Antibiotic resistance of Gram-positive and Gramnegative bacteria is becoming increasingly prevalent. For this reason, the search for new molecules that can overcome current resistance and also recover antibiotics that are no longer effective is becoming increasingly urgent. Our research group at the 'Polytechnic University of Marche' managed to study the effectiveness of certain antimicrobial peptides (AMPs). We decided to review our experience with AMPs by classifying them according to their origin and evaluating their effect on Gram-negative and Gram-positive bacteria. AMPs can derive from mammals, amphibians, microorganisms, and insects. In conclusion, our research experience shows that the richest source of AMPs are amphibians. However, the studies done are mainly in vitro or in animal models, requiring further human studies to assess the efficacy and safety of these molecules. AMPs may be a new therapeutic option for infections sustained by multi-resistant micro-organisms and for overcoming the mechanisms of resistance to antibiotics currently used. In particular, combining AMPs with antibiotics, including those with limited antimicrobial activity due to antimicrobial resistance, has often shown a synergistic effect, increasing or restoring their efficacy. The possibility of using manageable and relatively safe antibiotics again is crucial, considering the widespread increase in bacterial resistance in hospitals and the community. Despite a plethora of research on AMPs and their application as potential treatment on infectious diseases, this area needs further exploration. There is evidence that the characteristics of AMPs can seriously improve through structural chemical modifications and different delivery systems to become alternatives drugs to conventional antibiotics. The aim is to provide an overview of the possible sources from which AMPs are extracted, evaluating their action exclusively on Gram-positive and negative bacteria. This is to determine, based on our experience, which might be the most promising sources of AMPs for future research as well.
Although coagulase negative staphylococci are rarely associated with complicated diseases, in some cases they cause life-threatening infections. Here we described a clinical case of a bacteremia due to a methicillin- and linezolid-resistant Staphylococcus capitis in a patient previously treated with linezolid. Whole genome sequencing revealed the common mutation G2576T in all rDNA 23S alleles and several acquired resistance genes. Moreover, the isolate was epidemiologically distant from the NRCS-A clade, usually responsible for nosocomial infections in neonatal intensive care units. Our findings further confirm the ability of minor staphylococci to acquire antibiotic resistances and challenge the treatment of these infections.
Bacteremia , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Staphylococcus capitis , Infant, Newborn , Humans , Linezolid/pharmacology , Linezolid/therapeutic use , Anti-Bacterial Agents/pharmacology , Staphylococcal Infections/drug therapy , Coagulase/genetics , Microbial Sensitivity Tests , Staphylococcus/genetics , Bacteremia/drug therapy , Genomics , Hospitals
Psoriatic patients present various infectious risk factors, but there are few studies in the literature evaluating the actual impact of psoriasis in severe staphylococcal skin infections. Our narrative review of the literature suggests that psoriatic patients are at increased risk of both colonization and severe infection, during hospitalization, by S. aureus. The latter also appears to play a role in the pathogenesis of psoriasis through the production of exotoxins. Hospitalized psoriatic patients are also at increased risk of MRSA skin infections. For this reason, new molecules are needed that could both overcome bacterial resistance and inhibit exotoxin production. In our opinion, in the near future, topical quorum sensing inhibitors in combination with current anti-MRSA therapies will be able to overcome the increasing resistance and block exotoxin production. Supplementation with Vitamin E (VE) or derivatives could also enhance the effect of anti-MRSA antibiotics, considering that psoriatic patients with metabolic comorbidities show a low intake of VE and low serum levels, making VE supplementation an interesting new perspective.
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by painful nodules, abscesses, and fistulas, localized to the areas of the folds where apocrine glands are present: the armpits, groin, inframammary region, and genital or perineal region. The management is still challenging, and it includes mainly systemic antibiotics, immunosuppressors, and biologic agents. Antibiotics are frequently used in the management of HS for their anti-inflammatory, immunomodulatory, and antimicrobial properties, but no data have been reported regarding the use of dalbavancin in HS. The aim of our practice was to evaluate efficacy, flare, and disease-free survival after dalbavancin therapy in a selected population with HS. We report the experience of the Ancona Dermatology Clinic in treating HS flare-ups with dalbavancin and its rationale for use. Our observation shows that the use of dalbavancin is an effective and well-tolerated treatment for the management of Hurley stage II-III HS; currently, dalbavancin should be considered as a supportive therapy for selected patients.
