Antibiotics — Open Access Journal

Aim: This study investigated the susceptibility of Enterotoxigenic Escherichia coli to curcumin, as well as its synergistic effect with 12 antimicrobial drugs. Methods and Results: Our study shows that curcumin did not affect bacterial growth. The antimicrobial susceptibility of curcumin and antibiotic synergy were identified using disc diffusion on Mueller-Hinton agar. The strain of Enterotoxigenic Escherichia coli used was resistant to Ampicillin, Amoxicillin/Clavulanic acid, Ampicillin/Sulbactam, Ciprofloxacin, and Cefazolin. There was synergy between curcumin and the majority of antibiotics tested. Maximum synergy was observed with combinations of 330 µg/mL curcumin and Ceftazidime, followed by Cefotaxime, Amoxicillin/Clavulanic acid, Ampicillin, Aztreonam, Trimethoprim, Ciprofloxacin, Ceftriaxone, Cefazolin, Tetracycline, and Imipenem. Conclusion: Our findings indicated that curcumin might be useful as a combinatorial strategy to combat the antibiotic resistance of Enterotoxigenic Escherichia coli. Full article

The manuscripts contained in this special edition of Antibiotics represent a current review of the polymyxins as well as highlights from the 3rd International Polymyxin Conference, which was held in Madrid, Spain, April 25 to 26, 2018. The role of the polymyxin antibiotics has evolved over time based on the availability of alternative agents. After high rates of nephrotoxicity caused the drug class to fall out of favor, polymyxins were once against utilized in the 21st century to combat drug-resistant pathogens. However, the introduction of safer agents with activity against drug-resistant organisms has brought the future utility of polymyxins into question. The present review investigates the future niche of polymyxins by evaluating currently available and future treatment options for difficult-to-treat pathogens. The introduction of ceftazidime-avibactam, meropenem-vaborbactam and plazomicin are likely to decrease polymyxin utilization for infections caused by Enterobacteriaceae. Similarly, the availability of ceftolozane-tazobactam will reduce the use of polymyxins to counter multidrug-resistant Pseudomonas aeruginosa. In contrast, polymyxins will likely continue be an important option for combatting carbapenem-resistant Acinetobacter baumannii until better options become commercially available. Measuring polymyxin concentrations in patients and individualizing therapy may be a future strategy to optimize clinical outcomes while minimizing nephrotoxicity. Inhaled polymyxins will continue to be an adjunctive option for pulmonary infections but further clinical trials are needed to clarify the efficacy of inhaled polymyxins. Lastly, safer polymyxin analogs will potentially be an important addition to the antimicrobial armamentarium. Full article

Antimicrobial drug resistance (AMR) in pneumococci complicates the treatment of serious pneumococcal infections. Country-specific AMR patterns can help to establish guidelines for empiric therapy. The aim of the current study was to analyze the distribution of AMR among Streptococcus pneumoniae isolates at Jordan University Hospital (JUH) during 2000–2018. Paper-based and electronic clinical data registry records from 2000 to 2018 were retrospectively analyzed to study the AMR among pneumococcal isolates at JUH. Temporal trend analysis was done using two-tailed linear-by-linear test for association. The total number of unique pneumococcal isolates that were identified was 556, of which 544 isolates had antimicrobial susceptibility testing results. The most frequent specimens were eye (n = 117, 21.0%), bloodstream (n = 93, 16.7%) and sputum (n = 81, 14.6%). Invasive infections represented 23.6% of all unique isolates. The overall susceptibility of S. pneumoniae isolates during the study period to different antimicrobials was: 100% to vancomycin, 97.7% to ceftriaxone, 97.1% to cefotaxime, 94.9% to chloramphenicol, 89.7% to penicillin, 83.8% to levofloxacin, 67.7% to clindamycin and 52.1% to erythromycin. The prevalence of multi-drug resistance (MDR) was 8.6% (95% confidence interval: 6.4–11.5%). Trend analysis showed an increase in the prevalence of non-susceptibility to erythromycin, clindamycin and levofloxacin (p < 0.001). MDR prevalence increased from 1.6% in the first quarter to 14.6% in the fourth quarter (p < 0.001). The incidence of invasive infections declined over the study period (p < 0.001). The increase in the prevalence of AMR and MDR among pneumococcal isolates in Jordan demands judicious use of antimicrobials and regular surveillance of resistance. Full article

