, Anamaria Ratiu, Gabriel Cristian Bako, Cristian Adrian Ratiu and Liana Stefan
Antibiotics 2024, 13(3), 284; https://doi.org/10.3390/antibiotics13030284 - 20 Mar 2024
Viewed by 1066
Abstract
Infective spondylodiscitis (ISD), the infection of vertebral bodies and surrounding tissues, is a rare complication with major impact on the long-term survival of hemodialysis (HD) patients. Although the most frequent etiology is staphylococcal, identifying these pathogens in blood cultures and biopsy cultures [...] Read more.
Infective spondylodiscitis (ISD), the infection of vertebral bodies and surrounding tissues, is a rare complication with major impact on the long-term survival of hemodialysis (HD) patients. Although the most frequent etiology is staphylococcal, identifying these pathogens in blood cultures and biopsy cultures is often difficult. This paper aims to present suitable antibiotic combinations for the treatment of these patients, which is usually challenging in the case of an unidentified pathogen. We presented the therapies applied for 13 HD patients and 19 patients without chronic kidney disease (CKD), diagnosed with ISD between 2013 and 2023 in Bihor County. The percentage of positive blood cultures was low in both groups (30.78% HD vs. 15.78% non-HD). The average length of antibiotic therapy was 5.15 weeks in HD patients and 6.29 weeks in non-HD patients. The use of Carbapenem alone (e.g., Meropenem) for an average of 19.6 days for patients in HD when the pathogen was not identified has proven to be efficient in most cases, similarly to using Vancomycin and Fluoroquinolone/Cephalosporines in combination. Regarding the non-CKD patients, the use of Clindamycin in various combinations for an average of 30.3 days has proven to be efficient in more than 90% of cases of ISD with a nonidentified pathogen. Within 2 years after ISD was diagnosed, 12 of the 13 HD patients passed away, mainly due to cardiovascular causes. Unfortunately, there are no guidelines in the literature concerning the empiric treatment of ISD in the particular case of HD patients. Upon checking the literature on PubMed and Google Scholar, only 10 studies provided relevant data regarding ISD treatment for HD patients. More data about the treatment and evolution of these patients is needed in order to elaborate a truly relevant metanalysis. Full article
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19 pages, 5187 KiB  
Article
Incidence of Drug-Resistant Hospital-Associated Gram-Negative Bacterial Infections, the Accompanying Risk Factors, and Clinical Outcomes with Treatment
by Lorina Badger-Emeka, Abdullatif S. Al Rashed, Reem Y. Aljindan, Promise Madu Emeka, Sayed A. Quadri and Hayfa Habes Almutairi
Antibiotics 2023, 12(9), 1425; https://doi.org/10.3390/antibiotics12091425 - 9 Sep 2023
Cited by 3 | Viewed by 1393
Abstract
Extensive drug resistance to bacterial infections in hospitalised patients is accompanied by high morbidity and mortality rates due to limited treatment options. This study investigated the clinical outcomes of single and combined antibiotic therapies in extensive (XDR), multidrug-resistant (MDR) and susceptible strains (SS) [...] Read more.
