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1.
Orv Hetil ; 161(20): 807-812, 2020 05 01.
Artigo em Húngaro | MEDLINE | ID: mdl-32364358

RESUMO

Introduction: At the end of March, 2020, rapid tests detecting the presence of antiviral IgM and IgG antibodies against SARS-CoV-2 virus were introduced in Hungary for the identification of SARS-CoV-2 infection (COVID-19 disease). Aim: We evaluated two rapid tests (Anhui and Clungene) in comparison with those of real-time PCR tests considered as the gold standard in the detection of infection. Method: Between 16, March and 14, April, 2020, we performed rapid IgM and IgG detecting tests without PCR; PCR without rapid tests; and PCR WITH rapid tests in 4140, 3210 and 1654 patients, respectively. (Out of these 1654 patients, Anhui and Clungene tests were used for testing in 625 and 1029 patients, respectively.) Patients were considered as positive in PCR and rapid tests when PCR positivity and IgM or IgG positivity occurred at any time, respectively. (Note: Clungene test is also marketed as 'Lungene'.) Results: The prevalence of PCR positivity in 4864 patients tested with PCR was 6.3%. The sensitivity and specificity of Anhui and Clungene tests were 33.3% and 72.85%, and 35.48% and 85.02%, respectively. At 6% PCR positivity, the positive and negative predictive values of Anhui and Clungene were 7.28%, 94.48%, 13.13%, and 95.38%, respectively. Conclusion: The low positive predictive values indicate that Anhui and Clungene rapid tests detecting the presence of anti-IgM and anti-IgG against SARS-CoV-2 virus infection are not suitable for screening SARS-CoV-2 vírus infection in the general population. These results strongly support that Anhui and Clungene rapid tests detecting IgM and IgG antibodies against SARS-CoV-2 virus should not be used in the differential diagnosis of infection. Orv Hetil. 2020; 161(20): 807-812.


Assuntos
Anticorpos Antivirais , Infecções por Coronavirus/diagnóstico , Imunoensaio/métodos , Pneumonia Viral/diagnóstico , Anticorpos Antivirais/análise , Betacoronavirus , Técnicas de Laboratório Clínico , Humanos , Hungria , Imunoglobulina G/análise , Imunoglobulina M/análise , Pandemias , Valor Preditivo dos Testes , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade
2.
J Antibiot (Tokyo) ; 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32409678

RESUMO

Antibiotic resistance is one of the major challenges in healthcare of our time. To meet this challenge, we designed and prepared guanidine and lipophilic guanidine derivatives of the glycopeptide antibiotic teicoplanin to armed them with activity against the most threatening nosocomial bacteria, multiresistant enterococci. From teicoplanin and its pseudoaglycone, a series of N-terminal guanidine derivatives have been prepared with free and amide C-terminal parts. Six aliphatic and aromatic lipophilic carbodiimides were prepared and used for the synthesis of lipophilic guanidine teicoplanin conjugates. All new N-terminal guanidine antibiotics showed high activity against a standard panel of Gram-positive bacteria. Four selected derivatives displayed excellent antibacterial activity against a series of nosocomial VanA Enterococcus faecium strains.