In the past decade, multidrug-resistant (MDR) gram-negative bacteria have become a major problem, especially for patients in intensive care units. Recently, colistin became the last resort therapy for MDR gram-negative bacteria infections. However, nebulised colistin use was limited to adult patients. Thus, we investigated the efficacy and safety of nebulised colistin treatment against MDR microorganisms in the paediatric intensive care unit (PICU). Data of all patients admitted for various critical illnesses (January 2016 to January 2019) were reviewed. Differences between groups (with and without a history of nebulised colistin) were compared. Of 330 patients, 23 (6.97%) used nebulised colistin. Significant relationships were found between nebulised colistin usage and several prognostic factors (inotropic drug use (p = 0.009), non-invasive mechanical ventilation (p ≤ 0.001), duration in PICU (p ≤ 0.001), and C-reactive protein level (p = 0.003)). The most common microorganism in tracheal aspirate and sputum cultures was Pseudomonas aeruginosa (13 patients). The most common underlying diagnosis was cystic fibrosis, noted in 6 patients. No serious nephrotoxicity and neurotoxicity occurred. This study showed that colistin can be safely used directly in the airway of critically ill children. However, nebulised colistin use did not have a positive effect on mortality and prognosis. Full article

Infectious diseases remain a major burden in today’s world, causing high mortality rates and significant economic losses, with >9 million deaths per year predicted by 2030. Invasion of host cells by intracellular bacteria poses treatment challenges due to the poor permeation of antimicrobials into the infected cells. To overcome these limitations, mesoporous silica nanoparticles (MSNP) loaded with the antibiotic rifampicin were investigated as a nanocarrier system for the treatment of intracellular bacterial infection with specific interest in the influence of particle size on treatment efficiency. An intracellular infection model was established using small colony variants (SCV) of S. aureus in macrophages to systemically evaluate the efficacy of rifampicin-loaded MSNP against the pathogen as compared to a rifampicin solution. As hypothesized, the superior uptake of MSNP by macrophages resulted in an enhanced treatment efficacy of the encapsulated rifampicin as compared to free antibiotic. This study provides a potential platform to improve the performance of currently available antibiotics against intracellular infections. Full article

Polymyxins have been a mainstay for the treatment of extensively drug resistant (XDR) Gram-negative bacteria for the past two decades. Many questions regarding the clinical use of polymyxins have been answered, but whether the administration of polymyxins in combination with other antibiotics leads to better outcomes remains unknown. This review discusses the limitations of observational studies that suggest a benefit of combinations of colistin and carbapenems to treat infections caused by carbapenem-resistant Enterobacteriaceae (CRE), especially Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae, and summarizes the results of randomized controlled trials in which treatment with colistin in combination with meropenem or rifampin does not lead to better clinical outcomes than colisitn monotherapy in infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB). Although the introduction of new antibiotics makes it possible to treat certain strains of CRE and carbapenem-resistant P. aeruginosa (CRPA) with polymyxin-sparing regimens, the use of polymyxins is, for now, still necessary in CRAB and in CRE and CRPA harboring metallo-beta-lactamases. Therefore, strategies must be developed to optimize polymyxin-based treatments, informed by in vitro hollow fiber models, careful clinical observations, and high-quality evidence from appropriately designed trials. Full article

Antibiotic resistance has increased markedly in gram-negative bacteria over the last two decades, and in many cases has been associated with increased mortality and healthcare costs. The adoption of genotyping and next generation whole genome sequencing of large sets of clinical bacterial isolates has greatly expanded our understanding of how antibiotic resistance develops and transmits among bacteria and between patients. Diverse mechanisms of resistance, including antibiotic degradation, antibiotic target modification, and modulation of permeability through the bacterial membrane have been demonstrated. These fundamental insights into the mechanisms of gram-negative antibiotic resistance have influenced the development of novel antibiotics and treatment practices in highly resistant infections. Here, we review the mechanisms and global epidemiology of antibiotic resistance in some of the most clinically important resistance phenotypes, including carbapenem resistant Enterobacteriaceae, extensively drug resistant (XDR) Pseudomonas aeruginosa, and XDR Acinetobacter baumannii. Understanding the resistance mechanisms and epidemiology of these pathogens is critical for the development of novel antibacterials and for individual treatment decisions, which often involve alternatives to β-lactam antibiotics. Full article