Biofilm formation at the level of a wound plays an important role in its chronicization. The difficulty of its eradication has driven research toward the discovery and synthesis of new molecules that can act on biofilm to promote wound healing. This narrative review focuses on alternative molecules that can act and promote the eradication of methicillin-resistant Staphylococcus aureus, taking into consideration its antibiotic resistance, virulence, tendency toward the tenacious colonization of wounds by biofilms, and its increased prevalence in both community and hospital settings. A selection of promising studies were reported, analyzing the in vitro and/or in vivo efficacy of bacteriophages, metal nanoparticles, RNAIII inhibiting peptide (RIP), synthetized RIP derivatives, proteinase K and hamamelitannin.
Aspergillosis, which is mainly sustained by Aspergillus fumigatus, includes a broad spectrum of diseases. They are usually severe in patients with co-morbidities. The first-line therapy includes triazoles, for which an increasing incidence of drug resistance has been lately described. As a consequence of this, the need for new and alternative antifungal molecules is absolutely necessary. As peptides represent promising antimicrobial molecules, two lipopeptides (C14-NleRR-NH2, C14-WRR-NH2) were tested to assess the antifungal activity against azole-resistant A. fumigatus. Antifungal activity was evaluated by determination of minimum inhibitory concentrations (MICs), time-kill curves, XTT assay, optical microscopy, and checkerboard combination with isavuconazole. Both lipopeptides showed antifungal activity, with MICs ranging from 8 mg/L to 16 mg/L, and a dose-dependent effect was confirmed by both time-kill curves and XTT assays. Microscopy showed that hyphae growth was hampered at concentrations equal to or higher than MICs. The rising antifungal resistance highlights the usefulness of novel compounds to treat severe fungal infections. Although further studies assessing the activity of lipopeptides are necessary, these molecules could be effective antifungal alternatives that overcome the current resistances.
Daptomycin is active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and the on-label indications for its use include complicated skin and skin structure infections (cSSSI). We performed a narrative review of the literature with the aim to evaluate the role of daptomycin in the skin wound healing process, proposing our point of view on the possible association with other molecules that could improve the skin healing process. Daptomycin may improve wound healing in MRSA-infected burns, surgical wounds, and diabetic feet, but further studies in humans with histological examination are needed. In the future, the combination of daptomycin with other molecules with synergistic action, such as vitamin E and derivates, IB-367, RNA III-inhibiting peptide (RIP), and palladium nanoflowers, may help to improve wound healing and overcome forms of antibiotic resistance.
OBJECTIVES: Ceftolozane/tazobactam (C/T) is a novel cephalosporin and ß-lactamase inhibitor combination with great activity against Pseudomonas aeruginosa. To assess P. aeruginosa susceptibility to C/T, a surveillance study was conducted from October 2018 to March 2019 at the University Hospital 'Ospedali Riuniti' in Ancona, Italy. METHODS: Minimum inhibitory concentrations (MICs) to C/T were determined by Etest strip. Resistant isolates were characterized by phenotypic (broth microdilution antimicrobial susceptibility testing and modified Carbapenem Inactivation Method [mCIM]) and genotypic (Polymerase Chain Reaction [PCR], Pulsed Field Gel Electrophoresis [PFGE], and whole-genome sequencing [WGS]) methods. Clinical variables of patients infected by C/T-resistant P. aeruginosa were collected from medical records. RESULTS: Fifteen of 317 P. aeruginosa collected showed resistance to C/T (4.7%). Ten strains demonstrated carbapenemase activity by mCIM method, and PCR confirmed that eight strains harbored a blaVIM gene while the other two were positive for blaIMP. Additionally, three isolates carried acquired extended spectrum ß-lactamase genes (two isolates carried blaPER and one carried blaGES). Eight strains were strictly related by PFGE and WGS analysis confirmed that they belonged to sequence type (ST)111. The other STs found were ST175 (two isolates), ST235 (two isolates), ST70 (one isolate), ST621 (one isolate), and the new ST3354 (one isolate). Most patients had received previous antibiotic therapies, carried invasive devices, and experienced prolonged hospitalization. CONCLUSION: This study demonstrated the presence of C/T-resistant P. aeruginosa isolates in a regional hospital carrying a number of resistance mechanisms acquired by different high-risk clones.