3.
BMC Infect Dis ; 19(1): 1009, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779587

RESUMO

BACKGROUND: Although Streptococcus agalactiae is the leading causative agent of neonatal sepsis and meningitis, recently it is increasingly isolated from non-pregnant adults. The relation between its presence in the genitourinary tract and manifested clinical symptoms of STD patients remains an open question. In this study, a complex epidemiological investigation of GBS isolates from a venerology clinic was performed. METHODS: Ninety-six GBS isolates were serotyped and their genetic relatedness determined by PFGE. MLST was also performed for a subset of 20 isolates. The antibiotic susceptibility was tested with agar dilution. Surface proteins and the ST-17 hypervirulent clone was detected by PCR. RESULTS: The serotype prevalence was the following: V (29.2%), III (27.1%), Ia (22.9%), IV (10.4%), II (5.2%) and Ib (4.2%). A strong association was demonstrated between surface protein genes and serotypes. All isolates were fully susceptible to penicillin, but erythromycin and clindamycin resistance was high (41.7 and 35.4%, respectively), and 8 phenotypically macrolide sensitive isolates carried the ermB gene. 21.9% of all strains belonged to the hypervirulent ST17 clone, most being of serotype III and all were rib +. We found a few serotype IV isolates belonging to several STs and one serotype V/ST110 strain, containing a 44-bp deletion in the atr allele. CONCLUSIONS: The presence of silent ermB genes is of worry, as their expression upon macrolide exposure could lead to unforeseen therapeutic failure, while clindamycin is used for intrapartum antibiotic prophylaxis, in case of penicillin allergy. The other alarming result is the high prevalence of ST17 among these strains from STD patients, who could be sources of further infections. This is the first report from Hungary providing both serotyping and genotyping data of GBS isolates. These results could be helpful for vaccine production as the major vaccine candidates are capsular antigens or surface proteins.


Assuntos
Infecções Estreptocócicas/diagnóstico , Streptococcus agalactiae/genética , Adulto , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Feminino , Humanos , Hungria/epidemiologia , Macrolídeos/farmacologia , Testes de Sensibilidade Microbiana , Fenótipo , Prevalência , Sorogrupo , Infecções Estreptocócicas/epidemiologia , Streptococcus agalactiae/efeitos dos fármacos , Streptococcus agalactiae/isolamento & purificação , Streptococcus agalactiae/patogenicidade , Virulência/genética
4.
BMC Infect Dis ; 19(1): 584, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349818

RESUMO

BACKGROUND: Community-acquired sepsis is a life-threatening systemic reaction, which starts within ≤72 h of hospital admittance in an infected patient without recent exposure to healthcare risks. Our aim was to evaluate the characteristics and the outcomes concerning community-acquired sepsis among patients admitted to a Hungarian high-influx national medical center. METHODS: A retrospective, observational cohort study of consecutive adult patients hospitalized with community-acquired sepsis during a 1-year period was executed. Clinical and microbiological data were collected, patients with pre-defined healthcare associations were excluded. Sepsis definitions and severity were given according to ACCP/SCCM criteria. The primary outcome was in-hospital all-cause mortality. Secondary outcomes were intensive care unit (ICU) admittance, length-of-stay (LOS), source control and bacteraemia rates. Statistical differences were explored with classical comparison tests, predictors of in-hospital all-cause mortality were modelled by multivariate logistic regression. RESULTS: 214 patients (median age 60.0 ± 33.1 years, 57% female, median Charlson score 4.0 ± 5.0) were included, 32.7% of them (70/214) had severe sepsis, and 28.5% (61/214) had septic shock. Prevalent sources of infections were genitourinary (53/214, 24.8%) and abdominal (52/214, 24.3%). The causative organisms were dominantly E. coli (60/214, 28.0%), S. pneumoniae (18/214, 8.4%) and S. aureus (14/214, 6.5%), and bacteraemia was documented in 50.9% of the cases (109/214). In-hospital mortality was high (30/214, 14.0%), and independently associated with shock, absence of fever, male gender and the need for ICU admittance, but source control and de-escalation of empirical antimicrobial therapy were protective. ICU admittance was 27.1% (58/214), source control was achieved in 18.2% (39/214). Median LOS was 10.0 ± 8.0, ICU LOS was 8.0 ± 10.8 days. CONCLUSIONS: Community-acquired sepsis poses a significant burden of disease with characteristic causative agents and sources. Patients at a higher risk for poor outcomes might be identified earlier by the contributing factors shown above.