The aim of this study was to detect the prevalence of methicillin-resistant Staphylococcus sp. (MRS) in populations of companion animals that either have previously been exposed or have not been exposed to antibiotic therapy or veterinary facilities, and if owners’ healthcare profession had an influence on colonization with MRS. In addition, the antimicrobial resistance pheno- and genotype were investigated and risks for colonization with MRS were assessed. During this study, 347 nasal swabs (dogs n = 152; cats n = 107; rabbits n = 88) were investigated for the presence of methicillin-resistant Staphylococcus aureus (MRSA). In addition, 131 nasal swabs (dogs n = 79; cats n = 47; rabbits = 3; guinea pigs = 2) were examined for the presence of MRSA but also other MRS. In total, 23 MRS isolates belonged to nine staphylococcal species: Staphylococcus epidermidis (n = 11), Staphylococcus warneri (n = 3), Staphylococcus hominis (n = 2), Staphylococcus pseudintermedius (n = 2), and singletons Staphylococcus cohnii, Staphylococcus sciuri, Staphylococcus fleurettii, Staphylococcus lentus, and Staphylococcus haemolyticus. Twenty isolates displayed a multidrug-resistant phenotype. Various resistance and biocide resistance genes were detected among the examined staphylococci. Risk assessment for MRS colonization was conducted using a number of factors, including animal species, breed, age, gender, recent veterinary health care hospitalization, and antibiotic prescription, resulting in recent veterinary health care hospitalization being a significant risk factor. The detection of multidrug-resistant MRS in healthy animals is of importance due to their zoonotic potential. Full article

Antibiotic misuse, either by patients or healthcare professionals, is one of the major contributing factors to antimicrobial resistance. In many Middle Eastern countries including Egypt, there are no strict regulations regarding antibiotic dispensing by community pharmacies. In this study, we examined antibiotic dispensing patterns in Egyptian community pharmacies. About 150 community pharmacies were randomly chosen using convenience sampling from the five most populous urban districts of Minia Governorate in Egypt. Two simulated patient (SP) scenarios of viral respiratory tract infection requiring no antibiotic treatment were used to assess the actual antibiotics dispensing practice of. Face-to-face interviews were then conducted to assess the intended dispensing practice. Descriptive statistics were calculated to report the main study outcomes. In 238 visits of both scenarios, 98.3% of service providers dispensed amoxicillin. Although stated otherwise in interviews, most pharmacy providers (63%) dispensed amoxicillin without collecting relevant information from presenting SPs. Findings showed high rates of antibiotic misuse in community pharmacies. Discrepancies between interviews and patient simulation results also suggest a practice‒knowledge gap. Corrective actions, whether legislation, enforcement, education, or awareness campaigns about antibiotic misuse, are urgently needed to improve antibiotic dispensing practices in Egyptian community pharmacies. Full article

Plant metabolites that have shown activity against bacteria and/or environmental fungi represent valuable leads for the identification and development of novel drugs against clinically important human pathogenic fungi. Plants from the genus Eremophila were highly valued in traditional Australian Aboriginal medicinal practices, and E. alternifolia was the most prized among them. As antibacterial activity of extracts from E. alternifolia has been documented, this study addresses the question whether there is also activity against infectious fungal human pathogens. Compounds from leaf-extracts were purified and identified by 1- and 2-D NMR. These were then tested by disk diffusion and broth microdilution assays against ten clinically and environmentally relevant yeast and mould species. The most potent activity was observed with the diterpene compound, 8,19-dihydroxyserrulat-14-ene against Cryptococcus gattii and Cryptococcus neoformans, with minimum inhibition concentrations (MIC) comparable to those of Amphotericin B. This compound also exhibited activity against six Candida species. Combined with previous studies showing an antibacterial effect, this finding could explain a broad antimicrobial effect from Eremophila extracts in their traditional medicinal usage. The discovery of potent antifungal compounds from Eremophila extracts is a promising development in the search for desperately needed antifungal compounds particularly for Cryptococcus infections. Full article

A framework was developed to characterize the antimicrobial use/antimicrobial resistance complex in livestock systems in Indonesia, Vietnam, and Thailand. Farm profitability, disease prevention, and mortality rate reduction were identified as drivers toward antimicrobial use in livestock systems. It revealed that antimicrobial use was high in all sectors studied, and that routine preventative use was of particular importance to broiler production systems. Misleading feed labeling was identified as a hurdle to the collection of accurate antimicrobial use data, with farmers being unaware of the antimicrobials contained in some commercial feed. Economic analysis found that the cost of antimicrobials was low relative to other farm inputs, and that farm profitability was precariously balanced. High disease and poor prices were identified as potential drivers toward economic loss. The research indicates that antimicrobial use in small-scale poultry production systems improves feed conversion ratios and overall productivity. However, data were limited to quantify adequately these potential gains and their impacts on the food supply. During the study, all countries embraced and implemented policies on better management of antimicrobial use in livestock and surveillance of antimicrobial resistance. Future policies need to consider farm-level economics and livestock food supply issues when developing further antimicrobial use interventions in the region. Full article

