Antibiotics, Volume 9, Issue 3 (March 2020) – 39 articles

Antipathogenic compounds that target the virulence of pathogenic bacteria rather than their viability offer a promising alternative approach to treat infectious diseases. Using extracts from 30 Chinese herbs that are known for treating symptoms resembling infections, we identified an active compound falcarindiol from Notopterygium incisum Ting ex H. T. Chang that showed potent inhibitory activities against Pseudomonas aeruginosa multiple virulence factors. Falcarindiol significantly repressed virulence-related genes, including the type III secretion system (T3SS); quorum sensing synthase genes lasIR and rhlIR; lasB; motility-related genes fliC and fliG; and phenazine synthesis genes phzA1 and phzA2. P. aeruginosa swarming motility and pyocyanin production were reduced significantly. In a burned mouse model, falcarindiol treatment significantly reduced the mortality in mice infected with P. aeruginosa, indicating that falcarindiol is a promising antipathogenic drug candidate for treating P. aeruginosa infections. Full article

In an era of proliferating multidrug resistant bacterial infections that are exhausting the capacity of existing chemical antibiotics and in which the development of new antibiotics is significantly rarer, Western medicine must seek additional therapeutic options that can be employed to treat these infections. Among the potential antibacterial solutions are bacteriophage therapeutics, which possess very different properties from broad spectrum antibiotics that are currently the standard of care, and which can be used in combination with them and often provide synergies. In this review we summarize the state of the development of bacteriophage therapeutics and discuss potential paths to the implementation of phage therapies in contemporary medicine, focused on fixed phage cocktail therapeutics since these are likely to be the first bacteriophage products licensed for broad use in Western countries. Full article

Delafloxacin (DLX) is a recently-approved fluoroquinolone antibiotic, which is recommended for the treatment of “acute bacterial skin and skin structure infections”. A thorough literature survey revealed only a single published method for the estimation of DLX using UPLC-MS/MS technique in biological samples. There is no high-performance thin-layer chromatography (HPTLC) method has been reported for the estimation of DLX in dosage forms and/or biological samples. Therefore, a selective, sensitive, rapid and validated HPTLC-densitometry technique has been used for the estimation of DLX in human plasma for the first time. HPTLC quantification of DLX and internal standard (IS; gatifloxacin) was carried out on glass coated silica gel 60 F₂₅₄ HPTLC plates using the ternary mixture of ethyl acetate:methanol:ammonia solution 5:4:2 (%, v/v/v) as the mobile phase. Densitometric detection was done at 344 nm. The R_f values were recorded as 0.43 and 0.27 for the DLX and the IS, respectively. The linearity range of DLX was obtained as 16–400 ng/band. A simple protein precipitation method was used for the extraction of analyte from plasma using methanol. The proposed HPTLC technique was validated for “linearity, accuracy, precision, and robustness”. The proposed HPTLC technique was successfully utilized for the assessment of pharmacokinetic profile of DLX in rats after oral administration. After oral administration, the peak plasma concentration of DLX was obtained as 194.19 ng/ml in 1 h. The proposed HPTLC method could be applied in study of pharmacokinetic profile and therapeutic drug monitoring of DLX in clinical practice. Full article

Tuberculosis (TB) remains the deadliest Infectious disease worldwide, partially due to the increasing dissemination of multidrug and extensively drug-resistant (MDR/XDR) strains. Drug regimens containing the new anti-TB drugs bedaquiline (BDQ) and delamanid (DLM) appear as a last resort for the treatment of MDR or XDR-TB. Unfortunately, resistant cases to these drugs emerged just one year after their introduction in clinical practice. Early detection of resistant strains to BDQ and DLM is crucial to preserving the effectiveness of these drugs. Here, we present a systematic review aiming to define all available genotypic variants linked to different levels of resistance to BDQ and DLM that have been described through whole genomic sequencing (WGS) and the available drug susceptibility testing methods. During the review, we performed a thorough analysis of 18 articles. BDQ resistance was associated with genetic variants in Rv0678 and atpE, while mutations in pepQ were linked to a low-level of resistance for BDQ. For DLM, mutations in the genes ddn, fgd1, fbiA, and fbiC were found in phenotypically resistant cases, while all the mutations in fbiB were reported only in DLM-susceptible strains. Additionally, WGS analysis allowed the detection of heteroresistance to both drugs. In conclusion, we present a comprehensive panel of gene mutations linked to different levels of drug resistance to BDQ and DLM. Full article