Assuntos
Sepse/tratamento farmacológico , Choque Séptico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Estudos de Coortes , Infecções Comunitárias Adquiridas , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Feminino , Mortalidade Hospitalar , Hospitalização , Humanos , Hungria , Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Sepse/microbiologia , Sepse/mortalidade , Choque Séptico/microbiologia , Choque Séptico/mortalidade , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificação , Adulto Jovem
5.
Cells ; 8(3)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30884758

RESUMO

Intestinal dysbiosis is linked to numerous gastrointestinal disorders, including inflammatory bowel diseases. It is a question of debate if coxibs, selective inhibitors of cyclooxygenase (COX)-2, cause dysbiosis. Therefore, in the present study, we aimed to determine the effect of long-term (four weeks) selective inhibition of COX-2 on the small intestinal microbiota in the rat. In order to avoid mucosal damage due to topical effects and inflammation-driven microbial alterations, rofecoxib, a nonacidic compound, was used. The direct inhibitory effect of rofecoxib on the growth of bacteria was ruled out in vitro. The mucosa-sparing effect of rofecoxib was confirmed by macroscopic and histological analysis, as well as by measuring the intestinal levels of cytokines and tight junction proteins. Deep sequencing of bacterial 16S rRNA revealed that chronic rofecoxib treatment had no significant influence on the composition and diversity of jejunal microbiota. In conclusion, this is the first demonstration that long-term selective inhibition of COX-2 by rofecoxib does not cause small intestinal dysbiosis in rats. Moreover, inhibition of COX-2 activity is not likely to be responsible per se for microbial alterations caused by some coxibs, but other drug-specific properties may contribute to it.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Disbiose/patologia , Intestino Delgado/enzimologia , Intestino Delgado/patologia , Lactonas/farmacologia , Sulfonas/farmacologia , Animais , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Celecoxib/farmacologia , Dinoprostona/biossíntese , Disbiose/microbiologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Ratos Wistar , Fatores de Tempo
6.
J Antibiot (Tokyo) ; 72(7): 524-534, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30874609

RESUMO

Ten analogues of a teicoplanin pseudoaglycon derivative have been synthesized with the aim of optimizing the in vitro activity of the compound against VanA type vancomycin resistant enterococci (VRE) isolated from hospitalized patients. Teicoplanin, vancomycin, and oritavancin were used as reference antibiotics for the antibacterial evaluations. One of the new derivatives exhibited far superior activity than the original compound. The in vitro MICs measured were comparable to that of oritavancin against the investigated VRE strains.


Assuntos
Antibacterianos/farmacologia , Lipoglicopeptídeos/farmacologia , Teicoplanina/síntese química , Teicoplanina/farmacologia , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Infecção Hospitalar/microbiologia , Farmacorresistência Bacteriana , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Teicoplanina/análogos & derivados
7.
Infection ; 46(6): 855-860, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30191513

RESUMO

To describe the characteristics of adult invasive H. influenzae disease, 34 patients diagnosed at a single tertiary center between 2004 and 2017 were analyzed in a retrospective case series study. The annual estimated incidence was 0.1 cases/100.000 inhabitants. Dominant source of infection was pneumonia accompanied by sepsis (62%) and caused by nontypeable strains (74%) with low ampicillin resistance (14%). Survival (94%) and complication rates were high (35%). Main empirical treatments were ceftriaxone or levofloxacine.


Assuntos
Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana , Infecções por Haemophilus/epidemiologia , Haemophilus influenzae/fisiologia , Sepse/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ampicilina/uso terapêutico , Ceftriaxona/uso terapêutico , Feminino , Infecções por Haemophilus/complicações , Infecções por Haemophilus/diagnóstico , Infecções por Haemophilus/microbiologia , Haemophilus influenzae/efeitos dos fármacos , Humanos , Hungria/epidemiologia , Incidência , Levofloxacino/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sepse/diagnóstico , Sepse/microbiologia
8.
Front Chem ; 6: 359, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30186829

