Antibiotics

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12 pages, 1675 KiB

Open AccessArticle

Investigation of the Effect of pH on the Adsorption–Desorption of Doxycycline in Feed for Small Ruminants

by Rositsa Mileva, Tsvetelina Petkova, Zvezdelina Yaneva and Aneliya Milanova

Antibiotics 2023, 12(2), 268; https://doi.org/10.3390/antibiotics12020268 - 28 Jan 2023

Cited by 3 | Viewed by 2048

Abstract

Orally administered tetracycline antibiotics interact with feed, which may impact their bioavailability and efficacy. Therefore, the pH-dependent adsorption of doxycycline and its interaction with feed for ruminants was studied in vitro. Adsorption experiments on animal feed (135 and 270 mg) with initial doxycycline [...] Read more.

Orally administered tetracycline antibiotics interact with feed, which may impact their bioavailability and efficacy. Therefore, the pH-dependent adsorption of doxycycline and its interaction with feed for ruminants was studied in vitro. Adsorption experiments on animal feed (135 and 270 mg) with initial doxycycline concentrations of 35, 75, and 150 µg/mL were performed. Desorption experiments were conducted by agitation of a predetermined mass of doxycycline-loaded animal feed in PBS, at pH = 3.0, 6.0, and 7.4, to simulate changes in the gastrointestinal tract. Antibiotic concentrations were determined by LC-MS/MS analysis. The adsorption/desorption of doxycycline was described by mathematical models. Chemisorption with strong intermolecular interactions between the active functional groups of doxycycline and the organic biomass was found. The experimental release curve comprised three sections: initial prolonged 27–30% release (pH = 6.0), followed by moderate 56–59% release (pH = 3.0), and final 63–74% release (pH = 7.4). The sigmoidal model showed a considerable role of diffusion with an initial prevalence of desorption and a decreased desorption rate thereafter. The Weibull equation revealed an initial release stage followed by a lag time section and sustained release. The study of doxycycline adsorption by the animal feed proved a maximum 80% encapsulation efficiency and revealed initial diffusion followed by chemisorption. The highest release efficiency of 74% suggests high bioavailability of doxycycline after oral administration in ruminants. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

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11 pages, 8942 KiB

Open AccessArticle

Population Pharmacokinetic Analysis Proves Superiority of Continuous Infusion in PK/PD Target Attainment with Oxacillin in Staphylococcal Infections

by Irena Murínová, Martin Švidrnoch, Tomáš Gucký, Jan Hlaváč, Pavel Michálek, Ondřej Slanař and Martin Šíma

Antibiotics 2022, 11(12), 1736; https://doi.org/10.3390/antibiotics11121736 - 1 Dec 2022

Cited by 1 | Viewed by 2137

Abstract

Considering its very short elimination half-life, the approved oxacillin dosage might not be sufficient to maintain the pharmacokinetic/pharmacodynamics (PK/PD) target of time-dependent antibiotics. This study aimed to describe the population pharmacokinetics of oxacillin and to explore the probability of PK/PD target attainment by [...] Read more.

Considering its very short elimination half-life, the approved oxacillin dosage might not be sufficient to maintain the pharmacokinetic/pharmacodynamics (PK/PD) target of time-dependent antibiotics. This study aimed to describe the population pharmacokinetics of oxacillin and to explore the probability of PK/PD target attainment by using various dosing regimens with oxacillin in staphylococcal infections. Both total and unbound oxacillin plasma concentrations retrieved as a part of routine therapeutic drug-monitoring practice were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were used to generate the theoretical distribution of unbound oxacillin plasma concentration–time profiles at various dosage regimens. Data from 24 patients treated with oxacillin for staphylococcal infection have been included into the analysis. The volume of distribution of oxacillin in the population was 11.2 L, while the elimination rate constant baseline of 0.73 h⁻¹ increased by 0.3 h⁻¹ with each 1 mL/s/1.73 m² of the estimated glomerular filtration rate (eGFR). The median value of oxacillin binding to plasma proteins was 86%. The superiority of continuous infusion in achieving target PK/PD values was demonstrated and dosing according to eGFR was proposed. Daily oxacillin doses of 9.5 g, 11 g, or 12.5 g administered by continuous infusion have been shown to be optimal for achieving target PK/PD values in patients with moderate, mild, or normal renal function, respectively. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

