RESUMO
Dalbavancin is an effective antibiotic that is widely used to treat skin infection. Our aim was to determine the effect of dalbavancin administration on wound healing compared to that of vancomycin and to elucidate if epidermal growth factor receptor (EGFR), matrix metalloproteinase 1 (MMP-1), MMP-9, and vascular endothelial growth factor (VEGF) could be involved in its therapeutic mechanism. A mouse model of methicillin-resistant Staphylococcus aureus (MRSA) skin infection was established. Mice were treated daily with vancomycin (10 mg/kg) and weekly with dalbavancin at day 1 (20 mg/kg) and day 8 (10 mg/kg). After 14 days, wounds were excised, and bacterial counts were performed. Wound healing was assessed by histological and immunohistochemical staining, followed by protein extraction and immunoblotting. Our microbiological results confirmed that both dalbavancin and vancomycin are effective in reducing the bacterial load in wounds. The dalbavancin group showed a strong effect compared with infected untreated animals and the vancomycin-treated group. The wounds treated with dalbavancin showed robust epidermal coverage with reconstitution of the regular and keratinized epidermal lining and well-organized granulation tissue with numerous blood vessels, although slightly less than that in the uninfected group. While in the vancomycin-treated group the epithelium appeared, in general, still hypertrophic, the granulation tissue appeared even less organized. We observed elevated EGFR and VEGF expression in both treated groups, although it was higher in dalbavancin-treated mice. MMP-1 and MMP-9 were decreased in uninfected tissue and in both treated tissues compared with untreated infected wounds. This study showed faster healing with dalbavancin treatment that might be associated with higher EGFR and VEGF levels.
Assuntos
Antibacterianos/uso terapêutico , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Teicoplanina/análogos & derivados , Vancomicina/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Carga Bacteriana/efeitos dos fármacos , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Staphylococcus aureus/efeitos dos fármacos , Infecção da Ferida Cirúrgica/tratamento farmacológico , Teicoplanina/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVES: To evaluate the transferability of antibiotic resistance from an MDR clade B Enterococcus faecium and to characterize the genetic elements involved. METHODS: The erm(B)-positive strain E. faecium 37BA (donor) and strains E. faecium 64/3 and Listeria welshimeri 11857RF (recipients) were used in mating experiments. Donors and transconjugants were characterized using MIC assays, PFGE, Southern blotting and hybridization, quantitative RT-PCR (RT-qPCR), next-generation sequencing and PCR mapping. RESULTS: One E. faecium and one L. welshimeri transconjugant were selected for in-depth investigation. Both acquired an â¼40 kb plasmid carrying erm(B). An additional plasmid of â¼200 kb, encoding the full conjugation machinery, was detected in the donor and in the E. faecium transconjugant. Next-generation sequencing revealed a new 40 396 bp plasmid that was designated pEf37BA; it contained 10 antibiotic resistance genes, tet(M), tet(L), erm(B), aadE, sat4, aphA, spw, lsa(E), lnu(B) and pbp5, resulting from the recombination of pM7M2 of E. faecium with an MDR chromosomal region of Erysipelothrix rhusiopathiae. A pbp5-carrying circular form was also detected. The PBP5 amino acid sequence differed from the C46 variant by two mutations (S39T and D644N). Its expression was documented in both transconjugants. pEf37BA persisted in the absence of selective pressure. CONCLUSIONS: The MDR clade B E. faecium plasmid, deriving from the recombination of two different resistance regions, carried a pbp5 element and was transferable to different bacterial species. This finding further documents the dissemination of ampicillin resistance among community-associated E. faecium and the key role of commensal strains in the spread of antibiotic resistance.