Fungal associations with nematodes have attracted scientific attention because of the need to develop new biocontrol agents. In this context, Ijuhya vitellina, an antagonistic fungus previously isolated from the plant parasitic cyst nematode Heterodera filipjevi, was selected to carry out an in-depth metabolomic study for its active metabolites. Herein, three new nonapeptide peptaibols with leucinostatin based sequences were isolated and identified by 1, 2D NMR, and HR-ESI-MS-MS. The absolute configuration was assigned based on Marfay’s analysis and Mosher ester formation. The new leucinostatins manifested moderate nematicidal effect against the plant pathogenic nematode Pratylenchus penetrans with LD₉₀ values ranging from 5 to 7 µg/mL. Furthermore, a cyclodepsipeptide, named arthrichitin D, with five amino acid residues attached to a 3-hydroxy-2,4-dimethylhexadeca-4,6-dienoic fatty acid chain was discovered and showed weak nematicidal effect against Caenorhabditis elegans. Chaetoglobosin B and its 19-O-acetyl derivative were also obtained as minor metabolites, and the activity of chaetoglobosin B on the actin cytoskeleton of mammalian cells was assessed. Full article

Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The extent to which therapeutic drug monitoring (TDM) in clinical practice can reduce insufficient antibiotic concentrations is an ongoing matter of investigation. We retrospectively evaluated routine meropenem and piperacillin measurements in critically ill patients who received antibiotics as short infusions in the first year after initiating a beta-lactam TDM program. Total trough concentrations above 8.0 mg/L for meropenem and above 22.5 mg/L for piperacillin were defined as the breakpoints for target attainment. We included 1832 meropenem samples and 636 piperacillin samples. We found that 39.3% of meropenem and 33.6% of piperacillin samples did not reach the target concentrations. We observed a clear correlation between renal function and antibiotic concentration (meropenem, r = 0.53; piperacillin, r = 0.63). Patients with renal replacement therapy or creatinine clearance (CrCl) of <70 mL/min had high rates of target attainment with the standard dosing regimens. There was a low number of patients with a CrCl >100 mL/min that achieved the target concentrations with the maximum recommended dosage. Patients with impaired renal function only required TDM if toxic side effects were noted. In contrast, patients with normal renal function required different dosage regimens and TDM-guided therapy to reach the breakpoints of target attainment. Full article

Group living at high densities may result in the enhanced transmission of pathogens. Social insects are obligate group-living species, which often also exhibit high relatedness and frequent social interactions amongst individuals, resulting in a high risk of disease spread. Social species seem to exhibit immune systems that provide colonies of social insects with a certain level of flexibility for adjustment of immune activity according to the risk of disease spread. In bumblebees, Bombus terrestris, it was demonstrated that in group-kept individuals, immune component activity and immune gene expression is increased, potentially as a prophylactic adaptation. Here, I tested whether social environment influences the gene expression pattern of two lysozyme genes, which are components of the antimicrobial response of the bumblebee. In addition, I tested gene expression activation in different tissues (gut, fat body). The analysis revealed that the gene, the density of individuals, the tissue, and the interaction of the latter are the main factors that influence the expression of lysozyme genes. This is the first report of a tissue-specific response towards the social environment. This has implications for gene regulation, which must be responsive to social context-dependent information. Full article