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24 pages, 1902 KiB

Open AccessArticle

Individual Pharmacotherapy Management (IPM)—IV: Optimized Usage of Approved Antimicrobials Addressing Under-Recognized Adverse Drug Reactions and Drug-Drug Interactions in Polypharmacy

by Ursula Wolf, Henning Baust, Rüdiger Neef and Thomas Steinke

Antibiotics 2022, 11(10), 1381; https://doi.org/10.3390/antibiotics11101381 - 9 Oct 2022

Cited by 6 | Viewed by 2765

Abstract

Antimicrobial therapy is often a life-saving medical intervention for inpatients and outpatients. Almost all medical disciplines are involved in this therapeutic procedure. Knowledge of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) is important to avoid drug-related harm. Within the broad spectrum of [...] Read more.

Antimicrobial therapy is often a life-saving medical intervention for inpatients and outpatients. Almost all medical disciplines are involved in this therapeutic procedure. Knowledge of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) is important to avoid drug-related harm. Within the broad spectrum of antibiotic and antifungal therapy, most typical ADRs are known to physicians. The aim of this study was to evaluate relevant pharmacological aspects with which we are not so familiar and to provide further practical guidance. Individual pharmacotherapy management (IPM) as a synopsis of internal medicine and clinical pharmacology based on the entirety of the digital patient information with reference to drug information, guidelines, and literature research has been continuously performed for over 8 years in interdisciplinary intensive care and trauma and transplant patients. Findings from over 52,000 detailed medication analyses highlight critical ADRs and DDIs, especially in these vulnerable patients with polypharmacy. We present the most relevant ADRs and DDIs in antibiotic and antifungal pharmacology, which are less frequently considered in relation to neurologic, hemostaseologic, hematologic, endocrinologic, and cardiac complexities. Constant awareness and preventive strategies help avoid life-threatening manifestations of these inherent risks and ensure patient and drug safety in antimicrobial therapy. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

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19 pages, 2778 KiB

Open AccessArticle

Do Different Sutures with Triclosan Have Different Antimicrobial Activities? A Pharmacodynamic Approach

by Frederic C. Daoud, Fatima M’Zali, Arnaud Zabala, Nicholas Moore and Anne-Marie Rogues

Antibiotics 2022, 11(9), 1195; https://doi.org/10.3390/antibiotics11091195 - 3 Sep 2022

Cited by 4 | Viewed by 2058

Abstract

(1) Background: Three antimicrobial absorbable sutures have different triclosan (TS) loads, triclosan release kinetics and hydrolysis times. This in vitro study aims to analyse and compare their antimicrobial pharmacodynamics. (2) Methods: Time-kill assays were performed with eight triclosan-susceptible microorganisms common in surgical site [...] Read more.

(1) Background: Three antimicrobial absorbable sutures have different triclosan (TS) loads, triclosan release kinetics and hydrolysis times. This in vitro study aims to analyse and compare their antimicrobial pharmacodynamics. (2) Methods: Time-kill assays were performed with eight triclosan-susceptible microorganisms common in surgical site infections (SSIs) and a segment of each TS. Microbial concentrations were measured at T0, T4, T8 and T24 h. Similar non-triclosan sutures (NTS) were used as controls. Microbial concentrations were plotted and analysed with panel analysis. They were predicted over time with a double-exponential model and four parameters fitted to each TS × microorganism combination. (3) Results: The microbial concentration was associated with the triclosan presence, timeslot and microorganism. It was not associated with the suture material. All combinations shared a common pattern with an early steep concentration reduction from baseline to 4–8 h, followed by a concentration up to a 24-h plateau in most cases with a mild concentration increase. (4) Conclusions: Microorganisms seem to be predominantly killed by contact or near-contact killing with the suture rather than the triclosan concentration in the culture medium. No significant in vitro antimicrobial pharmacodynamic difference between the three TS is identified. Triclosan can reduce the suture microbial colonisation and SSI risk. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