Assuntos
Farmacorresistência Bacteriana Múltipla , Enterococcus faecium/efeitos dos fármacos , Enterococcus faecium/genética , Transferência Genética Horizontal , Genótipo , Proteínas de Ligação às Penicilinas/genética , Plasmídeos , Antibacterianos/farmacologia , Southern Blotting , Mapeamento Cromossômico , Conjugação Genética , Eletroforese em Gel de Campo Pulsado , Enterococcus faecium/classificação , Enterococcus faecium/isolamento & purificação , Genes Bacterianos , Voluntários Saudáveis , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Listeria/genética , Metiltransferases/genética , Testes de Sensibilidade Microbiana , Reação em Cadeia da Polimerase em Tempo RealRESUMO
In the past few years the increasing incidence of hospital infections with Acinetobacter baumannii, especially in immunocompromised patients, and its proneness to develop multidrug resistance have been raising considerable concern. This study examines the antimicrobial and antibiofilm activity of protegrin 1 (PG-1), an antimicrobial peptide from porcine leukocytes, against A. baumannii strains isolated from surgical wounds. PG-1 was tested both alone and combined with the antibiotics commonly used in clinical settings. Its antimicrobial activity was evaluated by determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), checkerboard assays, and time-kill experiments. Its effects on biofilm inhibition/eradication were tested with crystal violet staining. The strains were grown in subinhibitory or increasing PG-1 concentrations to test the development of resistance. Mammalian cell toxicity was tested by XTT assays. PG-1 MICs and MBCs ranged from 2 to 8 µg/ml. PG-1 was most active and demonstrated a synergistic interaction with colistin, a last resort antibiotic. Interestingly, antagonism was never observed. In time-kill experiments, incubation with 2 × MIC for 30 min suppressed all viable cells. PG-1 did not select resistant strains and showed a limited effect on cell viability, but it did exert a strong activity against multidrug-resistant A. baumannii. In contrast, in our experimental conditions it had no effect on biofilm inhibition/eradication. PG-1 thus seems to be a promising antimicrobial agent against multidrug-resistant Gram-negative infections.
Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Biofilmes/efeitos dos fármacos , Interações Medicamentosas , Ferida Cirúrgica/microbiologia , Acinetobacter baumannii/isolamento & purificação , Anti-Infecciosos/toxicidade , Peptídeos Catiônicos Antimicrobianos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Coloração e RotulagemRESUMO
Ceftobiprole is a fifth-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). One-year surveillance at the Regional Hospital of Ancona (Italy) disclosed a 12% ceftobiprole resistance rate (12/102 isolates; MIC, ≥4 mg/liter). Epidemiological characterization demonstrated that the resistant isolates all belonged to different clones. Penicillin-binding protein (PBP) analysis showed substitutions in all PBPs and a novel insertion in PBP2a. The mecB and mecC genes were not detected. Ceftobiprole susceptibility screening is essential to avoid therapeutic failure and the spread of ceftobiprole-resistant strains.
Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Proteínas de Ligação às Penicilinas/genética , Técnicas de Tipagem Bacteriana , Hospitais , Humanos , Itália , Staphylococcus aureus Resistente à Meticilina/classificação , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Mutação , Infecções Estafilocócicas/microbiologiaRESUMO
Prolonged hospitalization and antibiotic therapy are risk factors for the development of methicillin-resistant Staphylococcus aureus (MRSA) infections in thermal burn patients. We used a rat model to study the in vivo efficacy of daptomycin in the treatment of burn wound infections by S. aureus, and we evaluated the wound healing process through morphological and immunohistochemical analysis. A copper bar heated in boiling water was applied on a paraspinal site of each rat, resulting in two full-thickness burns. A small gauze was placed over each burn and inoculated with 5 × 107 CFU of S. aureus ATCC 43300. The study included two uninfected control groups with and without daptomycin treatment, an infected control group that did not receive any treatment, and two infected groups treated, respectively, with intraperitoneal daptomycin and teicoplanin. The main outcome measures were quantitative culture, histological evaluation of tissue repair, and immunohistochemical expression of wound healing markers: epidermal growth factor receptor (EGFR) and fibroblast growth factor 2 (FGF-2). The highest inhibition of infection was achieved in the group that received daptomycin, which reduced the bacterial load from 107 CFU/ml to about 103 CFU/g (P < 0.01). The groups treated with daptomycin showed better overall healing with epithelialization and significantly higher collagen scores than the other groups, and these findings were also confirmed by immunohistochemical data. In conclusion, our results support the hypothesis that daptomycin is an important modulator of wound repair by possibly reducing hypertrophic burn scar formation.