Biofilms located within the root canals of teeth are a unique and pressing concern in dentistry and in medical microbiology. These multispecies biofilms, which include fungi as well as bacteria, form in a protected site with low shear stress and low oxygen tension. Systemic antibiotics are of limited value because of the lack of blood flow of the site, and issues with innate and acquired resistance. Physical disruption using hand or rotary powered instruments does not reach all locations in the root canal system where biofilms are present. Alternative strategies including agitated irrigation fluids, continuous chelation, materials with highly alkaline pH, and antimicrobial nanoparticles are being explored to meet the challenge. Detection and quantification of biofilms using fluorescence-based optical methods could provide an indication of successful biofilm removal and an endpoint for physical and chemical treatments. Full article

Diabetic foot ulcers (DFUs) are major complications of Diabetes mellitus being responsible for significant morbidity and mortality. DFUs frequently become chronically infected by a complex community of bacteria, including multidrug-resistant and biofilm-producing strains of Staphylococcus aureus and Pseudomonas aeruginosa. Diabetic foot infections (DFI) are often recalcitrant to conventional antibiotics and alternative treatment strategies are urgently needed. Antimicrobial Peptides (AMPs), such as pexiganan and nisin, have been increasingly investigated and reported as effective antimicrobial agents. Here, we evaluated the antibacterial potential of pexiganan and nisin used in combination (dual-AMP) to control the growth of planktonic and biofilm co-cultures of S. aureus and P. aeruginosa clinical strains, co-isolated from a DFU. A DFU collagen three-dimensional (3D) model was used to evaluate the distribution and efficacy of AMPs locally delivered into the model. The concentration of pexiganan required to inhibit and eradicate both planktonic and biofilm-based bacterial cells was substantially reduced when used in combination with nisin. Moreover, incorporation of both AMPs in a guar gum delivery system (dual-AMP biogel) did not affect the dual-AMP antimicrobial activity. Importantly, the application of the dual-AMP biogel resulted in the eradication of the S. aureus strain from the model. In conclusion, data suggest that the local application of the dual-AMPs biogel constitutes a potential complementary therapy for the treatment of infected DFU. Full article

Background: The most important pathomechanism of Clostridioides difficile infections (CDI) is post-antibiotic intestinal dysbiosis. CDI affects both ambulatory and hospital patients. Aim: The objective of the study was to analyze the possibility of utilizing databases from the European Centre for Disease Prevention and Control subject to surveillance for the purpose of identifying areas that require intervention with respect to public health. Methods: The analysis encompassed data concerning CDI incidence and antibiotic consumption expressed as defined daily doses (DDD) and quality indicators for antimicrobial-consumption involving both ambulatory and hospital patients in 2016. Results: In 2016, in the European Union countries, total antibiotic consumption in hospital and outpatient treatment amounted to 20.4 DDD (SD 7.89, range 11.04–39.69); in ambulatory treatment using average of ten times more antibiotics than hospitals. In total, 44.9% of antibiotics used in outpatient procedures were broad-spectrum antibiotics. We have found a significant relationship between the quality of antibiotics and their consumption: The more broad-spectrum antibiotics prescribed, the higher the sales of antibiotics both in the community sector and in total. CDI incidence did not statistically significantly correlate with the remaining factors analyzed on a country-wide level. Conclusion: Antibiotic consumption and the CDI incidence may depend on many national variables associated with local systems of healthcare organization and financing. Their interpretation in international comparisons does not give clear-cut answers and requires caution. Full article

During the course of our ongoing screening for novel biologically active secondary metabolites, the rare Actinobacterium, Nonomuraea sp. 1808210CR was found to produce five unprecedented β-carboline derivatives, nonocarbolines A–E (1–5). Their structures were elucidated from high-resolution mass spectrometry, 1D and 2D nuclear magnetic resonance spectroscopy, and the absolute configuration of 4 was determined by using the modified Mosher method. Nonocarboline B (2) displayed moderate antifungal activity against Mucor hiemalis, while nonocarboline D (4) exhibited significant cytotoxic activity against the human lung carcinoma cell line A-549 with the IC₅₀ value of 1.7 µM. Full article