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15 pages, 3661 KiB

Open AccessArticle

Analysis of a Library of Escherichia coli Transporter Knockout Strains to Identify Transport Pathways of Antibiotics

by Lachlan Jake Munro and Douglas B. Kell

Antibiotics 2022, 11(8), 1129; https://doi.org/10.3390/antibiotics11081129 - 19 Aug 2022

Cited by 5 | Viewed by 2983

Abstract

Antibiotic resistance is a major global healthcare issue. Antibiotic compounds cross the bacterial cell membrane via membrane transporters, and a major mechanism of antibiotic resistance is through modification of the membrane transporters to increase the efflux or reduce the influx of antibiotics. Targeting [...] Read more.

Antibiotic resistance is a major global healthcare issue. Antibiotic compounds cross the bacterial cell membrane via membrane transporters, and a major mechanism of antibiotic resistance is through modification of the membrane transporters to increase the efflux or reduce the influx of antibiotics. Targeting these transporters is a potential avenue to combat antibiotic resistance. In this study, we used an automated screening pipeline to evaluate the growth of a library of 447 Escherichia coli transporter knockout strains exposed to sub-inhibitory concentrations of 18 diverse antimicrobials. We found numerous knockout strains that showed more resistant or sensitive phenotypes to specific antimicrobials, suggestive of transport pathways. We highlight several specific drug-transporter interactions that we identified and provide the full dataset, which will be a useful resource in further research on antimicrobial transport pathways. Overall, we determined that transporters are involved in modulating the efficacy of almost all the antimicrobial compounds tested and can, thus, play a major role in the development of antimicrobial resistance. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

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10 pages, 1708 KiB

Open AccessArticle

Effects of Levofloxacin, Aztreonam, and Colistin on Enzyme Synthesis by P. aeruginosa Isolated from Cystic Fibrosis Patients

by Arianna Pani, Valeria Lucini, Silvana Dugnani, Alice Schianchi and Francesco Scaglione

Antibiotics 2022, 11(8), 1114; https://doi.org/10.3390/antibiotics11081114 - 17 Aug 2022

Cited by 2 | Viewed by 2223

Abstract

(1) Background: Cystic fibrosis (CF) is characterized by chronic pulmonary inflammation and persistent bacterial infections. P. aeruginosa is among the main opportunistic pathogens causing infections in CF. P. aeruginosa is able to form a biofilm, decreasing antibiotic permeability. LOX, a lipoxygenase enzyme, is [...] Read more.

(1) Background: Cystic fibrosis (CF) is characterized by chronic pulmonary inflammation and persistent bacterial infections. P. aeruginosa is among the main opportunistic pathogens causing infections in CF. P. aeruginosa is able to form a biofilm, decreasing antibiotic permeability. LOX, a lipoxygenase enzyme, is a virulence factor produced by P. aeruginosa and promotes its persistence in lung tissues. The aim of this study is to evaluate if antibiotics currently used for aerosol therapy in CF are able to interfere with the production of lipoxygenase from open isolates of P. Aeruginosa from patients with CF. (2) Methods: Clinical isolates of P. aeruginosa from patients with CF were grown in Luria broth (LB). Minimum inhibitory concentration (MIC) was performed and interpreted for all isolated strains according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. We selected four antibiotics with different mechanisms of action: aztreonam, colistin, amikacin, and levofloxacin. We used human pulmonary epithelial NCI-H929 cells to evaluate LOX activity and its metabolites according to antibiotic action at increasing concentrations. (3) Results: there is a correlation between LOX secretion by clinical isolates of P. aeruginosa and biofilm production. Levofloxacin exhibits highly significant inhibitory activity compared to the control. Amikacin also exhibits significant inhibitory activity against LOX production. Aztreonam and colistin do not show inhibitory activity. These results are also confirmed for LOX metabolites. (4) Conclusions: among the evaluated antibiotics, levofloxacin and amikacin have an activity on LOX secretion. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