Assuntos
Antibacterianos/uso terapêutico , Queimaduras/tratamento farmacológico , Daptomicina/uso terapêutico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/prevenção & controle , Teicoplanina/uso terapêutico , Cicatrização/efeitos dos fármacos , Infecção dos Ferimentos/prevenção & controle , Animais , Carga Bacteriana/efeitos dos fármacos , Queimaduras/microbiologia , Proliferação de Células , Cicatriz/tratamento farmacológico , Modelos Animais de Doenças , Células Epiteliais/citologia , Receptores ErbB/biossíntese , Fator 2 de Crescimento de Fibroblastos/biossíntese , Masculino , Testes de Sensibilidade Microbiana , Ratos , Ratos Wistar , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Cicatrização/fisiologia , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologiaRESUMO
There is limited information on the variations of HIV-1 DNA mutation profile in reverse transcriptase (RT) and protease (PR) genes during suppressive antiretroviral treatment (plasma HIV-1 RNA continuously <50 copies/ml) with raltegravir (RAL)-based regimens in patients with baseline RT/PR resistant HIV. Twelve multidrug resistant (RT: 12/12, PR: 8/12) HIV-infected patients were followed during effectively suppressive RAL-based therapy. Total and integrated HIV-1 DNA were assessed by real time PCR at baseline and every 6 months. Ultrasensitive (threshold: 2.5 copies/ml) plasma HIV-1 RNA and genotypic analysis of RT and PR in proviral DNA were performed at baseline and at 24 months. Half of the patients had full viral suppression (plasma HIV-RNA < 2.5 copies/ml) at month 12. Total HIV-1 DNA declined significantly after 12 months of therapy (from 249.2 to 145.7 copies/106 cells, P = 0.023), and remained stable until 24 months, when total HIV-1 DNA levels raised, concomitantly with a less stringent suppression of HIV-1 RNA (81.8% of patients with >2.5 copies/ml). Integrated HIV-1 DNA did not show fluctuations during the study period. Sequencing of the PR and RT regions from HIV-1 DNA revealed changes in the resistance mutation profile in five patients. Total HIV-1 DNA declined after the introduction of RAL-based therapy, with a rebound after 2 years. No changes were observed in levels of integrated DNA, suggesting limited effect on archived HIV. The RT and PR sequence changes in archived HIV-1 DNA suggest that variation of the mutation profile can occur even in the absence of detectable HIV-1 RNA. J. Med. Virol. 88:2115-2124, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Fármacos Anti-HIV/uso terapêutico , DNA Viral/genética , Farmacorresistência Viral Múltipla , Protease de HIV/genética , Transcriptase Reversa do HIV/genética , HIV-1/enzimologia , HIV-1/genética , Raltegravir Potássico/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade , Feminino , Variação Genética , Genótipo , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , RNA Viral/sangue , RNA Viral/genética , Raltegravir Potássico/efeitos adversos , Carga ViralRESUMO
BACKGROUND: Health-related quality of life (HRQoL) has been recognized as a central measure of the overall health status in HIV patients. With the availability of different highly effective drug combinations, maximizing quality-adjusted survival has become a major target of HIV treatment. Although the association of HIV RNA and CD4 cell count with clinical HIV progression has been well established, the relation between these markers and HRQoL measures is still unclear. METHOD: This cross-sectional study investigated the relationship linking HIV RNA and CD4 to HRQoL measures in 181 triple-class-experienced patients with advanced HIV disease. The instrument used was the ISSQoL, a self-administered and HIV-specific HRQoL questionnaire. RESULTS: Data showed no correlation between HRQoL measures and CD4 counts. Higher HIV RNA levels were, however, associated with poor HRQoL scores in 3 out of 9 scales of social functioning, depression and anxiety, and satisfaction with quality of life. In multivariable analyses, only the satisfaction with quality of life mean score remained significantly lower for the HIV RNA â¯100,000 copies/mL group compared to the HIV RNA 50 to 10,000 copies/mL group. CONCLUSIONS: Although other determinants of HRQoL in people with HIV should also be considered, this finding suggests a negative impact of high viral load on perceived HRQoL that adds to other described determinants of lower quality of life in people with HIV, such as lower social support and self-reported symptoms.