Photodynamic antimicrobial chemotherapy (PAC) is an efficient tool for inactivating microorganisms. This technique is a good approach to inactivate the foodborne microorganisms, which are responsible for one of the major public health concerns worldwide—the foodborne diseases. In this work, response surface methodology (RSM) was used to evaluate the interaction of Eosin Y (EOS) concentration and irradiation time on Staphylococcus aureus counts and a sequence of designed experiments to model the combined effect of each factor on the response. A second-order polynomial empirical model was developed to describe the relationship between EOS concentration and irradiation time. The results showed that the derived model could predict the combined influences of these factors on S. aureus counts. The agreement between predictions and experimental observations (R²_adj = 0.9159, p = 0.000034) was also observed. The significant terms in the model were the linear negative effect of photosensitizer (PS) concentration, followed by the linear negative effect of irradiation time, and the quadratic negative effect of PS concentration. The highest reductions in S. aureus counts were observed when applying a light dose of 9.98 J/cm² (498 nM of EOS and 10 min. irradiation). The ability of the evaluated model to predict the photoinactivation of S. aureus was successfully validated. Therefore, the use of RSM combined with PAC is a promising approach to inactivate foodborne pathogens. Full article

Background: Actinomycosis of the tongue is an uncommon, suppurative infection of lingual mucosa, caused by actinomyces. The clinical diagnosis may present serious difficulties because of its ability to mimic other lesions, including both benign and malignant neoplasms. Methods: Here, we describe the case of a 52-years-old patient affected by an asymptomatic, tumor-like tongue swelling, then diagnosed as actinomycosis. A review of tongue localization of actinomycosis is also reported, with emphasis on clinical findings and therapy. Results and Conclusion: Early diagnosis and treatment, with pus drainage and systemic antibiotic therapy, are pivotal to avoid severe and life-threatening complications. Full article

AmpC-type β-lactamases severely impair treatment of many bacterial infections, due to their broad spectrum (they hydrolyze virtually all β-lactams, except fourth-generation cephalosporins and carbapenems) and the increasing incidence of plasmid-mediated versions. The original chromosomal AmpCs are often tightly regulated, and their expression is induced in response to exposure to β-lactams. Regulation of mobile ampC expression is in many cases less controlled, giving rise to constitutively resistant strains with increased potential for development or acquisition of additional resistances. We present here the identification of two integron-encoded ampC genes, bla_IDC-1 and bla_IDC-2 (integron-derived cephalosporinase), with less than 85% amino acid sequence identity to any previously annotated AmpC. While their resistance pattern identifies them as class C β-lactamases, their low isoelectric point (pI) values make differentiation from other β-lactamases by isoelectric focusing impossible. To the best of our knowledge, this is the first evidence of an ampC gene cassette within a class 1 integron, providing a mobile context with profound potential for transfer and spread into clinics. It also allows bacteria to adapt expression levels, and thus reduce fitness costs, e.g., by cassette-reshuffling. Analyses of public metagenomes, including sewage metagenomes, show that the discovered ampCs are primarily found in Asian countries. Full article

Staphylococcus aureus is an opportunist pathogen that is responsible for numerous types of infections. S. aureus is known for its ability to easily acquire antibiotic resistance determinants. Methicillin-resistant S. aureus (MRSA) is a leading cause of infections both in humans and animals and is usually associated with a multidrug-resistant profile. MRSA dissemination is increasing due to its capability of establishing new reservoirs and has been found in humans, animals and the environment. Despite the fact that the information on the incidence of MRSA in the environment and, in particular, in wild animals, is scarce, some studies have reported the presence of these strains among wildlife with no direct contact with antibiotics. This shows a possible transmission between species and, consequently, a public health concern. The aim of this review is to better understand the distribution, prevalence and molecular lineages of MRSA in European free-living animals. Full article

