Assuntos
Antibacterianos , Cefalosporinas , Streptococcus pneumoniae , Animais , Cefalosporinas/farmacocinética , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Cefalosporinas/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Camundongos , Streptococcus pneumoniae/efeitos dos fármacos , Modelos Animais de Doenças , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Humanos , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/microbiologiaRESUMO
Skin and soft tissue infections (SSTIs), and particularly diabetic-related foot infections (DFI), present diagnostic and therapeutic complexities, often leading to severe complications. This study aims to evaluate the in vitro efficacy of cefditoren and amoxicillin/clavulanic acid against typical DFI pathogens. Clinical samples from 40 patients with mild SSTIs were analyzed, revealing a predominance of Staphylococcus spp. and Streptococcus spp. species. Cefditoren exhibited activity against 90% of isolates, with superior potency over amoxicillin/clavulanic acid. These findings underscore the utility of cefditoren in empirical treatment of DFI, although a larger sample size would be desirable for further validation.
Assuntos
Combinação Amoxicilina e Clavulanato de Potássio , Antibacterianos , Cefalosporinas , Pé Diabético , Testes de Sensibilidade Microbiana , Humanos , Pé Diabético/tratamento farmacológico , Pé Diabético/microbiologia , Antibacterianos/uso terapêutico , Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Cefalosporinas/uso terapêutico , Streptococcus/efeitos dos fármacos , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções dos Tecidos Moles/microbiologia , Masculino , Feminino , Staphylococcus/efeitos dos fármacos , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To assess whether there is a significant difference in infection rate after surgery tooth extraction in two different hospitals from Norway and Spain where different surgical antimicrobial prophylaxis protocols are applied. METHODS: An analytical observational study was conducted, retrospective cohorts type, analyzing healthy patients with no risk factors, who were third molar tooth operated in maxillofacial services of two different hospitals: St. Olav in Trondheim (Norway) and Clínico San Carlos in Madrid (Spain). The collected variables were: age, number of tooth removed, anesthesia type, and observations about the course of the operation registered in the clinical history. To assess the development of postoperative infection, patient's data of those who chose the hospital as the place to remove the suture thread were collected in Norway, whereas in Spain a telephone survey was conducted to determine the course of the operation months later. RESULTS: In St. Olav Hospital 11.1% of patients operated received antibiotic regimen after surgery, while in Hospital San Carlos were 100%. The infection rate was 15% in St.Olav Hospital and 7.5% in Hospital San Carlos. These differences were no statistically significant. CONCLUSIONS: The routine administration of antibiotics to healthy patients with no risk factors undergoing impacted third molar surgical removal is a common clinical practice which it does not seem to be justified.
Assuntos
Antibacterianos/uso terapêutico , Antibioticoprofilaxia , Dente Serotino/cirurgia , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Extração Dentária/métodos , Dente Impactado/cirurgia , Adulto , Fatores Etários , Anestesia , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Masculino , Noruega/epidemiologia , Espanha/epidemiologia , Adulto JovemRESUMO
Semithin sections of colonies of three ATCC strains (Staphylococcus aureus, Escherichia coli, and Candida albicans) showed that their internal structure had specific patterns that evolved over the time. These patterns generally were defined by the presence of different layers composed of microorganisms with variable population densities and dead cells. The observed structures in this study could be explained as a particular form of biofilm with an air-semisolid interface.