Extensive drug resistance to bacterial infections in hospitalised patients is accompanied by high morbidity and mortality rates due to limited treatment options. This study investigated the clinical outcomes of single and combined antibiotic therapies in extensive (XDR), multidrug-resistant (MDR) and susceptible strains (SS) of hospital-acquired infections (HAIs). Cases of hospital-associated drug-resistant infections (HADRIs) and a few susceptible strains from hospital wards were selected for this study. Bacteria identifications (IDs) and antimicrobial susceptibility tests (ASTs) were performed with a Vitek 2 Compact Automated System. Patients’ treatment types and clinical outcomes were classified as alive improved (AI), alive not improved (ANI), or died. The length of hospital stay (LOHS) was acquired from hospital records. The HAI pathogens were Acinetobacter baumannii (28%), Escherichia coli (26%), Klebsiella pneumoniae (22%), Klebsiella (2%) species, Pseudomonas aeruginosa (12%), Proteus mirabilis (4%), and other Enterobacteriaceae. They were MDR (40.59%), XDR (24.75%), carbapenem-resistant Enterobacteriaceae (CRE, 21.78%) and susceptible (12%) strains. The treatments were either monotherapy or combined therapy with different outcomes. Monotherapy produced positive significant outcomes with E. coli infections, while for P. aeruginosa, there were no differences between the number of infections treated with either mono/combined therapies (50% each). Nonetheless, combined therapy had significant effects (p < 0.05) as a treatment for A. baumannii and K. pneumoniae infections. Clinical outcomes and LOHS varied with infecting bacteria. The prevalence of XDR and MDR HAIs was found to be significantly high, with no association with treatment type, LOHS, or outcome. Full article
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11 pages, 408 KiB  
Article
Resistance to Ceftazidime/Avibactam in Klebsiella pneumoniae KPC-Producing Isolates: A Real-Life Observational Study
by Laura Campogiani, Pietro Vitale, Alessandra Lodi, Alessandra Imeneo, Carla Fontana, Cartesio D’Agostini, Mirko Compagno, Luigi Coppola, Ilaria Spalliera, Vincenzo Malagnino, Elisabetta Teti, Marco Iannetta, Massimo Andreoni and Loredana Sarmati
Antibiotics 2023, 12(5), 820; https://doi.org/10.3390/antibiotics12050820 - 27 Apr 2023
Cited by 1 | Viewed by 1509
Abstract
Background: Ceftazidime/avibactam (CAZ-AVI) resistance amongst Enterobacterales is worryingly increasing worldwide. Objectives: The aim of this study was to collect and describe real-life data on CAZ-AVI-resistant Klebsiella pneumoniae (KP) isolates in our University Hospital, with the ultimate goal of evaluating possible risk factors related [...] Read more.
Background: Ceftazidime/avibactam (CAZ-AVI) resistance amongst Enterobacterales is worryingly increasing worldwide. Objectives: The aim of this study was to collect and describe real-life data on CAZ-AVI-resistant Klebsiella pneumoniae (KP) isolates in our University Hospital, with the ultimate goal of evaluating possible risk factors related to the acquisition of resistance. Methods: This is a retrospective observational study, including unique Klebsiella pneumoniae (KP) isolates resistant to CAZ-AVI (CAZ-AVI-R) and producing only KPC, collected from July 2019 to August 2021 at Policlinico Tor Vergata, Rome, Italy. The pathogen’s list was obtained from the microbiology laboratory; clinical charts of the corresponding patients were reviewed to collect demographic and clinical data. Subjects treated as outpatients or hospitalized for <48 h were excluded. Patients were then divided into two groups: S group, if they had a prior isolate of CAZ-AVI-susceptible KP-KPC, and R group, if the first documented isolate of KP-KPC was resistant to CAZ-AVI. Results: Forty-six unique isolates corresponding to 46 patients were included in the study. The majority of patients (60.9%) were hospitalized in an intensive care unit, 32.6% in internal medicine wards and 6.5% in surgical wards. A total of 15 (32.6%) isolates were collected from rectal swabs, representing a colonization. Amongst clinically relevant infections, pneumonia and urinary tract infections were the most commonly found (5/46, 10.9% each). Half of the patients received CAZ-AVI prior to isolation of the KP-KPC CAZ-AVI-R (23/46). This percentage was significantly higher in patients in the S group compared to patients in the R group (69.3% S group vs. 25% R group, p = 0.003). No differences between the two groups were documented in the use of renal replacement therapy or in the infection site. The clinically relevant CAZ-AVI-R KP infections (22/46, 47.8%) were all treated with a combination therapy, 65% including colistin and 55% including CAZ-AVI, with an overall clinical success of 38.1%. Conclusions: Prior use of CAZ-AVI was associated with the emergence of drug resistance. Full article
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11 pages, 1360 KiB  
Article
Combination Therapy versus Monotherapy in the Treatment of Stenotrophomonas maltophilia Infections: A Systematic Review and Meta-Analysis
by Abhisit Prawang, Naphatsawan Chanjamlong, Woranattha Rungwara, Wichai Santimaleeworagun, Taniya Paiboonvong, Thidarat Manapattanasatein, Prompiriya Pitirattanaworranat, Pongsakorn Kitseree and Sukrit Kanchanasurakit
Antibiotics 2022, 11(12), 1788; https://doi.org/10.3390/antibiotics11121788 - 9 Dec 2022
Cited by 6 | Viewed by 2378
Abstract
Stenotrophomonas maltophilia is a multidrug-resistant bacterium that is difficult to treat in hospitals worldwide, leading to high mortality. Published data describing the use of monotherapy or combination therapy and which one is better is still unclear. We aimed to investigate the efficacy of [...] Read more.