Assuntos
Fármacos Anti-HIV/classificação , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Qualidade de Vida , Carga Viral/efeitos dos fármacos , Adulto , Idoso , Contagem de Linfócito CD4 , Estudos Transversais , Feminino , Infecções por HIV/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Inquéritos e Questionários , Adulto JovemRESUMO
The occurrence of resistance or side effects in patients receiving antifungal agents leads to failure in the treatment of mycosis. The aim of this experimental study was to investigate the in vitro effects of IB-367 alone and in combination with three standard antifungal drugs, fluconazole (FLU), itraconazole (ITRA) and terbinafine (TERB), against 20 clinical isolates of dermatophytes belonging to three species. Minimum inhibitory concentrations (MICs), minimal fungicidal concentrations (MFCs), synergy test, time-kill curves, fungal biomass (FB) and hyphal damage using 2,3-bis-(2-methoxy-4-nitro-5-sulfenylamino carbonil)-2H-tetrazolium hydroxide assay (XTT) were performed to study the efficacy of IB-367. In this study, we observed that TERB and ITRA had MICs lower values for all the strains compared to IB-367 and FLU. Synergy was found in 35%, 30% and 25% of IB-367/FLU, IB-367/ITRA and IB-367/TERB interactions respectively. IB-367 exerted a fungicidal activity against Trichophyton mentagrophytes, T. rubrum and Microsporum canis at concentrations starting from 1x MIC. At a concentration of 5x MIC, IB-367 showed the highest rates of hyphae damage for M. canis 53% and T. mentagrophytes 50%; against the same isolates it caused a reduction of 1 log of the total viable count cell hyphae damage. We propose IB-367 as a promising candidate for the future design of antifungal drugs.
Assuntos
Antifúngicos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Sinergismo Farmacológico , Arthrodermataceae/isolamento & purificação , Contagem de Colônia Microbiana , Dermatomicoses/microbiologia , Fluconazol/farmacologia , Humanos , Hifas/efeitos dos fármacos , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Naftalenos/farmacologia , TerbinafinaRESUMO
Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative agent of acute bacterial skin and skin-structure infections (ABSSSI), one of the major challenges to the health system worldwide. Although the use of antibiotics as the first line of intervention for MRSA-infected wounds is recommended, important side effects could occur, including cytotoxicity or immune dysregulation, thus affecting the repair process. Here, we show that the oxazolidinone antibiotic linezolid (LZD) impairs wound healing by aberrantly increasing interleukin 1 ß (IL-1ß) production in keratinocytes. Mechanistically, LZD triggers a reactive oxygen species (ROS)-independent mitochondrial damage that culminates in increased tethering between the endoplasmic reticulum (ER) and mitochondria, which in turn activates the NLR family pyrin domain-containing 3 (NLRP3) inflammasome complex by promoting its assembly to the mitochondrial surface. Downregulation of ER-mitochondria contact formation is sufficient to inhibit the LZD-driven NLRP3 inflammasome activation and IL-1ß production, restoring wound closure. These results identify the ER-mitochondria association as a key factor for NLRP3 activation and reveal a new mechanism in the regulation of the wound healing process that might be clinically relevant.
Assuntos
Retículo Endoplasmático , Inflamassomos , Interleucina-1beta , Mitocôndrias , Proteína 3 que Contém Domínio de Pirina da Família NLR , Cicatrização , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Humanos , Animais , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Queratinócitos/metabolismo , Queratinócitos/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: There is no consensus on darunavir (DRV) target levels in plasma for clinical use, and information about variability in plasma concentrations is limited. AIM: : To investigate the variability in DRV plasma trough concentrations in the clinical setting, evaluating interindividual and intraindividual variabilities of plasma drug levels among HIV-infected patients receiving ritonavir (RTV)-boosted DRV (DRV/r) within salvage regimens, and evaluate the potential correlation between variability and virological response. METHODS: Sixty-two patients taking DRV/r (600/100 mg twice a day) were evaluated for trough plasma concentrations and immunovirological parameters after 6 months from the start of the regimen. A subgroup of patients (n = 21) was also evaluated for intraindividual variability (expressed as coefficient of variation) on 2 samples taken at different time points. Drug