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13 pages, 724 KiB

Open AccessArticle

Survey of the Knowledge, Attitudes and Practice towards Antibiotic Use among Prospective Antibiotic Prescribers in Serbia

by Olga Horvat, Ana Tomas Petrović, Milica Paut Kusturica, Dragica Bukumirić, Bojana Jovančević and Zorana Kovačević

Antibiotics 2022, 11(8), 1084; https://doi.org/10.3390/antibiotics11081084 - 10 Aug 2022

Cited by 6 | Viewed by 2757

Abstract

The complex issue of antibacterial resistance (ABR) requires actions taken with the One Health approach, involving both human and veterinarian medicine. It can spread from animals to humans through the food chain or through direct contact. Health profession students, as the future antibiotic [...] Read more.

The complex issue of antibacterial resistance (ABR) requires actions taken with the One Health approach, involving both human and veterinarian medicine. It can spread from animals to humans through the food chain or through direct contact. Health profession students, as the future antibiotic providers, can greatly impact antibiotic-related issues in the future. The study was conducted to evaluate knowledge, attitudes and practice of future antibiotic prescribers in relation to judicious use of antibiotics. This cross-sectional, questionnaire-based study was performed on 400 students of health professions who were allowed to prescribe antibiotics of the University of Novi Sad, Serbia. Students of medicine and students of dentistry showed a significantly higher knowledge score compared to students of veterinary medicine (p = 0.001). Multivariate regression identified predictors of adequate antibiotic knowledge: being a female student (B = 0.571; p = 0.020), higher grade average (B = 1.204; p = 0.001), students of medicine (B = 0.802; p = 0.006) and dentistry (B = 0.769; p = 0.026), and students who used a complete package of antibiotics during the last infection (B = 0.974; p = 0.001) or for the period recommended by the doctor (B = 1.964; p = 0.001). Out of the total sample, self-medication was reported among 42.8% of students. The identified predictors of self-medication were: more frequent (B = 0.587; p = 0.001) and irregular (B = 0.719; p = 0.007) antibiotic use, taking antibiotics until symptoms disappeared (B = 2.142; p = 0.001) or until the bottle was finished (B = 1.010; p = 0.001) during the last infection. It seems prudent to reevaluate the educational curricula regarding antibiotic use and ABR of prospective prescribers in Serbia. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

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18 pages, 2651 KiB

Open AccessArticle

Identification of Therapeutic Targets in an Emerging Gastrointestinal Pathogen Campylobacter ureolyticus and Possible Intervention through Natural Products

by Kanwal Khan, Zarrin Basharat, Khurshid Jalal, Mutaib M. Mashraqi, Ahmad Alzamami, Saleh Alshamrani and Reaz Uddin

Antibiotics 2022, 11(5), 680; https://doi.org/10.3390/antibiotics11050680 - 18 May 2022

Cited by 7 | Viewed by 3765

Abstract

Campylobacter ureolyticus is a Gram-negative, anaerobic, non-spore-forming bacteria that causes gastrointestinal infections. Being the most prevalent cause of bacterial enteritis globally, infection by this bacterium is linked with significant morbidity and mortality in children and immunocompromised patients. No information on pan-therapeutic drug targets [...] Read more.

Campylobacter ureolyticus is a Gram-negative, anaerobic, non-spore-forming bacteria that causes gastrointestinal infections. Being the most prevalent cause of bacterial enteritis globally, infection by this bacterium is linked with significant morbidity and mortality in children and immunocompromised patients. No information on pan-therapeutic drug targets for this species is available yet. In the current study, a pan-genome analysis was performed on 13 strains of C. ureolyticus to prioritize potent drug targets from the identified core genome. In total, 26 druggable proteins were identified using subtractive genomics. To the best of the authors’ knowledge, this is the first report on the mining of drug targets in C. ureolyticus. UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) was selected as a promiscuous pharmacological target for virtual screening of two bacterial-derived natural product libraries, i.e., postbiotics (n = 78) and streptomycin (n = 737) compounds. LpxC inhibitors from the ZINC database (n = 142 compounds) were also studied with reference to LpxC of C. ureolyticus. The top three docked compounds from each library (including ZINC26844580, ZINC13474902, ZINC13474878, Notoginsenoside St-4, Asiaticoside F, Paraherquamide E, Phytoene, Lycopene, and Sparsomycin) were selected based on their binding energies and validated using molecular dynamics simulations. To help identify potential risks associated with the selected compounds, ADMET profiling was also performed and most of the compounds were considered safe. Our findings may serve as baseline information for laboratory studies leading to the discovery of drugs for use against C. ureolyticus infections. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