Stenotrophomonas maltophilia is a multidrug-resistant bacterium that is difficult to treat in hospitals worldwide, leading to high mortality. Published data describing the use of monotherapy or combination therapy and which one is better is still unclear. We aimed to investigate the efficacy of monotherapy and combination therapy in the treatment of S. maltophilia infections. We performed a systematic review of combination therapy and additionally a systematic review and meta-analysis to determine the effects of monotherapy versus combination therapy on mortality in S. maltophilia infections. Electronic databases: Cochrane Library, PubMed, Embase, ClinicalTrials.gov, Scopus, and OpenGrey were accessed. Of the 5030 articles identified, 17 studies were included for a systematic review of combination therapy, of which 4 cohort studies were finally included for meta-analysis. We found there is a trend of favorable outcomes with respect to mortality in the use of combination therapy to treat complex or severe S. maltopholia infections. A meta-analysis of monotherapy showed a statistical significance in the decreasing rate of mortality in hospital-acquired pneumonia (hazard ratio 1.42; 95% confidence interval, 1.04–1.94) compared to combination therapy, but not significant in bacteremia (hazard ratio 0.76; 95% confidence interval, 0.18–3.18). Further studies should continue to explore this association. Full article
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10 pages, 1640 KiB  
Article
Fingolimod Promotes Antibacterial Effect of Doripenem against Carbapenem-Resistant Escherichia coli
by Hye-Won Jin, Hye-Rim Kim and Yong-Bin Eom
Antibiotics 2022, 11(8), 1043; https://doi.org/10.3390/antibiotics11081043 - 2 Aug 2022
Cited by 1 | Viewed by 1680
Abstract
The aim of this study was to determine whether fingolimod could synergize the antibacterial activity of doripenem against carbapenem-resistant Escherichia coli (CREC) and its potential as an antibiotic adjuvant for doripenem. The E. coli used in this study had the blaKPC gene [...] Read more.
The aim of this study was to determine whether fingolimod could synergize the antibacterial activity of doripenem against carbapenem-resistant Escherichia coli (CREC) and its potential as an antibiotic adjuvant for doripenem. The E. coli used in this study had the blaKPC gene and became resistant to many classes of antibiotics, particularly carbapenems. The minimum inhibitory concentrations (MICs) of fingolimod and doripenem were determined. To investigate the synergistic action between fingolimod and doripenem, synergy checkerboard, growth curve, and time-kill analyses were performed. A motility test was also performed using a semi-solid medium to determine whether fingolimod could inhibit the motility of E. coli, one of its virulence mechanisms. The expression levels of carbapenemase-, motility-, and efflux pump-related genes suppressed by fingolimod were analyzed by quantitative polymerase chain reaction (qPCR). Our study demonstrated that the combination of fingolimod and doripenem inhibited carbapenemase, biological activity and other CREC virulence factors. This study findings suggest the potential of fingolimod as an adjuvant to prevent antibiotic resistance in CREC. Full article
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37 pages, 623 KiB  
Article
Efficacy of Short-Term High Dose Pulsed Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome (PTLDS) and Associated Co-Infections: A Report of Three Cases and Literature Review
by Richard I. Horowitz and Phyllis R. Freeman
Antibiotics 2022, 11(7), 912; https://doi.org/10.3390/antibiotics11070912 - 7 Jul 2022
Cited by 4 | Viewed by 20186
Abstract
Lyme disease and associated co-infections are increasing worldwide and approximately 20% of individuals develop chronic Lyme disease (CLD)/Post-Treatment Lyme Disease Syndrome (PTLDS) despite early antibiotics. A seven- to eight-week protocol of double dose dapsone combination therapy (DDDCT) for CLD/PTLDS results in symptom remission [...] Read more.