Helicobacter pylori (H. pylori) eradication fails in a definite amount of patients despite one or more therapeutic attempts. Curing these patients is progressively more difficult, due to development of antibiotic resistance. Current guidelines suggest testing antibiotic susceptibility in H. pylori isolates following two therapeutic attempts. Aim: to evaluate the development of antibiotic resistance, MIC values trends and therapeutic outcomes in patients who failed at least one H. pylori eradication therapy. Methods: consecutive patients, referred to perform upper gastrointestinal endoscopy (UGIE) to our Unit from January 2009 to January 2019 following at least one therapeutic attempt were considered. Bacterial resistance towards clarithromycin, metronidazole and levofloxacin was tested. Patients received either a susceptibility-guided therapy or Pylera^®. Results: a total of 1223 patients were H. pylori positive, and antibiotic susceptibility was available for 1037. The rate of antibiotic resistance and MIC values significantly increased paralleling the number of previous therapeutic attempts. Eradication rates of antibiogram-tailored therapies remained stable, except for the sequential therapy if used as a third line. As a rescue treatment, the Pylera^® therapy achieved cure rates comparable to those of the other culture-guided therapies. Conclusions: A significant increase in the secondary resistance towards the three tested antibiotics was observed, both as rate and MIC values, in correlation with the number of therapy failures. These findings should be considered when administering an empirical second-line therapy. Pylera^® therapy eradication rates are comparable to culture-tailored therapies. Full article

Rising concern about the use of antibiotics in food production has resulted in many studies on the occurrence of antibiotic resistance genes (ARGs) in animal-associated bacterial communities. There are few baseline data on the abundance of ARGs on farms where chickens are intensively raised with little or no use of antibiotics. This study used a high-throughput quantitative PCR array to survey two antibiotic-free chicken farms for the occurrence of ARGs and mobile genetic elements known to enhance the spread of ARGs. No antibiotics had been used on the study farms for five years prior to this study. The results provide a baseline for the occurrence of resistance genes in the chicken production system without direct selective pressure. Full article

Being a multidrug-resistant and an invasive pathogen, Acinetobacter baumannii is one of the major causes of nosocomial infections in the current healthcare system. It has been recognized as an agent of pneumonia, septicemia, meningitis, urinary tract and wound infections, and is associated with high mortality. Pathogenesis in A. baumannii infections is an outcome of multiple virulence factors, including porins, capsules, and cell wall lipopolysaccharide, enzymes, biofilm production, motility, and iron-acquisition systems, among others. Such virulence factors help the organism to resist stressful environmental conditions and enable development of severe infections. Parallel to increased prevalence of infections caused by A. baumannii, challenging and diverse resistance mechanisms in this pathogen are well recognized, with major classes of antibiotics becoming minimally effective. Through a wide array of antibiotic-hydrolyzing enzymes, efflux pump changes, impermeability, and antibiotic target mutations, A. baumannii models a unique ability to maintain a multidrug-resistant phenotype, further complicating treatment. Understanding mechanisms behind diseases, virulence, and resistance acquisition are central to infectious disease knowledge about A. baumannii. The aims of this review are to highlight infections and disease-producing factors in A. baumannii and to touch base on mechanisms of resistance to various antibiotic classes. Full article

Water samples were collected at several wastewater treatment plants in southeast Florida, and water and sediment samples were collected along and around one outfall pipe, as well as along several transects extending both north and south of the respective outfall outlet. Two sets of samples were collected to address potential seasonal differences, including 38 in the wet season (June 2018) and 42 in the dry season (March 2019). Samples were screened for the presence/absence of 15 select antibiotic resistance gene targets using the polymerase chain reaction. A contrast between seasons was found, with a higher frequency of detections occurring in the wet season and fewer during the dry season. These data illustrate an anthropogenic influence on offshore microbial genetics and seasonal flux regarding associated health risks to recreational users and the regional ecosystem. Full article

The spectre of antimicrobial resistance looms very large indeed in the 21st century; the supply of efficacious conventional drugs is short and not guaranteed, for various reasons. It is time to look elsewhere for answers and for protocols which might be used in tandem with our diminishing arsenal in order to protect vital drugs. This could bridge the gap before new development in conventional antimicrobial therapy occurs, or might be a longer-term solution, particularly in the area of infectious disease prophylaxis (conventional-sensitive or -resistant). Reliable and safe protocols have been developed for the use of photoantimicrobials in this respect, offering much greater coverage, in terms of the microbial target, than Fleming ever imagined. Full article