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12 pages, 289 KiB

Open AccessArticle

Optimizing Doses of Ceftolozane/Tazobactam as Monotherapy or in Combination with Amikacin to Treat Carbapenem-Resistant Pseudomonas aeruginosa

by Worapong Nasomsong, Parnrada Nulsopapon, Dhitiwat Changpradub, Supanun Pungcharoenkijkul, Patomroek Hanyanunt, Tassanawan Chatreewattanakul and Wichai Santimaleeworagun

Antibiotics 2022, 11(4), 517; https://doi.org/10.3390/antibiotics11040517 - 13 Apr 2022

Cited by 5 | Viewed by 3087

Abstract

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a hospital-acquired pathogen with a high mortality rate and limited treatment options. We investigated the activity of ceftolozane/tazobactam (C/T) and its synergistic effects with amikacin to extend the range of optimal therapeutic choices with appropriate doses. The E-test [...] Read more.

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a hospital-acquired pathogen with a high mortality rate and limited treatment options. We investigated the activity of ceftolozane/tazobactam (C/T) and its synergistic effects with amikacin to extend the range of optimal therapeutic choices with appropriate doses. The E-test method is used to determine in vitro activity. The optimal dosing regimens to achieve a probability of target attainment (PTA) and a cumulative fraction of response (CFR) of ≥90% were simulated using the Monte Carlo method. Of the 66 CRPA isolates, the rate of susceptibility to C/T was 86.36%, with an MIC₅₀ and an MIC₉₀ of 0.75 and 24 µg/mL, respectively. Synergistic and additive effects between C/T and amikacin were observed in 24 (40%) and 18 (30%) of 60 CRPA isolates, respectively. The extended infusion of C/T regimens achieved a ≥90% PTA of 75% and a 100% fT > MIC at C/T MICs of 4 and 2 µg/mL, respectively. Only the combination of either a short or prolonged C/T infusion with a loading dose of amikacin of 20–25 mg/kg, followed by 15–20 mg/kg/day amikacin dosage, achieved ≥90% CFR. The C/T infusion, combined with currently recommended amikacin dose regimens, should be considered to manage CRPA infections. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

Review

Jump to: Research

13 pages, 1928 KiB

Open AccessReview

Should Airway Interstitial Fluid Be Used to Evaluate the Pharmacokinetics of Macrolide Antibiotics for Dose Regimen Determination in Respiratory Infection?

by Jianzhong Wang, Xueying Zhou, Sara T. Elazab, Seung-Chun Park and Walter H. Hsu

Antibiotics 2023, 12(4), 700; https://doi.org/10.3390/antibiotics12040700 - 3 Apr 2023

Viewed by 2304

Abstract

Macrolide antibiotics are important drugs to combat infections. The pharmacokinetics (PK) of these drugs are essential for the determination of their optimal dose regimens, which affect antimicrobial pharmacodynamics and treatment success. For most drugs, the measurement of their concentrations in plasma/serum is the [...] Read more.