RESUMO

The APO-type proline-arginine-rich host defense peptides exhibit potent in vitro killing parameters against Enterobacteriaceae but not to other bacteria. Because of the excellent in vivo properties against systemic and local infections, attempts are regularly made to further improve the activity spectrum. A C-terminal hydrazide analog of the Chex1-Arg20 amide (ARV-1502) shows somewhat improved minimal inhibitory concentration against Moraxellaceae. Here we compared the activity of the two peptides as well as an inactive dimeric reverse amide analog in a systemic Acinetobacter baumannii infection. Only the narrow spectrum amide derivative reduced the 6-h blood bacterial burden by >2 log10 units reaching statistical significance (p = 0.03 at 5 mg/kg and 0.031 at 2 mg/kg administered intramuscularly). The hydrazide derivative, probably due to stronger activity on cell membranes, lysed erythrocytes at lower concentrations, and caused toxic effects at lower doses (10 mg/kg vs. 25 mg/kg). In a limited study, the amide induced a >5-fold production of the anti-inflammatory cytokine IL-10 over untreated naïve mice and minor increases in the anti-inflammatory IL-4 and pro-inflammatory cytokines TNF-α and IL-6, in blood. The blood of hydrazide-treated mice exhibited significantly lowered levels of IL-10 and slightly decreased IL-4 and TNF-α. These results suggest that the improved efficacy of the narrow-spectrum amide analog is likely associated with increased anti-inflammatory cytokine production and better stimulation of the immune system. Although blood IL-6 and TNF-α levels are frequently used as markers of potential toxicity in drug development, we did not observe any notable increase in mice receiving the toxic polyamide antibiotic colistin.

9.
Front Chem ; 6: 309, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30155456

RESUMO

As monotherapy, modified proline-rich antimicrobial peptides (PrAMPs) protect animals from experimental bacteremia in a dose-dependent manner. We evaluated the in vitro synergy of a modified PrAMP, A3-APO, a dimer, previously shown to inhibit the 70 kDa bacterial heat shock protein DnaK, with imipenem or colistin against two antibiotic-resistant pathogens; a carbapenemase-expressing Klebsiella pneumoniae strain K97/09 and Acinetobacter baumannii (ATCC BAA-1605). Combining antimicrobials resulted in synergy for PrAMP/colistin combination against both K. pneumoniae and A. baumannii (ΣFIC = 0.08 both) and additive activity for the A3-APO/imipenem combination against K. pneumoniae (ΣFIC = 0.53). Chex1-Arg20, (designated as ARV-1502 in preclinical development), the single chain PrAMP monomer of A3-APO, showed synergy with meropenem against a carbapenem-resistant uropathogenic Escherichia coli strain (ΣFIC = 0.38). In a murine bacteremia model using K97/09, A3-APO at 1 mg/kg demonstrated improved survival when co-administered with standard (10 mg/kg) or subtherapeutic (1 mg/kg) doses of colistin at 36 h (p < 0.05). Surprisingly, the survival benefit of A3-APO was augmented when the A3-APO dose was decreased by 50% to 0.5 mg/kg (p < 0.02) in conjunction with a subtherapeutic colistin dose (1 mg/kg). ARV-1502, as monotherapy demonstrated prolonged (>24 h) activity in a mouse Escherichia coli infection assay. Co-treatment with ARV-1502 and subtherapeutic doses of ceftazidime (150 mg/kg) was studied in a mouse model of melioidosis. ARV-1502 provided a 50% improvement in long-term (62 days) survival, but only at the lowest of 3 administered doses; survival advantage was demonstrated at 2.5 mg/kg but not at 5 or 10 mg/kg. The mortality benefit of combination therapies was not routinely accompanied by a parallel decline in blood or tissue bacterial counts in surviving animals, suggesting that the anti-infective activity of the host defense peptides (HDP) is broader than simply bacterial eradication. In fact, the hormetic effect observed in either animal models suggest that low dose HDP treatment may change the dominant mode of action in experimental bacteremia.