Sea turtles can be considered a sentinel species for monitoring the health of marine ecosystems, acting, at the same time, as a carrier of microorganisms. Indeed, sea turtles can acquire the microbiota from their reproductive sites and feeding, contributing to the diffusion of antibiotic-resistant strains to uncontaminated environments. This study aims to unveil the presence of antibiotic-resistant bacteria in (i) loggerhead sea turtles stranded along the coast of Sicily (Mediterranean Sea), (ii) unhatched and/or hatched eggs, (iii) sand from the turtles’ nest and (iv) seawater. Forty-four bacterial strains were isolated and identified by conventional biochemical tests and 16S rDNA sequencing. The Gram-negative Aeromonas and Vibrio species were mainly found in sea turtles and seawater samples, respectively. Conversely, the Gram-positive Bacillus, Streptococcus, and Staphylococcus strains were mostly isolated from eggs and sand. The antimicrobial resistance profile of the isolates revealed that these strains were resistant to cefazolin (95.5%), streptomycin (43.2%), colistin and amoxicillin/clavulanic acid (34.1%). Moreover, metagenome analysis unveiled the presence of both antibiotic and heavy metal resistance genes, as well as the mobile element class 1 integron at an alarming percentage rate. Our results suggest that Caretta caretta could be considered a carrier of antibiotic-resistant genes. Full article

Infections are the most common reason why patients consult out-of-hours (OOH) primary care. Too often there is an overprescribing of antibiotics for self-limiting infections and general practitioners (GPs) do not always choose the guideline recommended antibiotics. To improve antibiotic prescribing quality, a better understanding is needed of the (non) antibiotic prescribing decisions of GPs. This study sets out to unravel GPs’ (non) antibiotic prescribing decisions in OOH primary care. We video-recorded 160 consultations on infections during OOH primary care by 21 GPs and performed video-elicitation interviews with each GP. GPs reflected on their decision-making process and communication while watching their consultation. A qualitative thematic analysis was used. GPs found that their (non) antibiotic prescribing decision-making was not only based on objective arguments, but also subconsciously influenced by their own interpretation of information. Often GPs made assumptions (about for example the patients’ reason for encounter or expectations for antibiotics) without objectifying or verifying this with the patient. From the beginning of the consultation GPs follow a dichotomous thinking process: urgent versus not urgent, viral versus bacterial, antibiotics versus no antibiotics. Safety-netting is an important but difficult tool in the OOH care context, with no long-term follow-up or relationship with the patient. GPs talk about strategies they use to talk about diagnostic uncertainty, what patients can expect or should do when things do not improve and the difficulties they encounter while doing this. This video- elicitation interview study provides actionable insights in GPs’ (non) antibiotic prescribing decisions during OOH consultations on infections. Full article

Despite the risk of emerging drug resistance that occurs with the frequent use of antimicrobial agents, targeted and prophylactic antibiotics have been considered crucial to opportunistic infection management among the HIV/AIDS-immunocompromised. As we recently demonstrated, the disrupted selective pressures that occur in AIDS-prevalent host populations increase the probability of novel emergence. This effect is concerning, given that bacterial strains unresponsive to first-line antibiotics can be particularly dangerous to hosts whose immune response is insufficient to fight infection in the absence of antibiotic support. While greater host susceptibility within a highly immunocompromised population may offer a fitness advantage to drug-resistant bacterial strains, this advantage could be mitigated by increased morbidity and mortality among the AIDS-immunocompromised. Using a Susceptible-Exposed-Infectious-Recovered (SEIR) epidemiological model parameterized to reflect conditions in an AIDS-prevalent host population, we examine the evolutionary relationship between drug-sensitive and -resistant strains of Mycobacterium tuberculosis. We explore this relationship when the fitness of the resistant strain is varied relative to that of the sensitive strain to investigate the likely long-term multi-strain dynamics of the AIDS-mediated increased emergence of drug resistance. Full article

The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen–minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration–time curve over 24 h ≥ 96 μg h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75–101) years, were investigated. The plasma-concentration–time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CL_cr − 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CL_cr − 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CL_cr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 μg/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CL_cr of 50–60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia. Full article