Assuntos
Candida albicans/crescimento & desenvolvimento , Escherichia coli/crescimento & desenvolvimento , Staphylococcus aureus/crescimento & desenvolvimento , Biofilmes/crescimento & desenvolvimento , Fatores de TempoRESUMO
OBJECTIVE: To evaluate cefditoren in inducer-substrate combinations to screen for AmpC induction. METHODS: 100 clinical isolates (25 P. aeruginosa, 25 E. cloacae, 14 M. morganii, 13 S. marcescens, 12 C. freundii, 7 P. rettgeri, and 4 E. aerogenes) were tested by the Kirby-Bauer disc approximation method using cefditoren and ceftazidime discs as substrates, and cefditoren and imipenem discs as inducers. RESULTS: None of the strains showed induction of AmpC with cefditoren-ceftazidime as inducer-substrate combination. Imipenem-cefditoren as inducer-substrate combination was not useful for evaluating strains of P. aeruginosa since no inhibition zones surrounding the cefditoren disc were found. Among evaluable enterobacteria (those showing substrate inhibition zone), inducible Amp C was detected in 48 out of 63 (76.2%) with cefditoren, and in 33 out of 68 (48.5%) isolates with ceftazidime as substrate. Significantly (p=0.013) higher number of AmpC producers were detected with cefditoren versus ceftazidime (76.2% vs. 48.5%), due to the differences found for E. cloacae (72.8% vs. 21.7%; p=0.0009) and S. marcescens (100% vs. 54.5%; p=0.03). Higher mean reductions of diameters around substrate discs were found for cefditoren (4.17 mm) vs. ceftazidime (3.79 mm), reaching statistical significance (p<0.05) for indol-positive proteae: M. morganii (5.32 mm vs. 3.92 mm) and P. rettgeri (3.47 mm vs. 2.64 mm). CONCLUSION: Cefditoren showed no induction capability, and when used as substrate (with imipenem as inducer) it offered detection rates of AmpC inducible enterobacteria higher than the imipenem-ceftazidime combination, mainly for Enterobacter spp. and Serratia spp., with higher diameter reductions for indol-positive proteae.
Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Proteínas de Bactérias/genética , Ceftazidima/farmacologia , Cefalosporinas/farmacologia , beta-Lactamases/genética , Infecções Bacterianas/microbiologia , Enterobacteriaceae/efeitos dos fármacos , Humanos , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Especificidade da EspécieRESUMO
This study explored tigecycline exposure-bacterial responses in pharmacodynamic simulations (in vitro kinetic model) using different inocula. One meticillin-resistant vancomycin-heteroresistant Staphylococcus aureus, one Enterococcus faecium and one extended-spectrum beta-lactamase-producing Escherichia coli with equal tigecycline minimum inhibitory concentrations/minimum bactericidal concentrations (MICs/MBCs) (0.12/0.25 microg/mL) were used. A computerised pharmacodynamic bicompartmental model simulated three tigecycline twice-daily dosing regimens over 48h: 50mg (100mg loading dose); 100mg; and 150 mg. Areas under bacterial growth curves were calculated, and differences between the growth curve used as control and the killing curve of bacteria exposed to tigecycline (ABBC) were determined. With standard inocula [ca. 1 x 10(6)colony-forming units (CFU)/mL], linear increases in area under the concentration-time curve (AUC)/MIC (25.6 for 50mg, 53.76 for 100mg and 79.52 for 150 mg) produced linear increases in activity against Gram-positive organisms (mean ABBCs of 120.60, 143.20 and 195.80 log CFU x h/mL for S. aureus and of 95.75, 172.55 and 216.90 log CFUxh/mL for E. faecium, respectively), with the activity of the 150 mg regimen being significantly higher (P<0.01) than that of the other two regimens. ABBCs obtained with the 100mg regimen using standard inocula were similar to those obtained with the 150 mg regimen when using high inocula (ca. 1 x 10(7)CFU/mL). Against E. coli, the highest dosing regimen was required to obtain significant antibacterial activity compared with control (mean ABBCs of 145.75 log CFU x h/mL with standard inocula and 63.33 log CFU x h/mL with high inocula). An increase in tigecycline dosing appears to be an interesting therapeutic option to maximise antibacterial activity owing to its linear pharmacokinetics and pharmacodynamics, especially when severe infections with high bacterial load are suspected.