10.
Amino Acids ; 49(9): 1647-1651, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28664267

RESUMO

Host defense peptides are preferably administered as topical therapeutic agents. We have investigated whether peptide A3-APO can enter the circulation when applied to the ear skin. Efficacy of peptide monotherapy as transdermal administration option was assessed in a systemic mouse Acinetobacter baumannii model. A3-APO reduced mortality and demonstrated a statistically significant reduction of blood bacterial counts, regardless whether it was administered prior or after bacterial challenge. The peptidic metabolite of A3-APO was efficacious when applied to the ear or tail.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bacteriemia/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Infecções por Acinetobacter/microbiologia , Infecções por Acinetobacter/mortalidade , Infecções por Acinetobacter/patologia , Acinetobacter baumannii/patogenicidade , Acinetobacter baumannii/fisiologia , Administração Cutânea , Sequência de Aminoácidos , Animais , Arginina/química , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Bacteriemia/patologia , Carga Bacteriana/efeitos dos fármacos , Carbapenêmicos/farmacologia , Colistina/farmacologia , Modelos Animais de Doenças , Orelha , Humanos , Camundongos , Prolina/química , Pele/metabolismo , Análise de Sobrevida
11.
Front Chem ; 5: 15, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28373972

RESUMO

Proline-rich antimicrobial peptides (PrAMPs) represent promising alternative therapeutic options for the treatment of multidrug-resistant bacterial infections. PrAMPs are predominantly active against Gram-negative bacteria by inhibiting protein expression via at least two different modes of action, i.e., blocking the ribosomal exit tunnel of 70S ribosomes (oncocin-type binding) or inhibiting the assembly of the 50S ribosomal subunit (apidaecin-type binding). The in vivo efficacy and favorable biodistribution of oncocins confirmed the therapeutic potential of short PrAMPs for the first time, whereas the in vivo evaluation of apidaecins is still limited despite the promising efficacy of apidaecin-analog Api88 in an intraperitoneal murine infection model. Here, the in vivo efficacy of apidaecin-analog Api137 was studied, which rescued all NMRI mice from a lethal intraperitoneal infection with E. coli ATCC 25922 when administered three times intraperitoneal at doses of 0.6 mg/kg starting 1 h after infection. When Api88 and Api137 were administered intravenous or intraperitoneal at doses of 5 and 20 mg/kg, their plasma levels were similarly low (<3 µg/mL) and four-fold lower than for oncocin-analog Onc72. This contradicted earlier expectation based on the very low serum stability of Api88 with a half-life time of only ~5 min compared to ~6 and ~3 h for Api137 and Onc72, respectively. Pharmacokinetic data relying on a sensitive mass spectrometry method utilizing multiple reaction monitoring and isotope-labeled peptides revealed that Api88 and Api137 were present in blood, urine, and kidney, and liver homogenates at similar levels accompanied by the same major metabolites comprising residues 1-16 and 1-17. The pretended discrepancy was solved, when all peptides were incubated in peritoneal lavage. Api137 was rapidly degraded at the C-terminus, while Api88 was rather stable despite releasing the same degradation products. Onc72 was very stable explaining its higher plasma levels compared to Api88 and Api137 after intraperitoneal administration illuminating its good in vivo efficacy. The data indicate that the degradation of therapeutic peptides should be studied in serum and further body fluids. Moreover, the high efficacy in murine infection models and the fast clearance of Api88 and Api137 within ~60 min after intravenous and ~90 min after intraperitoneal injections indicate that their in vivo efficacy relates to the maximal peptide concentration achieved in blood.

12.
Int J Pharm ; 523(1): 151-158, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28341150

RESUMO

A multilayer mat for dispensing colistin sulfate through a body surface was prepared by electrospinning. The fabricated system comprised various polyvinyl alcohol fibrous layers prepared with or without the active ingredient. One of the electrospun layers contained water-soluble colistin sulfate and the other was prepared from the same polymer type and composition without the active drug and was finally heat-treated. The heat treatment modified the supramolecular structure and conferred the polymer nanofibre with the rate-controlling function. The microstructure of different layers was tracked by positron annihilation lifetime spectroscopy, and detailed morphological analysis of the fibre mats was performed using a scanning electron microscope. The drug-release profiles of various layer arrangements were studied in relation to their antimicrobial activity. The finite element method was applied to overcome the challenge of diffusion-controlled drug release from multilayer polymer scaffolds. The finite element method was first verified using analytical solutions for a simple arrangement (one drug-loaded swellable fibre and one rate-controlling nonswellable fibre) under perfect sink conditions and in a well-stirred finite volume. The effect of alternate layer arrangements on the drug-release profiles was also investigated to plan for controlled topical drug release from fibrous scaffolds. This design is expected to aid in increasing local effectiveness, thus reducing the systemic loading and the consequent side effects of colistin.