concentrations were assayed by high-performance liquid chromatography with ultraviolet detection, and the values were expressed as medians with interquartile range (IQR). Genotypic sensitivity score and genotypic inhibitory quotient were calculated. RESULTS: DRV/r was used with a median of 3 other antiretroviral drugs (raltegravir use 88.7%). Median plasma concentrations were 3.22 mcg/mL (IQR, 2.04-5.69) for DRV and 0.44 mcg/mL (IQR, 0.21-0.70) for RTV. Both drugs showed a high interindividual variability in plasma concentrations (61% and 99.3%, respectively). Only 3 patients (4.8%) had undetectable DRV plasma levels. DRV plasma concentrations showed a significant positive correlation with age (r = 0.298, P = 0.019), but no significant correlation between DRV genotypic inhibitory quotient and HIV-RNA plasma levels (P = 0.614) was found. Intraindividual coefficients of variation were 58.4% for DRV and 47.1% for RTV. Patients with undetectable HIV-RNA showed a trend for lower intraindividual coefficients of variation compared with patients with detectable HIV-RNA (55.9% versus 83.8%, P = 0.156). No major interaction effects with other antiretroviral drugs were found. CONCLUSIONS: In a context of salvage therapy, both DRV and RTV plasma levels showed high interindividual and intraindividual variabilities. Lower intraindividual variability could be beneficial in maintaining viral suppression.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/sangue , Ritonavir/sangue , Sulfonamidas/sangue , Adulto , Idoso , Cromatografia Líquida de Alta Pressão/métodos , Darunavir , Quimioterapia Combinada , Feminino , Genótipo , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Ritonavir/uso terapêutico , Terapia de Salvação , Sulfonamidas/uso terapêutico , Fatores de Tempo , Adulto JovemRESUMO
We investigated the efficacy of tigecycline and FS8, alone or combined, in preventing prosthesis biofilm in a rat model of staphylococcal vascular graft infection. Graft infections were established in the back subcutaneous tissue of adult male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with 2 x 107 colony-forming units of Staphylococcus aureus, strain Smith diffuse. The study included a control group, a contaminated group that did not receive any antibiotic prophylaxis, and three contaminated groups that received: (i) intraperitoneal tigecycline, (ii) FS8-soaked graft, and (iii) tigecycline plus FS8-soaked graft, respectively. Each group included 15 animals. The infection burden was evaluated by using sonication and quantitative agar culture. Moreover, an in vitro binding-study was performed to quantify the how much FS8 was coated to the surface of the prosthesis. Tigecycline, combined with FS8, against the adherent bacteria showed MICs (2.00 mg/L) and MBCs (4.00 mg/L) four-fold lower with respect to tigecycline alone in in vitro studies. The rat groups treated with tigecycline showed the lowest bacterial numbers (4.4 x 104 ± 1.2 x 104 CFU/mL). The FS8-treated group showed a good activity and significant differences compared to control group with bacterial numbers of 6.8 x 104 ± 2.0 x 104 CFU/mL. A stronger inhibition of bacterial growth was observed in rats treated with a combined FS8 and tigecycline therapy than in those that were singly treated with bacterial numbers of 101 CFU/mL graft. In conclusion, the ability to affect biofilm formation as well, its property to be an antibiotic enhancer suggests FS8 as alternative or additional agent to use in conjunction with conventional antimicrobial for prevention of staphylococcal biofilm related infection.
Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Minociclina/análogos & derivados , Oligopeptídeos/farmacologia , Infecções Relacionadas à Prótese/prevenção & controle , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Antibacterianos/química , Modelos Animais de Doenças , Masculino , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Minociclina/farmacologia , Oligopeptídeos/química , Polietilenotereftalatos/química , Ligação Proteica , Percepção de Quorum/efeitos dos fármacos , Ratos , Ratos Wistar , Staphylococcus aureus/fisiologia , TigeciclinaRESUMO
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.
Assuntos
Bacteriemia , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Staphylococcus capitis , Recém-Nascido , Humanos , Linezolida/farmacologia , Linezolida/uso terapêutico , Antibacterianos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Coagulase/genética , Testes de Sensibilidade Microbiana , Staphylococcus/genética , Bacteriemia/tratamento farmacológico , Genômica , HospitaisRESUMO
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.