Assuntos
Antibacterianos/farmacologia , Simulação por Computador , Enterococcus faecium/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Minociclina/análogos & derivados , Relação Dose-Resposta a Droga , Escherichia coli/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Minociclina/farmacologia , Células-Tronco , Tigeciclina , beta-Lactamases/metabolismoRESUMO
The tigecycline susceptibility of six different Enterobacteriaceae strains with reported high tigecycline MICs was determined in quintuplicate by four methodologies using Mueller-Hinton agar and broth from six manufacturers. The MICs determined by Etest were a >or=1-fold dilution lower than those determined by broth microdilution and agar dilution, with the highest modal values given by agar dilution. The highest modal MICs were obtained using Oxoid medium, and the lowest inhibition zone values (disc diffusion) were obtained using Oxoid and bioMérieux media. The lowest MICs were obtained by Etest using Difco or Merck media.
Assuntos
Antibacterianos/farmacologia , Meios de Cultura/química , Enterobacteriaceae/efeitos dos fármacos , Minociclina/análogos & derivados , Humanos , Testes de Sensibilidade Microbiana/métodos , Minociclina/farmacologia , TigeciclinaRESUMO
BACKGROUND: Odontogenic infections are polymicrobial. This study explores the in vitro killing activity by concentrations similar to those found in crevicular fluid of tinidazole in combination with amoxicillin/clavulanic acid, clindamycin and levofloxacin against four groups of high-density mixed inocula of anaerobes (Prevotella buccae, Fusobacterium nucleatum, and Veillonella spp.) and facultative (Capnocytophaga spp. and Streptococcus spp.) isolates of periodontal pathogens. METHODS: Killing curves were assessed under strict anaerobic conditions with antibiotics alone and in combination with tinidazole at concentrations similar to those achieved in crevicular fluid against approximately 10(7) colony forming units (CFU)/ml inoculum (1:1:1:1:1 proportion of the five bacterial isolates) of the four bacterial groups. Group 1 did not include beta-lactamase-producing strains; groups 2, 3, and 4 included one, two, and three beta-lactamase-producing strains, respectively. RESULTS: In single-drug experiments, at 48 hours, tinidazole alone did not show significant killing of the entire bacterial population, whereas reductions in the initial inocula > or =2.09 log(10) CFU/ml with clindamycin, > or =3.26 log(10) CFU/ml with amoxicillin/clavulanic acid, and > or =3.83 log(10) CFU/ml with levofloxacin were obtained. When combined with tinidazole, reductions were significantly higher for all antibiotics: > or =5.28 log(10) CFU/ml with clindamycin, > or =4.78 log(10) CFU/ml with amoxicillin/clavulanic acid, and > or =6.17 log(10) CFU/ml with levofloxacin. CONCLUSION: In addition to its high activity against anaerobic periodontal pathogens, tinidazole offered synergism with other antibiotics against the large strict anaerobic subpopulation and the small facultative subpopulation of a high-density mixed inocula of odontogenic pathogens under strict anaerobic conditions, similar to those of odontogenic infections.