Assuntos
Antibacterianos/química , Colistina/química , Sistemas de Liberação de Medicamentos , Nanofibras/química , Álcool de Polivinil/química , Simulação por Computador , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos
13.
J Antibiot (Tokyo) ; 70(5): 664-670, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28144040

RESUMO

A selection of nine derivatives of teicoplanin pseudoaglycon were tested in vitro against clinical vancomycin-resistant Enterococcus strains possessing vanA, vanB or both genes. The bacteria were characterized by PCR for the identification of their resistance genes. The tested compounds contain lipoic acid, different carbohydrates and aryl groups as lipophilic moieties. About one-third of the teicoplanin-resistant strains were shown to be susceptible to one or more of the glycopeptide derivatives.


Assuntos
Antibacterianos/farmacologia , Enterococcus/efeitos dos fármacos , Teicoplanina/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/genética , Carbono-Oxigênio Ligases/genética , Farmacorresistência Bacteriana/genética , Enterococcus/genética , Testes de Sensibilidade Microbiana , Reação em Cadeia da Polimerase , Teicoplanina/síntese química , Teicoplanina/química , Vancomicina/farmacologia , Resistência a Vancomicina
14.
J Antibiot (Tokyo) ; 70(2): 152-157, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27353163

RESUMO

A series of lipophilic teicoplanin pseudoaglycon derivatives, including alkyl-, aryl-, calixarene- and protected sugar-containing conjugates, were prepared using azide-alkyne click chemistry. Out of the conditions applied, the CuSO4-ascorbate reagent system proved to be more efficient than the Cu(I)I-Et3N-mediated reaction. Some of the new compounds have high in vitro activity against glycopeptide-resistant Gram-positive bacteria, including vanA-positive Enterococcus faecalis. A few of them also display promising in vitro anti-influenza activity.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Teicoplanina/análogos & derivados , Triazóis/química , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana , Estrutura Molecular , Teicoplanina/síntese química , Teicoplanina/farmacologia
15.
Ann Clin Microbiol Antimicrob ; 15(1): 53, 2016 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-27646968

RESUMO

BACKGROUND: In the 1990s, azithromycin became the drug of choice for many infectious diseases but emerging resistance to the drug has only been reported in the last decade. In the last 5 years, the National Neisseria gonorrhoeae Reference Laboratory of Hungary (NNGRLH) has also observed an increased number of N. gonorrhoeae strains resistant to azithromycin. The aim of this study was to determine the most frequent sequence types (ST) of N. gonorrhoeae related to elevated levels of azithromycin MIC (minimal inhibitory concentration). Previously and currently isolated azithromycin-resistant strains have been investigated for the existence of molecular relationship. METHODS: Maldi-Tof technic was applied for the identification of the strains isolated from outpatients attending the reference laboratory. Testing antibiotic susceptibility of azithromycin, cefixime, ceftriaxone, tetracycline, spectinomycin and ciprofloxacin was carried out for all the identified strains, using MIC strip test Liofilchem(®). N. gonorrhoeae multiantigen sequence typing (NG-MAST) was performed exclusively on azithromycin-resistant isolates. A phylogenetic tree was drawn using MEGA6 (Molecular Evolutionary Genetics Analysis Version 6.0) Neighbour-Joining method. RESULTS: Out of 192 N. gonorrhoeae isolates, 30.0 % (58/192) proved resistant to azithromycin (MIC > 0.5 mg/L). Of the azithromycin-resistant isolates, ST1407, ST4995 and ST11064 were the most prevalent. Based on the phylogenetic analysis, the latter two STs are closely related. CONCLUSIONS: In contrast to West-European countries, in our region, resistance to azithromycin has increased up to 30 % in the last 5 years, so the recommendation of the European Guideline -500 mg of ceftriaxone combined with 2 g of azithromycin as first choice therapy against N. gonorrhoeae- should be seriously considered in case of Hungary.


Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Farmacorresistência Bacteriana/genética , Gonorreia/epidemiologia , Neisseria gonorrhoeae/genética , Adulto , Alelos , Técnicas de Tipagem Bacteriana , Cefixima/farmacologia , Ceftriaxona/farmacologia , Ciprofloxacino/farmacologia , Feminino , Expressão Gênica , Gonorreia/tratamento farmacológico , Gonorreia/microbiologia , Humanos , Hungria/epidemiologia , Masculino , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/classificação , Neisseria gonorrhoeae/efeitos dos fármacos , Neisseria gonorrhoeae/isolamento & purificação , Filogenia , Porinas/genética , Porinas/metabolismo , Prevalência , Espectinomicina/farmacologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Tetraciclina/farmacologia , Proteína B de Ligação a Transferrina/genética , Proteína B de Ligação a Transferrina/metabolismo
16.
J Antimicrob Chemother ; 71(4): 1003-11, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26832757

RESUMO

OBJECTIVES: To evaluate the efficacy of antimicrobial peptide Onc112 in a lethal Escherichia coli infection model and the pharmacokinetics of Onc72 and Onc112 administered intravenously or intraperitoneally in mice. METHODS: Onc72, Onc112 and their major metabolites in blood, kidneys, liver, brain and urine were quantified by MS using multiple reaction monitoring (MRM) and isotope-labelled peptides. RESULTS: Onc112 rescued all animals when administered intraperitoneally at a dose of 2.5 mg/kg and was thus slightly more efficient than Onc72. The MRM method provided limits of quantification in plasma, urine and kidney, liver and brain homogenates of 7-80 µg/L, well below the MICs of 2-4 mg/L. Onc72 and Onc112 reached all organs within 10 min when administered intraperitoneally (5 mg/kg). Their initial concentrations in plasma were 11.9 and 22.6 mg/L, respectively, with elimination t1/2 values of ∼14 and 21 min. The peptide concentrations in blood remained above their MICs for 20 min for Onc72 and 80 min for Onc112. The highest peptide concentrations were detected in kidney homogenates, which also contained the highest content of metabolites, indicating, together with the results from analysis of urine samples, that both peptides are cleared through the kidneys. CONCLUSIONS: Onc72 and Onc112 reach organs, including the brain, within 10 min after intravenous and intraperitoneal administration. Onc112 remained in blood at concentrations above its MIC for 80 min. The pharmacokinetic profiles explain the high in vivo efficacies in models of systemic infection and indicate the potential use of these agents for the treatment of urinary tract infections.


Assuntos
Antibacterianos/farmacocinética , Peptídeos Catiônicos Antimicrobianos/farmacocinética , Animais , Antibacterianos/administração & dosagem , Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Modelos Animais de Doenças , Monitoramento de Medicamentos , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/mortalidade , Feminino , Injeções Intraperitoneais , Camundongos , Sepse/tratamento farmacológico , Sepse/microbiologia , Sepse/mortalidade , Fatores de Tempo , Distribuição Tecidual , Resultado do Tratamento
17.
Amino Acids ; 48(1): 203-11, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26319645