We investigated fosfomycin susceptibility in Escherichia coli clinical isolates from South Korea, including community-onset, hospital-onset, and long-term care facility (LTCF)-onset isolates. The resistance mechanisms and genotypes of fosfomycin-resistant isolates were also identified. Finally, the in vitro efficacy of combinations of fosfomycin with other antibiotics were examined in susceptible or extended spectrum β-lactamase (ESBL)-producing E. coli isolates. The fosfomycin resistance rate was 6.7% and was significantly higher in LTCF-onset isolates than community-onset and hospital-onset isolates. Twenty-one sequence types (STs) were identified among 19 fosfomycin-resistant E. coli isolates, showing diverse genotypes. fosA3 was found in only two isolates, and diverse genetic variations were identified in three genes associated with fosfomycin resistance, namely, GlpT, UhpT, and MurA. Some fosfomycin-resistant E. coli isolates carried no mutations. In vitro time-kill assays showed that fosfomycin alone did not exhibit an excellent killing activity, compared with ciprofloxacin in susceptible isolates and with ertapenem in ESBL producers. However, combining fosfomycin with cefixime or piperacillin-tazobactam eradicated susceptible or ESBL-producing isolates, respectively, even with 0.5× minimum inhibitory concentrations. Overall, we found a relatively high fosfomycin resistance rate in E. coli isolates from South Korea. Based on their genotypes and resistance mechanisms, most of the fosfomycin-resistant E. coli isolates might occur independently. Antibiotic combinations with fosfomycin could be a suitable therapeutic option for infections caused by E. coli isolates. Full article

Tree barks are mainly considered as wood wastes from forestry activities, but represent valuable resources as they may contain antimicrobial compounds. Here, we aimed to evaluate the possible antimicrobial activities of bark extracts and to characterize the chemical composition of the most active extract. Ten methanol bark extracts were tested in vitro against 17 bacterial strains and 5 yeast strains, through minimum inhibitory concentration (MIC) and minimum bactericidal (or fungicidal) concentration (MBC/MFC) assays. The extract from Prunus avium (E2-4) displayed the largest bactericidal activity against Gram-positive bacteria, with a lethal effect on 6 out of 8 strains. Antibiofilm assays of E2-4 were performed by crystal violet staining and enumeration of adhered bacteria. Assays demonstrated a biofilm inhibitory effect of E2-4 against Staphylococcus aureus CIP 53.154 at concentrations equal to or higher than 250 µg/mL. Chemical profiling of E2-4 by ¹³C nuclear magnetic resonance (NMR) revealed the presence of dihydrowogonin as a major constituent of the extract. E2-4 was fractionated by centrifugal partition chromatography and the three fractions containing dihydrowogonin were tested for their antibacterial and antibiofilm activities, revealing similar activities to those of E2-4. Dihydrowogonin was positively assessed as an interesting antimicrobial compound, which could be valued from wastes of Prunus avium barks. Full article

The aims of this study were to obtain preliminary data and test the clinical efficacy of a novel nonporous dense-polytetrafluoroethylene (d-PTFE) membrane (permamem^®, botiss) in alveolar ridge preservation (ARP) procedures with a flapless approach. A traumatic extraction was performed in the premolar maxillary area, and a d-PTFE membrane was used to seal the alveolar cavity: no biomaterial was used to graft the socket and the membrane was left intentionally exposed and stabilized with sutures. The membrane was removed after four weeks and dental implants were placed four months after the procedure. The primary outcome variables were defined as the dimensional changes in the ridge width and height after four months. A total of 15 patients were enrolled in this study. The mean width of the alveolar cavity was 8.9 ± 1.1 mm immediately after tooth extraction, while four months later a mean reduction of 1.75 mm was experienced. A mean vertical reduction of 0.9 ± 0.42 mm on the buccal aspect and 0.6 ± 0.23 mm on the palatal aspect were recorded at implant placement. Within the limitations of this study, the d-PTFE membrane proved to be effective in alveolar ridge preservation, with the outcomes of the regeneration not affected by the complete exposure of this biomaterial. Full article