Assuntos
Antibacterianos/administração & dosagem , Bactérias Anaeróbias/efeitos dos fármacos , Doenças Periodontais/tratamento farmacológico , Tinidazol/administração & dosagem , Amoxicilina/administração & dosagem , Ácido Clavulânico/administração & dosagem , Clindamicina/administração & dosagem , Sinergismo Farmacológico , Quimioterapia Combinada , Líquido do Sulco Gengival/microbiologia , Humanos , Levofloxacino , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Ofloxacino/administração & dosagem , Doenças Periodontais/microbiologiaRESUMO
Interference of cefditoren (CDN) and amoxicillin/clavulanic acid (AMC) with biofilm production was studied using 11 Streptococcus pneumoniae isolates with minimum inhibitory concentrations (MICs) ranging from 0.015microg/mL to 0.5microg/mL for CDN and from 0.06microg/mL to 2microg/mL for AMC (except for one isolate with an AMC MIC of 8microg/mL) and 5 Haemophilus influenzae isolates with MICs of 0.03-0.06microg/mL for CDN and 0.5-16microg/mL for AMC. Slime production was assessed in antibiotic-free medium and with 0.03microg/mL CDN or 1/0.5microg/mL AMC by measuring the optical density at 450nm (OD(450)). Significantly lower mean OD(450) values were obtained for S. pneumoniae with antibiotics compared with controls (CDN, 0.088 vs. 0.118, P=0.003; and AMC, 0.095 vs. 0.112, P=0.003), with significant correlation between both antibiotics (r=0.752; P=0.008). Percent reduction in OD(450) values was higher for CDN compared with AMC (24.02% vs. 15.92%; P=0.008). For H. influenzae, significantly lower mean OD(450) values were obtained with CDN compared with controls (0.083 vs. 0.096; P=0.043) but not with AMC (0.086 vs. 0.095; P=0.08). Comparing percent reductions in S. pneumoniae versus H. influenzae for each antibiotic, no differences were found for AMC (15.92% vs. 9.40%; P=0.36), with a tendency for CDN (24.02% vs. 13.79%; P=0.069). Different beta-lactams may have different capabilities of interfering with S. pneumoniae biofilm development when tested under the same experimental conditions.
Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/fisiologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/fisiologia , beta-Lactamas/farmacologia , Técnicas de Tipagem Bacteriana , Biofilmes/crescimento & desenvolvimento , Genótipo , Haemophilus influenzae/classificação , Haemophilus influenzae/isolamento & purificação , Humanos , Testes de Sensibilidade Microbiana , Sistema Respiratório/microbiologia , Infecções Respiratórias/microbiologia , Sorotipagem , Streptococcus pneumoniae/classificação , Streptococcus pneumoniae/isolamento & purificaçãoRESUMO
This study explored the influence of vancomycin tolerance and protein binding on the bactericidal activity of vancomycin versus daptomycin (protein binding 36.9% vs. 91.7%, respectively) against four vancomycin-tolerant methicillin-resistant Staphylococcus aureus (MRSA) [minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC)=0.5/16, 1/32, 2/32 and 1/32microg/mL for vancomycin and 1/1, 1/2, 2/2 and 2/4microg/mL for daptomycin]. Killing curves were performed with vancomycin/daptomycin concentrations equal to serum peak concentrations (C(max)) (65.70/98.60microg/mL) and trough concentrations (C(min)) (7.90/9.13microg/mL) in the presence and absence of a physiological human albumin concentration (4g/dL), controlled with curves with the theoretical free drug fraction of vancomycin/daptomycin C(max) (41.45/8.18microg/mL) and C(min) (4.98/0.76microg/mL). Vancomycin C(max) and C(min) concentrations, regardless of the media, showed a bacteriostatic profile not reaching a reduction of 99% or 99.9% of the initial inocula during the 24-h experimental time period. Daptomycin antibacterial profiles significantly differed when testing C(max) and C(min). C(max) was rapidly bactericidal (< or =4h) with >5 log(10) reduction in the initial inocula for all strains, regardless of the presence or not of albumin or the use of concentrations similar to free C(max). C(min) exhibited similar final colony counts at 0h and 24h in curves with albumin, but with >3 log colony-forming units (CFU)/mL reduction at < or =4h for strains with an MIC of 1microg/mL and ca. 2 logCFU/mL reduction at < or =6h for strains with an MIC of 2microg/mL. This activity was significantly higher than the activity of the free C(min) fraction. The results of this study reinforce the idea that pharmacodynamics using concentrations calculated using reported protein binding are unreliable. Daptomycin exhibited rapid antibacterial activity against vancomycin-tolerant MRSA isolates even against those with high daptomycin MICs in the presence of physiological albumin concentrations.