Macrolide antibiotics are important drugs to combat infections. The pharmacokinetics (PK) of these drugs are essential for the determination of their optimal dose regimens, which affect antimicrobial pharmacodynamics and treatment success. For most drugs, the measurement of their concentrations in plasma/serum is the surrogate for drug concentrations in target tissues for therapy. However, for macrolides, simple reliance on total or free drug concentrations in serum/plasma might be misleading. The macrolide antibiotic concentrations of serum/plasma, interstitial fluid (ISF), and target tissue itself usually yield very different PK results. In fact, the PK of a macrolide antibiotic based on serum/plasma concentrations alone is not an ideal predictor for the in vivo efficacy against respiratory pathogens. Instead, the PK based on drug concentrations at the site of infection or ISF provide much more clinically relevant information than serum/plasma concentrations. This review aims to summarize and compare/discuss the use of drug concentrations of serum/plasma, airway ISF, and tissues for computing the PK of macrolides. A better understanding of the PK of macrolide antibiotics based on airway ISF concentrations will help optimize the antibacterial dose regimen as well as minimizing toxicity and the emergence of drug resistance in clinical practice. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

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24 pages, 4104 KiB

Open AccessReview

Phenolic Compounds in Bacterial Inactivation: A Perspective from Brazil

by Angélica Correa Kauffmann and Vinicius Silva Castro

Antibiotics 2023, 12(4), 645; https://doi.org/10.3390/antibiotics12040645 - 24 Mar 2023

Cited by 36 | Viewed by 5715

Abstract

Phenolic compounds are natural substances that are produced through the secondary metabolism of plants, fungi, and bacteria, in addition to being produced by chemical synthesis. These compounds have anti-inflammatory, antioxidant, and antimicrobial properties, among others. In this way, Brazil represents one of the [...] Read more.

Phenolic compounds are natural substances that are produced through the secondary metabolism of plants, fungi, and bacteria, in addition to being produced by chemical synthesis. These compounds have anti-inflammatory, antioxidant, and antimicrobial properties, among others. In this way, Brazil represents one of the most promising countries regarding phenolic compounds since it has a heterogeneous flora, with the presence of six distinct biomes (Cerrado, Amazon, Atlantic Forest, Caatinga, Pantanal, and Pampa). Recently, several studies have pointed to an era of antimicrobial resistance due to the unrestricted and large-scale use of antibiotics, which led to the emergence of some survival mechanisms of bacteria to these compounds. Therefore, the use of natural substances with antimicrobial action can help combat these resistant pathogens and represent a natural alternative that may be useful in animal nutrition for direct application in food and can be used in human nutrition to promote health. Therefore, this study aimed to (i) evaluate the phenolic compounds with antimicrobial properties isolated from plants present in Brazil, (ii) discuss the compounds across different classes (flavonoids, xanthones, coumarins, phenolic acids, and others), and (iii) address the structure–activity relationship of phenolic compounds that lead to antimicrobial action. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

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16 pages, 312 KiB

Open AccessReview

Efficacy of Combination Therapies for the Treatment of Multi-Drug Resistant Gram-Negative Bacterial Infections Based on Meta-Analyses

by Takumi Umemura, Hideo Kato, Mao Hagihara, Jun Hirai, Yuka Yamagishi and Hiroshige Mikamo

Antibiotics 2022, 11(4), 524; https://doi.org/10.3390/antibiotics11040524 - 14 Apr 2022

Cited by 14 | Viewed by 6080

Abstract

There is increasing evidence regarding the optimal therapeutic strategies for multidrug-resistant (MDR) bacteria that cause common infections and are resistant to existing antibiotics. Combination therapies, such as β-lactam combined with β-lactamase inhibitors or combination antibiotics, is a therapeutic strategy to overcome MDR bacteria. [...] Read more.

There is increasing evidence regarding the optimal therapeutic strategies for multidrug-resistant (MDR) bacteria that cause common infections and are resistant to existing antibiotics. Combination therapies, such as β-lactam combined with β-lactamase inhibitors or combination antibiotics, is a therapeutic strategy to overcome MDR bacteria. In recent years, the therapeutic options have expanded as certain combination drugs have been approved in more countries. However, only a handful of guidelines support these options, and the recommendations are based on low-quality evidence. This review describes the significance and efficacy of combination therapy as a therapeutic strategy against Gram-negative MDR pathogens based on previously reported meta-analyses. Full article

(This article belongs to the Special Issue Clinical Pharmacology and Pharmacy of Antimicrobial Agents)

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