Neutrophils are important assets in defense against invading bacteria like staphylococci. However, (dysfunctioning) neutrophils can also serve as reservoir for pathogens that are able to survive inside the cellular environment. Staphylococcus aureus is a notorious facultative intracellular pathogen. Most vulnerable for neutrophil dysfunction and intracellular infection are immune-deficient patients or, as has recently been described, severely injured patients. These dysfunctional neutrophils can become hide-out spots or “Trojan horses” for S. aureus. This location offers protection to bacteria from most antibiotics and allows transportation of bacteria throughout the body inside moving neutrophils. When neutrophils die, these bacteria are released at different locations. In this review, we therefore focus on the capacity of several groups of antibiotics to enter human neutrophils, kill intracellular S. aureus and affect neutrophil function. We provide an overview of intracellular capacity of available antibiotics to aid in clinical decision making. In conclusion, quinolones, rifamycins and sulfamethoxazole-trimethoprim seem very effective against intracellular S. aureus in human neutrophils. Oxazolidinones, macrolides and lincosamides also exert intracellular antibiotic activity. Despite that the reviewed data are predominantly of in vitro origin, these findings should be taken into account when intracellular infection is suspected, as can be the case in severely injured patients. Full article

The aim of this paper was to highlight the most widely antibiotic protocols applied to the dental field, especially in the surgical treatment of impacted wisdom teeth. Once these protocols were screened, all the possible advantages or disadvantages for each drug and each posology were recorded in this review. In recent years, the need to use these protocols has been debated in the literature. The data obtained by this review underlined how antibiotic protocols applied to oral surgery treatments only included surgeries performed on patients who did not present other systemic pathologies. The first literature review obtained 140 results, and then after the application of the inclusion criteria, 12 papers were selected. The results showed that the most commonly used protocol involved the use of penicillin and clavulanate, obtaining safe clinical and prophylactic results in the management of infections. This widely used protocol seems to guarantee high predictability and safety. The presented review highlights the current possibility of antibiotic resistance affecting patients due to drug misuse. Further clinical studies are required to state specific guidelines; however, oral surgeons involved in third molar surgery should evaluate the local and general health conditions of the patients before suggesting any drug measures for patients. Full article

Staphylococcus aureus has been an exceptionally successful pathogen, which is still relevant in modern age-medicine due to its adaptability and tenacity. This bacterium may be a causative agent in a plethora of infections, owing to its abundance (in the environment and in the normal flora) and the variety of virulence factors that it possesses. Methicillin-resistant S. aureus (MRSA) strains—first described in 1961—are characterized by an altered penicillin-binding protein (PBP2a/c) and resistance to all penicillins, cephalosporins, and carbapenems, which makes the β-lactam armamentarium clinically ineffective. The acquisition of additional resistance determinants further complicates their eradication; therefore, MRSA can be considered as the first representative of multidrug-resistant bacteria. Based on 230 references, the aim of this review is to recap the history, the emergence, and clinical features of various MRSA infections (hospital-, community-, and livestock-associated), and to summarize the current advances regarding MRSA screening, typing, and therapeutic options (including lipoglycopeptides, oxazolidinones, anti-MRSA cephalosporins, novel pleuromutilin-, tetracycline- and quinolone-derivatives, daptomycin, fusidic acid, in addition to drug candidates in the development phase), both for an audience of clinical microbiologists and infectious disease specialists. Full article

In response to the occurrence of antibiotic resistance, there has been rapid developments in the field of metal-based antimicrobials. Although it is largely assumed that metals provide broad-spectrum microbial efficacy, studies have shown that this is not always the case. Therefore, in this study, we compared the susceptibilities of 93 clinical isolates belonging to the species Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus against six metals, namely aluminum, copper, gallium, nickel, silver and zinc. To provide qualitative comparative information, the resulting zones of growth inhibition were compared to the minimal inhibitory concentrations of three indicator strains E. coli ATCC 25922, P. aeruginosa ATCC 27853 and S. aureus ATCC 25923. Here, we demonstrate that the metal efficacies were species- and isolate-specific. Only several isolates were either resistant or sensitive to all of the six metals, with great variability found between isolates. However, the greatest degree of similarity was found with the E. coli isolates. In contrast, the susceptibilities of the remaining two collections, S. aureus and P. aeruginosa, were more highly dispersed. Using this information, we have shown that metals are not equal in their efficacies. Hence, their use should be tailored against a particular microorganism and care should be taken to ensure the use of the correct concentration. Full article