Assuntos
Albuminas/metabolismo , Antibacterianos/farmacologia , Daptomicina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Viabilidade Microbiana/efeitos dos fármacos , Vancomicina/farmacologia , Antibacterianos/metabolismo , Contagem de Colônia Microbiana , Daptomicina/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Ligação Proteica , Vancomicina/metabolismoRESUMO
The in vitro activity of tinidazole against anaerobic periodontal pathogens (25 Prevotella buccae, 18 Prevotella denticola, 10 Prevotella intermedia, 6 Prevotella melaninogenica, 5 Prevotella oralis, 10 Fusobacterium nucleatum and 8 Veillonella spp.) was determined by agar dilution. MIC(90) values (minimum inhibitory concentration for 90% of the organisms) were 8 microg/mL for Veillonella spp., 4 microg/mL for P. intermedia, 2 microg/mL for P. buccae, 1 microg/mL for Fusobacterium spp. and 0.5 microg/mL for other Prevotella spp. Cidal activity was studied by killing curves with tinidazole and amoxicillin (alone and in combination) at concentrations similar to those achieved in crevicular fluid (41.2 microg/mL tinidazole and 14.05 microg/mL amoxicillin) against an inoculum of ca. 10(7)colony-forming units/mL of four bacterial groups, each one composed of four different strains of the following periodontal isolates: Prevotella spp., Fusobacterium spp. and Veillonella spp. (anaerobes) and one amoxicillin-susceptible Streptococcus spp. (facultative) in a proportion of 1:1:1:1. When only beta-lactamase-negative Prevotella or Fusobacterium strains were tested, significantly higher reductions were found with amoxicillin (>4 log reduction at 48 h) versus controls. The presence of beta-lactamase-positive Prevotella spp. or F. nucleatum strains rendered amoxicillin inactive (no reductions at 48 h), with no differences from controls. Amoxicillin+tinidazole produced >3 log reduction at 24h and >4 log reduction at 48 h regardless of the presence or not of beta-lactamase-positive strains. The presence in crevicular fluid of beta-lactamases produced by beta-lactamase-positive periodontal pathogens may have ecological and therapeutic consequences since it may protect beta-lactamase-negative periodontal pathogens from amoxicillin treatment. In vitro, tinidazole offered high antianaerobic activity against beta-lactamase-positive and -negative periodontal pathogens, avoiding amoxicillin inactivation.
Assuntos
Antibacterianos/farmacologia , Fusobacterium/efeitos dos fármacos , Doenças Periodontais/microbiologia , Prevotella/efeitos dos fármacos , Streptococcus/efeitos dos fármacos , Tinidazol/farmacologia , Veillonella/efeitos dos fármacos , Amoxicilina/farmacologia , Bactérias Anaeróbias/efeitos dos fármacos , Proteínas de Bactérias/biossíntese , Humanos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Resistência beta-Lactâmica , beta-Lactamases/biossínteseRESUMO
This study explores the killing kinetics within 12 h of four oral third-generation cephalosporins against ten Streptococcus pneumoniae strains exhibiting cefotaxime minimum inhibitory concentrations (MICs) from 0.03 to 2 microg/ml. Killing curves were performed with concentrations achievable in serum after standard doses (0.015-4 microg/ml). Reductions of 90% were achieved with all compounds at serum-achievable concentrations for strains exhibiting cefotaxime MIC < or = 0.5 microg/ml. Against strains with cefotaxime MIC > or = 1 microg/ml, only cefditoren reached a 90% reduction with concentrations of 0.5-1 microg/ml doses. At 4 microg/ml, cefditoren and cefotaxime reached 99.9% reduction in seven of the ten strains studied. At serum-achievable concentrations, cefdinir and cefixime were not bactericidal against strains exhibiting cefotaxime MIC > or = 0.25 microg/ml and > or = 0.5 microg/ml, respectively. Cefditoren showed the best killing kinetic profiles and this observation may be important when choosing an oral third-generation cephalosporin as initial or sequential therapy.