Lyme disease and associated co-infections are increasing worldwide and approximately 20% of individuals develop chronic Lyme disease (CLD)/Post-Treatment Lyme Disease Syndrome (PTLDS) despite early antibiotics. A seven- to eight-week protocol of double dose dapsone combination therapy (DDDCT) for CLD/PTLDS results in symptom remission in approximately 50% of patients for one year or longer, with published culture studies indicating higher doses of dapsone demonstrate efficacy against resistant biofilm forms of Borrelia burgdorferi. The purpose of this study was, therefore, to evaluate higher doses of dapsone in the treatment of resistant CLD/PTLDS and associated co-infections. A total of 25 patients with a history of Lyme and associated co-infections, most of whom had ongoing symptoms despite several courses of DDDCT, took one or more courses of high dose pulsed dapsone combination therapy (200 mg dapsone × 3–4 days and/or 200 mg BID × 4 days), depending on persistent symptoms. The majority of patients noticed sustained improvement in eight major Lyme symptoms, including fatigue, pain, headaches, neuropathy, insomnia, cognition, and sweating, where dapsone dosage, not just the treatment length, positively affected outcomes. High dose pulsed dapsone combination therapy may represent a novel therapeutic approach for the treatment of resistant CLD/PTLDS, and should be confirmed in randomized, controlled clinical trials. Full article
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Review

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14 pages, 550 KiB  
Review
Aminoglycosides for the Treatment of Severe Infection Due to Resistant Gram-Negative Pathogens
by Michaël Thy, Jean-François Timsit and Etienne de Montmollin
Antibiotics 2023, 12(5), 860; https://doi.org/10.3390/antibiotics12050860 - 6 May 2023
Cited by 10 | Viewed by 5397
Abstract
Aminoglycosides are a family of rapidly bactericidal antibiotics that often remain active against resistant Gram-negative bacterial infections. Over the past decade, their use in critically ill patients has been refined; however, due to their renal and cochleovestibular toxicity, their indications in the treatment [...] Read more.
Aminoglycosides are a family of rapidly bactericidal antibiotics that often remain active against resistant Gram-negative bacterial infections. Over the past decade, their use in critically ill patients has been refined; however, due to their renal and cochleovestibular toxicity, their indications in the treatment of sepsis and septic shock have been gradually reduced. This article reviews the spectrum of activity, mode of action, and methods for optimizing the efficacy of aminoglycosides. We discuss the current indications for aminoglycosides, with an emphasis on multidrug-resistant Gram-negative bacteria, such as extended-spectrum β-lactamase-producing Enterobacterales, carbapenemase-producing Enterobacterales, multidrug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii. Additionally, we review the evidence for the use of nebulized aminoglycosides. Full article
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10 pages, 1023 KiB  
Review
Comparing the Outcomes of Ceftaroline plus Vancomycin or Daptomycin Combination Therapy versus Vancomycin or Daptomycin Monotherapy in Adults with Methicillin-Resistant Staphylococcus aureus Bacteremia—A Meta-Analysis
by Chienhsiu Huang, Ihung Chen and Lichen Lin
Antibiotics 2022, 11(8), 1104; https://doi.org/10.3390/antibiotics11081104 - 15 Aug 2022
Cited by 9 | Viewed by 3411
Abstract
Introduction: Combination therapy with daptomycin plus ceftaroline to treat methicillin-resistant Staphylococcus aureus bacteremia has been reported to reduce methicillin-resistant Staphylococcus aureus bacteremia-related mortality. The purpose of the current meta-analysis was to compare the clinical outcome of methicillin-resistant Staphylococcus aureus bacteremia in patients treated [...] Read more.
Introduction: Combination therapy with daptomycin plus ceftaroline to treat methicillin-resistant Staphylococcus aureus bacteremia has been reported to reduce methicillin-resistant Staphylococcus aureus bacteremia-related mortality. The purpose of the current meta-analysis was to compare the clinical outcome of methicillin-resistant Staphylococcus aureus bacteremia in patients treated with daptomycin or vancomycin plus ceftaroline combination therapy versus daptomycin or vancomycin monotherapy. Methods: Studies were included if they directly compared the efficacy of daptomycin or vancomycin plus ceftaroline combination therapy with that of daptomycin or vancomycin monotherapy in the treatment of methicillin-resistant Staphylococcus aureus bacteremia in adult patients. Results: One randomized controlled trial and five retrospective studies were included in the meta-analysis. The combination therapy group had an in-hospital mortality, duration of bacteremia, and adverse event rate similar to those patients who had monotherapy. There was less bacteremia recurrence in the combination group. Initial combination therapy with ceftaroline for the treatment of methicillin-resistant Staphylococcus aureus bacteremia showed a trend of reducing the risk of in-hospital mortality in the current meta-analysis. Conclusions: Randomized controlled trials are needed to further study the role of initial combination therapy with daptomycin or vancomycin plus ceftaroline in the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Full article
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