This study compared the activity of cefepime + zidebactam (FEP-ZID) and selected currently available antibacterial agents against a panel of multidrug-resistant (MDR) clinical isolates chosen to provide an extreme challenge for antibacterial activity. FEP–ZID had a very broad and potent in vitro spectrum of activity, and was highly active against many MDR isolates of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii. Notably, it inhibited isolates producing carbapenemases of Ambler classes A, B, and D, and P. aeruginosa isolates with multiple resistance mechanisms including combinations of upregulated efflux, diminished or non-functional OprD porins, and AmpC overproduction. Its clinical role will be determined initially by the breakpoints assigned to it, comparison studies with other investigational β-lactamase inhibitor combinations, and ultimately by the developing body of therapeutic outcome data. Full article

Polymyxin B remains an antibiotic of last resort because of its toxicities. Although newer therapies are becoming available, it is anticipated that resistance to these agents will continue to emerge, and understanding the safest and most efficacious manner to deliver polymyxin B will remain highly important. Recent data have demonstrated that polymyxin B may be less nephrotoxic than colistin. Pharmacokinetically, polymyxin B is primarily eliminated via non-renal pathways, and most do not recommend adjusting the dose for renal impairment. However, some recent studies suggest a weak relationship between polymyxin B clearance and patient creatinine clearance. This review article will describe the clinical pharmacokinetics of polymyxin B and address relevant issues in chemistry and assays available. Full article

Objective: The objective of this review is to describe the outcomes of patients treated with ceftaroline in the non-Food and Drug Administration (FDA) approved indication of methicillin-resistant Staphylococcus aureus (MRSA) infections in both pediatric and adult populations. Data sources: A systematic overview was conducted by searching PubMed, Medline, and The Cochrane Library up to January 2019. Study selection and data extraction: All English-language clinical trials and case reports related to the efficacy of ceftaroline in new, not-yet-approved FDA indications in MRSA infections in pediatric or adult populations. Data synthesis: In the case of MRSA bacteremia (MRSAB) infections, three different randomized studies in pediatric patients showed effectiveness of ceftaroline. When used in the case of adult populations with MRSA bacteremia, a small trial of 16 patients showed 50% clinical success in patients with acute bacterial skin and skin structure infections versus 63% clinical success in patients with community-acquired bacterial pneumonia. Another case series of six refractory case reports showed 50% clinical success of ceftaroline in patients with MRSA. Conclusions: Although there are few case reports and limited data to date, ceftaroline fosamil should continue to be studied as an alternative therapy in MRSA infections in both pediatric and adult populations. Clinical success rates of ceftaroline were, in most cases, considered high when treating patients with MRSA infection. More clinical trials need to be studied. In the specific case of MRSA bacteremia, the treatment options remain few and ceftaroline should be extensively studied for the salvage treatment of MRSAB. Full article

Several studies have investigated antimicrobial resistance in low- and middle-income countries, but to date little attention has been paid to the Pacific Islands Countries and Territories (PICTs). This study aims to review the literature on antibiotic resistance (ABR) in healthcare settings in PICTs to inform further research and future policy development for the region. Following the PRISMA-ScR checklist health databases and grey literature sources were searched. Three reviewers independently screened the literature for inclusion, data was extracted using a charting tool and the results were described and synthesised. Sixty-five studies about ABR in PICTs were identified and these are primarily about New Caledonia, Fiji and Papua New Guinea. Ten PICTs contributed the remaining 21 studies and nine PICTs were not represented. The predominant gram-positive pathogen reported was community-acquired methicillin resistant S. aureus and the rates of resistance ranged widely (>50% to <20%). Resistance reported in gram-negative pathogens was mainly associated with healthcare-associated infections (HCAIs). Extended spectrum beta-lactamase (ESBL) producing K. pneumoniae isolates were reported in New Caledonia (3.4%) and Fiji (22%) and carbapenem resistant A. baumannii (CR-ab) isolates in the French Territories (24.8%). ABR is a problem in the PICTs, but the epidemiology requires further characterisation. Action on strengthening surveillance in PICTs needs to be prioritised so strategies to contain ABR can be fully realised. Full article