Background: Recent scientific reports on the use of high dose tigecycline monotherapy as a “drug of last resort” warrant further research into the use of this regimen for the treatment of severe multidrug-resistant, Gram-negative bacterial infections. In the current study, the therapeutic efficacy of tigecycline monotherapy was investigated and compared to meropenem monotherapy in a newly developed rat model of fatal lobar pneumonia–septicemia. Methods: A Klebsiella pneumoniae producing extended-spectrum β-lactamase (ESBL) and an isogenic variant producing K. pneumoniae carbapenemase (KPC) were used in the study. Both strains were tested for their in vitro antibiotic susceptibility and used to induce pneumonia–septicemia in rats, which was characterized using disease progression parameters. Therapy with tigecycline or meropenem was initiated at the moment that rats suffered from progressive infection and was administered 12-hourly over 10 days. The pharmacokinetics of meropenem were determined in infected rats. Results: In rats with ESBL pneumonia–septicemia, the minimum dosage of meropenem achieving survival of all rats was 25 mg/kg/day. However, in rats with KPC pneumonia–septicemia, this meropenem dosage was unsuccessful. In contrast, all rats with KPC pneumonia–septicemia were successfully cured by administration of high-dose tigecycline monotherapy of 25 mg/kg/day (i.e., the minimum tigecycline dosage achieving 100% survival of rats with ESBL pneumonia–septicemia in a previous study). Conclusions: The current study supports recent literature recommending high-dose tigecycline as a last resort regimen for the treatment of severe multidrug-resistant bacterial infections. The use of ESBL- and KPC-producing K. pneumoniae strains in the current rat model of pneumonia–septicemia enables further investigation, helping provide supporting data for follow-up clinical trials in patients suffering from severe multidrug-resistant bacterial respiratory infections. Full article

Cancer patients are more susceptible to several bacterial infections, particularly urinary tract infections caused by uropathogenic E. coli (UPEC). The objective of this work was detection and the phylogenetic characterization of hospital-acquired isolates of uropathogenic E. coli in cancer patients and the determination of its relation with antibiotic resistance. A total of 110 uropathogenic E. coli responsible for hospital-acquired urinary tract infections in cancer patients were included in this study. A triplex PCR was employed to segregate different isolates into four different phylogenetic groups (A, B1, B2 and D). Drug resistance was evaluated by the disc diffusion method. All of the isolates were multiple drug-resistant (MDR) and 38.18% of all UPEC isolates were extended-spectrum beta-lactamase (ESBL) producers from which 52% were positive for the blaCTX-M gene, 40% for the blaTEM gene, and 17% for the blaSHVgene. Among 42 ESBL-producing uropathogenic E. coli isolates, the majority belonged to phylogenetic group B2 (43%), followed by group D (36%), group A (19%) and group B1 (2%). Our results have shown the emergence of MDR isolates among uropathogenic E. coli with the dominance of phylogenetic group B2. Groups A and B1 were relatively less common. The most effective drug in all phylogenetic groups was imipenem. Full article

In recent years, due to the dramatic increase in and global spread of bacterial resistance to a number of commonly used antibacterial agents, many studies have been directed at investigating drugs whose primary therapeutic purpose is not antimicrobial action. In an era where it is becoming increasingly difficult to find new antimicrobial drugs, it is important to understand these antimicrobial effects and their potential clinical implications. Numerous studies report the antibacterial activity of non-steroidal anti-inflammatory drugs, local anaesthetics, phenothiazines such as chlorpromazine, levomepromazine, promethazine, trifluoperazine, methdilazine and thioridazine, antidepressants, antiplatelets and statins. Several studies have explored a possible protective effect of statins inreducing the morbidity and mortality of many infectious diseases. Various non-antibiotic agents exhibit antimicrobial activity via multiple and different mechanisms of action. Further studies are required in the field to further investigate these antimicrobial properties in different populations. This is of paramount importance in the antimicrobial resistance era, where clinicians have limited therapeutic options to combat problematic infections. Full article