Pseudomonas Infections , Pseudomonas aeruginosa , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cephalosporins/pharmacology , Cephalosporins/therapeutic use , Drug Resistance, Multiple, Bacterial/genetics , Hospitals , Humans , Pseudomonas Infections/microbiology , Tazobactam/pharmacology , Tazobactam/therapeutic use
Results have been implemented with additional data, which have been commented in the following paragraphs [...].
Background: Ceftazidime/avibactam is a new cephalosporin/beta-lactamase inhibitor combination approved in 2015 by the FDA for the treatment of complicated intra-abdominal and urinary tract infection, hospital-acquired pneumoniae and Gram-negative infections with limited treatment options. Methods: In this retrospective study, we evaluate the efficacy of ceftazidime/avibactam treatment in 81 patients with Gram-negative infection treated in our center from January 2018 to December 2019. The outcome evaluated was 30-days survival or relapse of infection after the first positive blood culture. Results: the majority of patients were 56 male (69%), with median age of 67. Charlson's Comorbidity Index was >3 in 58 patients. In total, 46% of the patients were admitted into the medical unit, 41% in the ICU, and 14% in the surgical ward. Of the patients, 78% had nosocomial infections, and 22% had healthcare-related infections. The clinical failure rate was 35%: 13 patients died within 30 days from the onset of infection. The outcome was influenced by the clinical condition of the patients: solid organ transplantation (p = 0.003) emerged as an independent predictor of mortality; non-survival patients most frequently had pneumonia (p = 0.009) or mechanical ventilation (p = 0.049). Conclusion: Ceftazidime−avibactam showed high efficacy in infections caused by MDR Gram-negative pathogens with limited therapeutic options.
MRSA represents one of the largest problems in wound healing as a result of its increasing incidence and the complex therapeutic approach required to treat it. The need for new solutions to overcome antibiotic resistance led to the development of antimicrobial molecules that are effective at blocking quorum sensing. This special report provides an up-to-date review, based on the latest evidence in the literature, of old and new molecules that can positively influence the process of wound healing via their action on MRSA quorum sensing. Quorum sensing-inhibiting molecules, applied topically or injected in situ, have excellent potential to improve both MRSA eradication and quality of wound healing, especially when combined with conventional systemic MRSA therapy. Further human studies are needed to evaluate the efficacy of these molecules.
Anti-Infective Agents , Methicillin-Resistant Staphylococcus aureus , Wound Infection , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Humans , Quorum Sensing , Wound Infection/drug therapy
Antibiotic resistance is rapidly increasing, and new anti-infective therapies are urgently needed. In this regard, antimicrobial peptides (AMPs) may represent potential candidates for the treatment of infections caused by multiresistant microorganisms. In this narrative review, we reported the experience of our research group over 20 years. We described the AMPs we evaluated against Gram-positive, Gram-negative, and fungi. In conclusion, our experience shows that AMPs can be a key option for treating multiresistant infections and overcoming resistance mechanisms. The combination of AMPs allows antibiotics and antifungals that are no longer effective to exploit the synergistic effect by restoring their efficacy. A current limitation includes poor data on human patients, the cost of some AMPs, and their safety, which is why studies on humans are needed as soon as possible.
ABSTRACT: The occurrence of COVID-19 pandemic had a significant negative effect on health care systems over the last year. Health care providers were forced to focus mainly on COVID-19 patients, neglecting in many cases equally important diseases, both acute and chronic. Therefore, also screening and diagnostic strategies for HIV could have been significantly impaired.This retrospective, multicenter, observational study aimed at assessing the number and characteristics of new HIV/AIDS diagnoses during COVID-19 pandemic in Italy and compared characteristics of people living with HIV at diagnosis between pre- and post-COVID-19 era (2019 vs 2020).Our results showed a significant reduction of HIV diagnoses during pandemic. By contrast, people living with HIV during pandemic were older and were diagnosed in earlier stage of disease (considering CD4+ T cell count) compared to those who were diagnosed the year before. Moreover, there was a significant decrease of new HIV diagnoses among men who have sex with men, probably for the impact of social distancing and restriction applied by the Italian Government. Late presentation incidence, if numbers in 2020 were lower than those in 2019, is still an issue.Routinely performing HIV testing in patients with suspected SARS-CoV-2 infection is identifying and linking to care underdiagnosed people living with HIV earlier. Thus, combined tests (HIV and SARS-CoV-2) should be implemented in patients with SARS-CoV-2 symptoms overlapping HIV's ones. Lastly, our results lastly showed how urgent implementation of a national policy for HIV screening is necessary.