Assuntos
Antibacterianos/farmacologia , Cefotaxima/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Cefdinir , Cefalosporinas/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Activity of simulated serum concentrations after oral therapy with 400 mg cefditoren pivoxil b.i.d., 500 mg cefuroxime axetil b.i.d. and 875/125 mg amoxicillin/clavulanic acid b.i.d. and t.i.d. regimens was explored over 24 h against Streptococcus pneumoniae. METHODS: Computerized pharmacodynamic simulations were performed against strains with penicillin/amoxicillin/cefuroxime/cefditoren minimum inhibitory concentrations (MICs, microg/ml) and serotypes: strain 1 (0.25/0.12/1/0.12; serotype 6A), strain 2 (2/4/ 2/0.25; serotype 6B), strain 3 (4/16/4/0.5; serotype 14), and strain 4 (4/16/8/1; serotype 14). RESULTS: Bactericidal activity (> or =3 log(10) reduction) at 12 and 24 h was obtained against all strains with cefditoren, against strains 1 and 2 with cefuroxime and amoxicillin/clavulanic acid t.i.d., but only against strain 1 with amoxicillin/clavulanic acid b.i.d.. Bactericidal activity at 24 h was related to T > MIC of >30% dosing interval, 1.7-2.0 log(10) reductions with T > MIC of 20-30%, and <1 log(10) reduction or regrowth with T > MIC of 0%. CONCLUSIONS: It is difficult to achieve pharmacodynamic coverage and bactericidal activity by physiological concentrations of oral beta-lactams against penicillin-resistant pneumococcal strains exhibiting higher amoxicillin versus penicillin MICs. Cefditoren may offer alternatives.
Assuntos
Amoxicilina/farmacologia , Atividade Bactericida do Sangue/fisiologia , Resistência às Penicilinas/efeitos dos fármacos , Penicilinas/antagonistas & inibidores , Penicilinas/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , beta-Lactamas/farmacologia , Humanos , Testes de Sensibilidade Microbiana/métodos , Resistência às Penicilinas/fisiologia , Streptococcus pneumoniae/isolamento & purificação , Streptococcus pneumoniae/fisiologiaRESUMO
The aim of this study was to explore bactericidal activity of total and free serum simulated concentrations after the oral administration of cefditoren (400 mg, twice daily [bid]) versus the oral administration of amoxicillin-clavulanic acid extended release formulation (2,000/125 mg bid) against Haemophilus influenzae. A computerized pharmacodynamic simulation was performed, and colony counts and beta-lactamase activity were determined over 48 h. Three strains were used: ampicillin-susceptible, beta-lactamase-negative ampicillin-resistant (BLNAR) (also resistant to amoxicillin-clavulanic acid) and beta-lactamase-positive amoxicillin-clavulanic acid-resistant (BLPACR) strains, with cefditoren MICs of < or =0.12 microg/ml and amoxicillin-clavulanic acid MICs of 2, 8, and 8 microg/ml, respectively. Against the ampicillin-susceptible and BLNAR strains, bactericidal activity (> or =3 log(10) reduction) was obtained from 6 h on with either total and free cefditoren or amoxicillin-clavulanic acid. Against the BLPACR strain, free cefditoren showed bactericidal activity from 8 h on. In amoxicillin-clavulanic acid simulations the increase in colony counts from 4 h on occurred in parallel with the increase in beta-lactamase activity for the BLPACR strain. Since both BLNAR and BLPACR strains exhibited the same MIC, this was due to the significantly lower (P < or = 0.012) amoxicillin concentrations from 4 h on in simulations with beta-lactamase positive versus negative strains, thus decreasing the time above MIC (T>MIC). From a pharmacodynamic point of view, the theoretical amoxicillin T>MIC against strains with elevated ampicillin/amoxicillin-clavulanic acid MICs should be considered with caution since the presence of beta-lactamase inactivates the antibiotic, thus rendering inaccurate theoretical calculations. The experimental bactericidal activity of cefditoren is maintained over the dosing interval regardless of the presence of a mutation in the ftsI gene or beta-lactamase production.
Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Genes Bacterianos/genética , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/genética , Peptidoglicano Glicosiltransferase/genética , beta-Lactamases/genética , Combinação Amoxicilina e Clavulanato de Potássio/sangue , Antibacterianos/sangue , Cefalosporinas/sangue , Contagem de Colônia Microbiana , Cinética , Testes de Sensibilidade Microbiana , Ligação Proteica , Espectrofotometria UltravioletaRESUMO
Pharmacodynamic parameters and bactericidal activity against Streptococcus pneumoniae were investigated by simulating total and free serum concentrations of cefpodoxime versus cefditoren. Total drug T>MIC against the penicillin-intermediate (PISP) and resistant (PRSP) strains were 70.6% and 42.9% for cefpodoxime, and 89.6% and 62.5% for cefditoren, respectively. Comparing activity of free versus total cefpodoxime, there were reductions of 8.5% and 19.1% in T>MIC, related to bactericidal activity reductions from approximately 4.5 to 3 log(10), and from 3 to 2.5 log(10 )against PISP and PRSP, respectively, at 10-12h. For cefditoren, reductions of 45.4% and 100% in T>MIC, were related to bactericidal activity reductions from approximately 5.5 to 2-2.5 log(10 )and from approximately 2.5 to 1.5 log(10 )against PISP and PRSP, respectively, at 10-12h. Higher differences in activity were found against the less resistant strains when comparing total versus free-drug profile.
Assuntos
Antibacterianos/farmacologia , Proteínas Sanguíneas/metabolismo , Ceftizoxima/análogos & derivados , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana , Streptococcus pneumoniae/efeitos dos fármacos , Antibacterianos/farmacocinética , Ceftizoxima/farmacologia , Simulação por Computador , Testes de Sensibilidade Microbiana , Modelos Biológicos , Ligação Proteica , CefpodoximaRESUMO
OBJECTIVES: Attempts to interpret antibiotic pharmacodynamics using reported protein binding may underestimate true activity. To elucidate this issue we examined bacterial killing kinetics at cefditoren concentrations equal to C(max) in the presence of 90% human serum or albumin at physiological concentrations. METHODS: Killing curves (final inocula of approximately 10(7) cfu/mL, cefditoren concentration of 4.2 mg/L) were performed against Streptococcus pneumoniae strains exhibiting cefditoren MICs (mg/L) of 0.12 (strain 1), 0.25 (strain 2) and 0.5 (strain 3) in different media: (i) C(max)-MH, Mueller-Hinton broth plus 5% lysed horse blood (MH), (ii) C(max)-HS, MH broth with a final human serum concentration of 90%; and (iii) C(max)-HAlb, MH broth with 4 g/dL human albumin. Killing curves were also performed with a final cefditoren concentration of 0.5 mg/L (similar to free-drug C(max) considering 88% protein binding) in MH broth (12% C(max)). RESULTS: No significant differences were found between the different media or concentrations with strain 1 (log(10) reductions >or=4 at 24 h). Against strains 2 and 3, we observed significantly higher initial inocula decreases at 24 h for C(max)-HS as compared with C(max)-HAlb or 12% C(max). Bactericidal activity (>or=3 log(10) reduction) was obtained at 24 h against the three strains only with C(max)-HS and C(max)-MH. CONCLUSIONS: The presence of physiological concentrations of human albumin, but not 90% human serum, limited bactericidal activity as did the use of concentrations similar to free-drug C(max), suggesting that extrapolation of active drug from total drug by using the protein binding rate is not an accurate method to study antibacterial activity.