RESUMO
OBJECTIVES: We investigated the in vivo efficacy of tigecycline, a new glycylcycline (a tetracycline derivative), in the management of methicillin-resistant Staphylococcus aureus (MRSA)-infected experimental surgical wounds in rats. The main outcome measures were quantitative bacterial culture, histological examination and immunohistochemical expression of matrix metalloproteinase-9 (MMP-9) and collagen IV. METHODS: An animal model was used to compare the in vivo efficacy of teicoplanin and tigecycline in the treatment of burn wound infections by S. aureus. A copper bar, heated in boiling water, was placed on the paraspinal site of each rat, resulting in full thickness burns. A small gauze was placed over each burn and then inoculated with 5 × 10(7) cfu of S. aureus ATCC 43300. To mimic the clinical situation in burn patients, surgical debridement was performed 48 h after the injury. The wounds were left to heal by secondary intention. The study included an uninfected control group that did not receive any treatment, a contaminated group that did not receive any treatment, and two contaminated groups treated with intraperitoneal tigecycline (2 mg/kg) and teicoplanin (7 mg/kg), respectively. RESULTS: All antibiotic treatments were significantly effective. Tigecycline showed the highest antimicrobial activity, with a better impact on histological results. Infected rats treated with tigecycline showed a significant decrease in MMP-9 expression both in epithelium and in dermis compared with rats treated with teicoplanin. CONCLUSIONS: Tigecycline, besides its antimicrobial activity, exerts an important modulatory effect on MMP-9, accelerating wound healing in staphylococcal-infected burns.
Assuntos
Queimaduras/complicações , Metaloproteinase 9 da Matriz/metabolismo , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Minociclina/análogos & derivados , Infecções Estafilocócicas/tratamento farmacológico , Cicatrização , Infecção dos Ferimentos/tratamento farmacológico , Animais , Carga Bacteriana , Modelos Animais de Doenças , Histocitoquímica , Imuno-Histoquímica , Masculino , Inibidores de Metaloproteinases de Matriz , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Minociclina/administração & dosagem , Ratos , Ratos Wistar , Infecções Estafilocócicas/microbiologia , Teicoplanina/administração & dosagem , Tigeciclina , Resultado do Tratamento , Infecção dos Ferimentos/microbiologiaRESUMO
BACKGROUND: We investigated the efficacy of tigecycline and rifampin alone or combined in preventing ureteral stent infection due to Enterococcus faecalis. MATERIALS AND METHODS: The activities of the two antibiotics were previously studied in vitro in absence or in presence of biofilm. For in vivo research, the study included a control group without bacterial challenge to evaluate the sterility of surgical procedure, a challenged control group that did not receive any antibiotic prophylaxis and, for each bacterial strain, three challenged groups that received: (1) 2 mg/kg intraperitoneal tigecycline, immediately after stent implantation; (2) rifampin-coated ureteral stents where 0.2 cm(2) sterile ureteral stents were incubated in 10 mg/L rifampin solution for 30 min immediately before implantation; and (3) intraperitoneal tigecycline plus rifampin-coated ureteral stent at the above concentrations. Ureteral stents were explanted at d 5 following implantation and biofilm bacteria enumerated. RESULTS: The in vitro studies showed that the biofilm was strongly affected by the presence of rifampin and, in its presence, tigecycline had MICs and MBCs lower than those obtained in the absence of rifampin. Intraperitoneal tigecycline exerted stronger effect than rifampin on bacterial numbers. The combination rifampin plus tigecycline showed efficacies higher than that of each single compound. CONCLUSION: These results highlight the potential usefulness of tigecycline in preventing enterococcal ureteral stent infections and the role of rifampin as an interesting antibiotic enhancer.
Assuntos
Antibioticoprofilaxia , Biofilmes , Enterococcus faecalis/isolamento & purificação , Infecções por Bactérias Gram-Positivas/prevenção & controle , Minociclina/análogos & derivados , Rifampina/uso terapêutico , Stents/microbiologia , Ureter/microbiologia , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Biofilmes/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Enterococcus faecalis/efeitos dos fármacos , Feminino , Técnicas In Vitro , Minociclina/farmacologia , Minociclina/uso terapêutico , Ratos , Ratos Wistar , Rifampina/farmacologia , Tigeciclina , Resultado do TratamentoRESUMO
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.
RESUMO
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.
Assuntos
Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Infecção dos Ferimentos , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Humanos , Percepção de Quorum , Infecção dos Ferimentos/tratamento farmacológicoRESUMO
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.
RESUMO
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.
RESUMO
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.