Bartonella henselae can cause various infections in humans, ranging from benign and self-limiting diseases to severe and life-threatening diseases as well as persistent infections that are difficult to treat. To develop more effective treatments for persistent Bartonella infections, in this study, we performed a high-throughput screen of an FDA-approved drug library against stationary phase B. henselae using the SYBR Green I/propidium iodide (PI) viability assay. We identified 110 drug candidates that had better activity against stationary phase B. henselae than ciprofloxacin, and among the top 52 drug candidates tested, 41 drugs were confirmed by microscopy to have higher activity than the current frontline antibiotic erythromycin. The identified top drug candidates include pyrvinium pamoate, daptomycin, methylene blue, azole drugs (clotrimazole, miconazole, sulconazole, econazole, oxiconazole, butoconazole, bifonazole), aminoglycosides (gentamicin and streptomycin, amikacin, kanamycin), amifostine (Ethyol), antiviral Lopinavir/ritonavir, colistin, nitroxoline, nitrofurantoin, verteporfin, pentamidine, berberine, aprepitant, olsalazine, clinafloxacin, and clofoctol. Pyrvinium pamoate, daptomycin, methylene blue, clotrimazole, and gentamicin and streptomycin at their respective maximum drug concentration in serum (C_max) had the capacity to completely eradicate stationary phase B. henselae after 3-day drug exposure in subculture studies. While the currently used drugs for treating bartonellosis, including rifampin, erythromycin, azithromycin, doxycycline, and ciprofloxacin, had very low minimal inhibitory concentration (MIC) against growing B. henselae, they had relatively poor activity against stationary phase B. henselae, except aminoglycosides. The identified FDA-approved agents with activity against stationary phase B. henselae should facilitate development of more effective treatments for persistent Bartonella infections. Full article

This study developed a patient-level audit tool to assess the appropriateness of antibiotic prescribing in acute National Health Service (NHS) hospitals in the UK. A modified Delphi process was used to evaluate variables identified from published literature that could be used to support an assessment of appropriateness of antibiotic use. At a national workshop, 22 infection experts reached a consensus to define appropriate prescribing and agree upon an initial draft audit tool. Following this, a national multidisciplinary panel of 19 infection experts, of whom only one was part of the workshop, was convened to evaluate and validate variables using questionnaires to confirm the relevance of each variable in assessing appropriate prescribing. The initial evidence synthesis of published literature identified 25 variables that could be used to support an assessment of appropriateness of antibiotic use. All the panel members reviewed the variables for the first round of the Delphi; the panel accepted 23 out of 25 variables. Following review by the project team, one of the two rejected variables was rephrased, and the second neutral variable was re-scored. The panel accepted both these variables in round two with a 68% response rate. Accepted variables were used to develop an audit tool to determine the extent of appropriateness of antibiotic prescribing at the individual patient level in acute NHS hospitals through infection expert consensus based on the results of a Delphi process. Full article