Orbignya speciosa (babassu) is an important palm tree in Brazil whose fixed almond oil is used in popular medicine and especially in food, in addition to being a research target for the manufacture of biofuels. The aim of this study was to evaluate the fixed almond oil physicochemical characterization and its antibacterial activity in isolation and in association with aminoglycosides against standard and multidrug-resistant bacteria. Analyses such as water content, pH, acidity, peroxide index, relative density, and refractive index indicate the stability and chemical quality of the oil. In the oil’s GC/MS chemical composition analysis, a high saturated fatty acid (76.90%) content was observed. Lauric acid (56.28%) and oleic acid (23.10%) were the major oil components. In the antibacterial test, a more significant oil activity was observed against K. pneumoniae KP-ATCC 10031 (minimal inhibitory concentration (MIC) = 406.37 μg/mL) and Staphylococcus aureus ATCC 6538 (MIC = 812.75 μg/mL), but for the other strains—including standard and multi-resistant strains—the oil presented an MIC ≥ 1024 μg/mL. Furthermore, a synergistic effect was observed when the oil was associated with amikacin and gentamicin against S. aureus (SA-10) and an antagonistic effect was observed with amikacin against Escherichia coli. Data indicate the O. speciosa oil as a valuable nutritional source of lauric, oleic, and myristic fatty acids with an ability to modulate aminoglycoside activity. Full article

Despite advancements in therapy, pneumonia remains the leading cause of death due to infectious diseases. Novel treatment strategies are desperately needed to optimize the antimicrobial therapy of patients suffering from this disease. One such strategy that has recently garnered significant attention is the use of inhaled antibiotics to rapidly achieve therapeutic concentrations directly at the site of infection. In particular, there is significant interest in the role of inhaled polymyxins for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia, due to their retained activity against multi-drug resistant Gram-negative pathogens, including Acinetobacter baumannii and Pseudomonas aeruginosa. This review will provide a comprehensive overview of the pharmacokinetic/pharmacodynamic profile, clinical outcomes, safety, and potential role of inhaled polymyxins in clinical practice. Full article

The aim of this study was to characterize a collection of methicillin-resistant Staphylococcus aureus (MRSA) isolates of human and animal origin from Serbia. In total, 36 MRSA isolates—30 obtained from humans and six from companion animals—were investigated by PCR for the presence of antibiotic and biocide resistance determinants and virulence genes (PVL—Panton–Valentine leukocidin, ETs—exfoliative toxins, TSST—toxic shock syndrome toxin, SEs—staphylococcal enterotoxins, and MSCRAMMs—microbial surface components recognizing adhesive matrix molecules and biofilm). Isolates were analyzed by staphylococcal cassette chromosome mec (SCCmec), spa, and dru typing, as well as by multiple locus variable number of tandem repeat analyses (MLVA), multilocus sequence typing (MLST), and subsequently, eBURST. The majority of human MRSA isolates were resistant to gentamicin, erythromycin, clindamycin, and ciprofloxacin. Different antibiotic resistance genes were detected: aac-aphD, ant(6′)-Ia, erm(A), erm(B), erm(C), tet(K), tet(M), fexA, and cat_pC221. All isolates were susceptible to teicoplanin and linezolid. SCCmec type III was prevalent in human isolates, while SCCmec elements in animals were mostly nontypeable. t037 was the predominant spa type in human and t242 in animal MRSA isolates. The prevalent dru type was dt11c in human and dt10a in animal MRSA isolates. MRSA isolates exhibited 27 different MLVA types. ST239 was predominant in human, while ST5 was prevalent in canine MRSA isolates. PVL was found in two, while tsst-1 was detected in three human isolates. Human-associated clones belonging to ST5, ST45, and ST239 MRSA clones were discovered in companion animals, which suggests anthropozoonotic transmission. Full article

Multidrug efflux systems play a prominent role in medicine, as they are important contributors to bacterial antibiotic resistance. NorA is an efflux pump transporter from the major facilitator superfamily that expels numerous drug compounds across the inner membrane of Staphylococcus aureus (S. aureus). The design of novel inhibitors to combat drug efflux could offer new opportunities to avoid the problem of antibiotic resistance. In this study, we performed molecular modeling studies in an effort to discover novel NorA efflux pump inhibitors. A group of over 673 compounds from the PubChem database with a high (>80%) level of similarity to the chemical structure of capsaicin was used to study the binding affinity of small molecule compounds for the NorA efflux pump. Ten potential lead compounds displayed a good druggability profile, with one in particular (CID 44330438) providing new insight into the molecular mechanism of the inhibition of major facilitator superfamily (MFS) efflux pump transporters. It is our hope that the overall strategy described in this study, and the structural information of the potential novel inhibitors thus identified, will stimulate others to pursue the development of better drugs to tackle multidrug resistance in S. aureus. Full article