RESUMO

Native and designer cationic antimicrobial peptides are increasingly acknowledged as host defense molecules rather than true antimicrobials. Due to their ability to activate the innate immune system, these structures are used to treat uninfected and bacterially-infected wounds, including those harboring Acinetobacter baumannii. Previously we documented that when administered intramuscularly or topically in liquid formulations, the proline-rich host defense peptide dimer A3-APO accelerates uninfected wound re-epithelization and eliminates systemic and local A. baumannii, methicillin-resistant Staphylococcus aureus and other pathogen load from infected lesions better than conventional antibiotics. In the current study we sought to produce and characterize a novel delivery system, suitable for immediate and convenient application in non-hospital environments. The APO monomer was incorporated into polyvinyl alcohol nanofibers and the complex was polymerized into a solid patch dressing. Mice were subjected to skin abrasion where the wounds were either left uninfected or were inoculated with a near lethal dose of multidrug resistant A. baumannii strain. Analyzed after 3 days, APO monomer-containing patches improved wound appearance significantly better than polymer patches without antibiotics. When compared to colistin, the APO patches accelerated wound healing, and statistically significantly reduced wound size and wound bacterial load. The in vivo antimicrobial effect was more extensive than after intramuscular administration of the peptide drug, by using only one tenth of the active pharmaceutical ingredient. These data suggest that the APO monomer-impregnated nanofiber dressing can be developed as an economical first-line treatment option to skin injuries in general and battlefield burn and blast injuries in particular.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Portadores de Fármacos/química , Nanofibras/química , Álcool de Polivinil/química , Pele/microbiologia , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/crescimento & desenvolvimento , Animais , Peptídeos Catiônicos Antimicrobianos/química , Química Farmacêutica , Sistemas de Liberação de Medicamentos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pele/lesões
19.
Expert Rev Anti Infect Ther ; 13(7): 871-81, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25835521

RESUMO

Cationic antimicrobial peptides were first thought to fight infection in animal models by disintegrating bacterial peptides and later by inhibiting bacteria-specific intracellular processes. However, ever increasing evidences indicate that cationic peptides accumulate around and modulate the immune system both systemically and in cutaneous and mucosal surfaces where injuries and infections occur. Native and designer antibacterial peptides as well as cationic peptides, never considered as antibiotics, promote wound healing at every step of cutaneous tissue regeneration. This article provides an introductory list of examples of how cationic peptides are involved in immunostimulation and epithelial tissue repair, eliminating wound infections and promoting wound healing in potential therapeutic utility in sight. Although a few antimicrobial peptides reached the Phase II clinical trial stage, toxicity concerns limit the potential administration routes. Resistance induction to both microbiology actions and the integrity of the innate immune system has to be carefully monitored.


Assuntos
Anti-Infecciosos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Queimaduras/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Infecção dos Ferimentos/tratamento farmacológico , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Infecciosos/farmacologia , Queimaduras/diagnóstico , Humanos , Resultado do Tratamento , Cicatrização/fisiologia , Infecção dos Ferimentos/diagnóstico
20.
Eur J Med Chem ; 94: 73-86, 2015 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-25752526

RESUMO

Despite the close structural similarity between the heptapeptide cores of the glycopeptide antibiotics teicoplanin and ristocetin, synthetically modified derivatives of their aglycons show significantly different antibacterial and antiviral properties. The teicoplanin aglycon derivatives with one exception proved to be potent antibacterials but they did not exhibit anti-influenza virus activity. In contrast, the aglycoristocetin derivatives generally showed high anti-influenza virus activity and possessed moderate antibacterial activity. A systematic structure-activity relationship study has been carried out on ristocetin and teicoplanin aglycon derivatives, to explore which structural differences are responsible for these markedly different biological activities. According to electronic circular dichroism and in silico conformational studies, it was found that the differences in anti-influenza virus activity are mainly determined by the conformation of the heptapeptide core of the antibiotics controlled by the presence or absence of chloro substituents. Knowledge of the bioactive conformation will help to design new analogs with improved anti-influenza virus activity. For the teicoplanin derivatives, it was shown that derivatization to improve the antiviral efficacy was accompanied by a significant decrease in antibacterial activity.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Antivirais/química , Antivirais/farmacologia , Relação Estrutura-Atividade , Técnicas de Química Sintética , Dicroísmo Circular , Simulação por Computador , Espectroscopia de Ressonância Magnética , Orthomyxoviridae/efeitos dos fármacos , Conformação Proteica , Ristocetina/química , Teicoplanina/análogos & derivados , Teicoplanina/química , Teicoplanina/farmacologia
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