Delivery of Health Care/organization & administration , HIV Infections/epidemiology , Mass Screening/statistics & numerical data , Adult , CD4 Lymphocyte Count/statistics & numerical data , COVID-19/epidemiology , Cross-Sectional Studies , Female , HIV Infections/diagnosis , Humans , Italy/epidemiology , Male , Mass Screening/organization & administration , Middle Aged , Pandemics , Retrospective Studies , Risk Factors , SARS-CoV-2
Metallo-ß-lactamases (MBLs) are among the most challenging bacterial enzymes to overcome. Aztreonam (ATM) is the only ß-lactam not hydrolyzed by MBLs but is often inactivated by co-produced extended-spectrum ß-lactamases (ESBL). We assessed the activity of the combination of ATM with old and new ß-lactamases inhibitors (BLIs) against MBL and ESBL co-producing Gram-negative clinical isolates. Six Enterobacterales and three non-fermenting bacilli co-producing MBL and ESBL determinants were selected as difficult-to-treat pathogens. ESBLs and MBLs genes were characterized by PCR and sequencing. The activity of ATM in combination with seven different BLIs (clavulanate, sulbactam, tazobactam, vaborbactam, avibactam, relebactam, zidebactam) was assessed by microdilution assay and time-kill curve. ATM plus avibactam was the most effective combination, able to restore ATM susceptibility in four out of nine tested isolates, reaching in some cases a 128-fold reduction of the MIC of ATM. In addition, relebactam and zidebactam showed to be effective, but with lesser reduction of the MIC of ATM. E. meningoseptica and C. indologenes were not inhibited by any ATM-BLI combination. ATM-BLI combinations demonstrated to be promising against MBL and ESBL co-producers, hence providing multiple options for treatment of related infections. However, no effective combination was found for some non-fermentative bacilli, suggesting the presence of additional resistance mechanisms that complicate the choice of an active therapy.
Among the most common complications of both chronic wound and surgical sites are staphylococcal skin infections, which slow down the wound healing process due to various virulence factors, including the ability to produce biofilms. Furthermore, staphylococcal skin infections are often caused by methicillin-resistant Staphylococcus aureus (MRSA) and become a therapeutic challenge. The aim of this narrative review is to collect the latest evidence on old and new anti-staphylococcal therapies, assessing their anti-biofilm properties and their effect on skin wound healing. We considered antibiotics, quorum sensing inhibitors, antimicrobial peptides, topical dressings, and antimicrobial photo-dynamic therapy. According to our review of the literature, targeting of biofilm is an important therapeutic choice in acute and chronic infected skin wounds both to overcome antibiotic resistance and to achieve better wound healing.
BACKGROUND: LL-37 is the only human antimicrobial peptide that belongs to the cathelicidins. The aim of the study was to evaluate the efficacy of LL-37 in the management of MRSA-infected surgical wounds in mice. METHODS: A wound on the back of adult male BALB/c mice was made and inoculated with Staphylococcus aureus. Two control groups were formed (uninfected and not treated, C0; infected and not treated, C1) and six contaminated groups were treated, respectively, with: teicoplanin, LL-37, given topically and /or systemically. Histological examination of VEGF expression and micro-vessel density, and bacterial cultures of wound tissues, were performed. RESULTS: Histological examination of wounds in the group treated with topical and intraperitoneal LL-37 showed increased re-epithelialization, formation of the granulation tissue, collagen organization, and angiogenesis. CONCLUSIONS: Based on the mode of action, LL-37 has a potential future role in the management of infected wounds.