Staphylococcus aureus RnpA is thought to be a unique dual functional antimicrobial target that is required for two essential cellular processes, precursor tRNA processing and messenger RNA degradation. Herein, we used a previously described whole cell-based mupirocin synergy assay to screen members of a 53,000 compound small molecule diversity library and simultaneously enrich for agents with cellular RnpA inhibitory activity. A medicinal chemistry-based campaign was launched to generate a preliminary structure activity relationship and guide early optimization of two novel chemical classes of RnpA inhibitors identified, phenylcarbamoyl cyclic thiophene and piperidinecarboxamide. Representatives of each chemical class displayed potent anti-staphylococcal activity, limited the protein’s in vitro ptRNA processing and mRNA degradation activities, and exhibited favorable therapeutic indexes. The most potent piperidinecarboxamide RnpA inhibitor, JC2, displayed inhibition of cellular RnpA mRNA turnover, RnpA-depletion strain hypersusceptibility, and exhibited antimicrobial efficacy in a wax worm model of S. aureus infection. Taken together, these results establish that the whole cell screening assay used is amenable to identifying small molecule RnpA inhibitors within large chemical libraries and that the chemical classes identified here may represent progenitors of new classes of antimicrobials that target RnpA. Full article

Otosyphilis is one contributing cause of hearing loss in adult patients. There are limited studies on the treatment regimens of otosyphilis. Penicillin G sodium (PGS) plus additional medications, such as benzathine penicillin and probenecid, is an effective regimen. This study investigated the efficacy of PGS alone for the treatment of otosyphilis. We conducted a retrospective study and included all consecutive patients diagnosed with otosyphilis who received only PGS treatment. The study period was from 2009 to 2013. The PGS treatment regimen was PGS 4 mu intravenously every four hours (24 mu/day) for 14 days. Clinical and audiogram outcomes were evaluated one year after treatment. There were 34 otosyphilis patients that were treated with PGS. After one year of treatment, 18 patients (52.9%) had a clinical improvement and 11 patients (32.4%) had an audiogram improvement. In conclusion, PGS at 24 mu/day for two weeks provided an audiogram improvement one year after treatment in one-third of the patients. Full article

Bacteriophages represent an alternative strategy to combat pathogenic bacteria. Currently, Mycobacterium tuberculosis infections constitute a major public health problem due to extensive antibiotic resistance in some strains. Using a non-pathogenic species of the same genus as an experimental model, Mycobacterium smegmatis, here we have set up a basic methodology for mycobacteriophage growth and we have explored directed evolution as a tool for increasing phage infectivity and lytic activity. We demonstrate mycobacteriophage adaptation to its host under different conditions. Directed evolution could be used for the development of future phage therapy applications against mycobacteria. Full article

Given the increase in antibiotic-resistant bacteria, alongside the alarmingly low rate of newly approved antibiotics for clinical usage, we are on the verge of not having effective treatments for many common infectious diseases. Historically, antibiotic discovery has been crucial in outpacing resistance and success is closely related to systematic procedures—platforms—that have catalyzed the antibiotic golden age, namely the Waksman platform, followed by the platforms of semi-synthesis and fully synthetic antibiotics. Said platforms resulted in the major antibiotic classes: aminoglycosides, amphenicols, ansamycins, beta-lactams, lipopeptides, diaminopyrimidines, fosfomycins, imidazoles, macrolides, oxazolidinones, streptogramins, polymyxins, sulphonamides, glycopeptides, quinolones and tetracyclines. During the genomics era came the target-based platform, mostly considered a failure due to limitations in translating drugs to the clinic. Therefore, cell-based platforms were re-instituted, and are still of the utmost importance in the fight against infectious diseases. Although the antibiotic pipeline is still lackluster, especially of new classes and novel mechanisms of action, in the post-genomic era, there is an increasingly large set of information available on microbial metabolism. The translation of such knowledge into novel platforms will hopefully result in the discovery of new and better therapeutics, which can sway the war on infectious diseases back in our favor. Full article

The rapid growth of antimicrobial resistance against several frontline antibiotics has encouraged scientists worldwide to develop new alternatives with unique mechanisms of action. Antimicrobial peptides (AMPs) have attracted considerable interest due to their rapid killing and broad-spectrum activity. Peptidomimetics overcome some of the obstacles of AMPs such as high cost of synthesis, short half-life in vivo due to their susceptibility to proteolytic degradation, and issues with toxicity. This review will examine the development of short cationic peptidomimetics as antimicrobials. Full article

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, 25 to 26 April 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