Dalbavancin is a lipoglycopeptide approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI). The aim of the study was to evaluate the efficacy and safety in all patients who received at least one administration of dalbavancin. METHODS: We carried out a retrospective study of the use of dalbavancin in 55 patients at the Azienda Ospedaliera Ospedali Riuniti Umberto I (Ancona, Italy) from February 2017 to May 2020 and compared "on label" and "off label" use of dalbavancin in ABSSSI and non-ABSSSI. RESULTS: A total of 55 patients were included in the study. The median age was 61 years; 51% had ABSSSI; 24% had prosthetic joint infections, and 14% had osteomyelitis. A total of 53% received a single 1500 mg infusion of dalbavancin, and 18% received a second dose 14 days later; 24% of patients received further doses at 14-day intervals. In 91% of cases, patients achieved clinical objectives with dalbavancin: 96% of patients with ABSSSI and 69% of those with prosthetic joint infections. CONCLUSIONS: Dalbavancin was shown to have an excellent tolerability profile and to be a highly successful therapeutic approach even in those cases treated "off-label".
BACKGROUND: Ceftaroline represents a novel fifth-generation cephalosporin to treat infections caused by methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Ceftaroline susceptibility of 239 MRSA isolates was assessed by disk diffusion and a MIC test strip following both EUCAST and CLSI guidelines. Non-susceptible isolates were epidemiologically characterized by pulsed-field gel electrophoresis, spa typing, and multilocus sequence typing, and further investigated by PCR and whole genome sequencing to detect penicillin-binding protein (PBP) mutations as well as antibiotic resistance and virulence genes. RESULTS: Fourteen isolates out of two hundred and thirty-nine (5.8%) were non-susceptible to ceftaroline (MIC > 1 mg/L), with differences between the EUCAST and CLSI interpretations. The characterized isolates belonged to seven different pulsotypes and three different clones (ST228/CC5-t041-SCCmecI, ST22/CC22-t18014-SCCmecIV, and ST22/CC22-t022-SCCmecIV), confirming a clonal diffusion of ceftaroline non-susceptible strains. Mutations in PBPs involved PBP2a for ST228-t041-SCCmecI strains and all the other PBPs for ST22-t18014-SCCmecIV and ST22-t022-SCCmecIV clones. All isolates harbored antibiotic resistance and virulence genes with a clonal distribution. CONCLUSION: Our study demonstrated that ceftaroline non-susceptibile isolates belonged not only to ST228 strains (the most widespread clone in Italy) but also to ST22, confirming the increasing role of these clones in hospital infections.
Almost 13 months have passed since the World Health Organization (WHO) declared the coronavirus disease 19 (COVID-19) pandemic, caused by the SARS-CoV-2, on March 11th, 2020. During this period, we have realized that the most effective weapon we have to prevent SARS-CoV-2 infection, or to make it less aggressive, is vaccines. Currently, according to the WHO document "Draft landscape of COVID-19 candidate vaccines," there are 275 vaccines in development against the virus, although at the moment there are four preparations in distribution in the United States and in Europe. The characteristics of these vaccines are quite different from each other and may even be unfamiliar in the medical field. In particular, among dermatologists, knowledge of vaccines is of fundamental importance, especially in atopic dermatitis. Atopic patients are aware of having a predisposition to develop allergies, and so they are asking dermatologists about the safety of the vaccines currently available against the SARS-CoV-2. This article provides an up-to-date overview of this topic by reviewing current literature and sharing our personal experience.
COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Dermatitis, Atopic/etiology , Dermatologists/standards , Practice Patterns, Physicians'/standards , COVID-19 Vaccines/adverse effects , Clinical Competence , Dermatitis, Atopic/prevention & control , Europe , Humans
INTRODUCTION: Dalbavancin is a bactericidal lipoglycopeptide active against gram-positives. Its use has been approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI). METHODS: We conducted a narrative review of the literature on the safety profile of dalbavancin. The bibliographic research was carried out on the PubMed database on 6 November 2020 by seeking combinations of the following keywords: dalbavancin, adverse effects, safety, drug interactions, and skin infections. RESULTS: Five double-blind Phase 3 randomized clinical trials, 2 open-label randomized trials, and 4 retrospective studies were identified. No statistically significant differences were found between dalbavancin and comparators in the incidence of adverse events. Retrospective studies confirm the low incidence of adverse events. CONCLUSION: Dalbavancin is a therapeutic option that has demonstrated an excellent safety profile, also in relation to the other MRSA therapies available. Its use represents a cost-effective solution for the treatment of those patients with ABSSSI who would need hospitalization. One limitation of this study is that most of the available data are from Phase III clinical trials. Further real-life studies with a larger sample size are therefore needed to better assess the safety profile of the dalbavancin, especially to investigate the true incidence of rare adverse events.
