RESUMO
This study aims to evaluate the antibacterial activity of Lactobacillus acidophilus, alone and in combination with ciprofloxacin, against otitis media-associated bacteria. L. acidophilus cells were isolated from Vitalactic B (VB), a commercially available probiotic product containing two lactobacilli species, L. acidophilus and Lactiplantibacillus (formerly Lactobacillus) plantarum. The pathogenic bacterial samples were provided by Al-Shams Medical Laboratory (Baqubah, Iraq). Bacterial identification and antibiotic susceptibility testing for 16 antibiotics were performed using the VITEK2 system. The minimum inhibitory concentration of ciprofloxacin was also determined. The antimicrobial activity of L. acidophilus VB1 cell-free supernatant (La-CFS) was evaluated alone and in combination with ciprofloxacin using a checkerboard assay. Our data showed significant differences in the synergistic activity when La-CFS was combined with ciprofloxacin, in comparison to the use of each compound alone, against Pseudomonas aeruginosa SM17 and Proteus mirabilis SM42. However, an antagonistic effect was observed for the combination against Staphylococcus aureus SM23 and Klebsiella pneumoniae SM9. L. acidophilus VB1 was shown to significantly co-aggregate with the pathogenic bacteria, and the highest co-aggregation percentage was observed after 24 h of incubation. The anti-biofilm activities of CFS and biosurfactant (BS) of L. acidophilus VB1 were evaluated, and we found that the minimum biofilm inhibitory concentration that inhibits 50% of bacterial biofilm (MBIC50) of La-CFS was significantly lower than MBIC50 of La-BS against the tested pathogenic bacterial species. Lactobacillus acidophilus, isolated from Vitane Vitalactic B capsules, demonstrated promising antibacterial and anti-biofilm activities against otitis media pathogens, highlighting its potential as an effective complementary/alternative therapeutic strategy to control bacterial ear infections.
Assuntos
Antibacterianos , Biofilmes , Ciprofloxacina , Lactobacillus acidophilus , Testes de Sensibilidade Microbiana , Otite Média , Probióticos , Lactobacillus acidophilus/efeitos dos fármacos , Lactobacillus acidophilus/fisiologia , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Antibacterianos/farmacologia , Otite Média/microbiologia , Ciprofloxacina/farmacologia , Probióticos/farmacologia , Humanos , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Bactérias/classificação , Doença Crônica , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Antibiose , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologiaRESUMO
Combination therapy with ampicillin plus ceftriaxone (AMP+CRO) is the first-line therapy for treating severe infections due to Enterococcus faecalis. However, the pharmacokinetic/pharmacodynamic (PK/PD) index linked to the in vivo efficacy of the combination is not yet defined, hindering dose optimization in the clinic. Because classical PK/PD indices are not directly applicable to antimicrobial combinations, two novel indices were tested in the optimized murine model of infection by E. faecalis to delineate the potentiation of AMP by CRO: the time above the CRO threshold (T>threshold) and the time above the AMP instantaneous MIC (T>MICi). The potential clinical relevance was evaluated by simulating human doses of AMP and CRO. Hill's equation fitted well the exposure-response data in terms of T>threshold, with a CRO threshold of 1 mg/L. The required exposures were 46%, 49%, and 52% for stasis and 1- and 2-log10 killing, respectively. Human ceftriaxone doses of 2 g every 12 h (q12h) would reach the target in >90% of strains with thresholds ≤64 mg/L. The AMP T>MICi index also fitted well, and the required exposures were 37%, 41%, and 46% for stasis and 1- and 2-log10 killing, respectively. In humans, the addition of CRO would allow use of lower AMP doses to reach the same T>MICi and to treat strains with higher MICs. This is the first report of the PK/PD indices and required magnitudes linked to AMP+CRO against E. faecalis; these results can be used as the basis to guide the design of clinical trials to improve combined therapy against enterococci.
Assuntos
Antibacterianos , Ceftriaxona , Humanos , Camundongos , Animais , Ceftriaxona/uso terapêutico , Antibacterianos/uso terapêutico , Enterococcus faecalis , Ampicilina/uso terapêutico , Testes de Sensibilidade Microbiana , MitomicinaRESUMO
Infections caused by KPC-producing Klebsiella pneumoniae (Kp-KPC) are associated with high mortality rates due to the increased number of resistant isolates and the scarcity of therapeutic options. This scenario reinforces the urgent need for new chemotherapeutics. Herein, we investigated the effects of 1,10-phenanthroline-5,6-dione (phendione) and its metal-based complexes, [Cu(phendione)3 ](ClO4 )2 .4H2 O (Cu-phendione) and [Ag(phendione)2 ]ClO4 (Ag-phendione), both alone and also combined with carbapenems (meropenem (MEM), and imipenem), against 46 clonally distinct clinical strains of Kp-KPC. All isolates were found to be multidrug resistant in accordance with their susceptibility patterns by disk diffusion method. Compounds geometric mean (GM)-MIC and GM-MBC values (µmol l-1 ), respectively, were: phendione, 42·06 and 71·27; Cu-phendione, 9·88 and 13·75; and Ag-phendione, 10·10 and 13·06. Higher synergism rates of MEM-containing combinations were observed by the checkerboard assay, particularly with the two metal complexes. Moreover, drug combinations were able to re-sensitize 87% of the phenotypically non-susceptible strains. Time-kill studies, with MEM plus Cu-phendione or Ag-phendione, indicated that combinations with 0·5× MIC of each agent produce synergistic effects after 9-12 h. The MEM plus Ag-phendione eradicated about 106 CFU per ml of bacteria. These findings support the effectiveness of the re-sensitizing combinatorial approach and provide evidence that phendione-based compounds offer real promise in the fight against Kp-KPC infections.
Assuntos
Carbapenêmicos/farmacologia , Complexos de Coordenação/farmacologia , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Fenantrolinas/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/farmacologia , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Humanos , Imipenem/farmacologia , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , beta-Lactamases/genética , beta-Lactamases/metabolismo , beta-Lactamases/farmacologiaRESUMO
Fosfomycin combined with other antimicrobials has shown good efficacy against multidrug-resistant (MDR) bacteria in both in vitro and clinical studies; however, the activity of fosfomycin combined with other antimicrobials against metallo-ß-lactamase (MBL)-producing Pseudomonas aeruginosa strains has not been tested. The objective of this study was to determine the synergism and optimal intravenous dosing regimens of fosfomycin with meropenem against MDR and MBL-producing P. aeruginosa strains. The MICs of both antimicrobials were determined by the checkerboard method and analyzed by two synergism tests with 19 clones of P. aeruginosa isolates, 10 of which were MBL producers. A pharmacodynamic (PD) analysis was performed for meropenem (administered at 1 g every 8 h [q8h], 1.5 g every 6 h [q6h], and 2 g q8h) and fosfomycin (administered at 4 g q8h, 4 g q6h, 6 g q8h, and 8 g q8h) regimens with a dose reduction for renal impairment by determining the probability of target attainment (PTA) for target PD indices of meropenem (the percentage of the time in a 24-h duration at which the free drug concentration remains above the MIC [fT>MIC], ≥40%) and fosfomycin (the ratio of the area under the free drug concentration-versus-time curve over 24 h and the MIC [fAUC/MIC], ≥40.8). The combination reduced the MIC50 and MIC90 by 8-fold. Seven (44%) isolates with MICs in the intermediate or resistant ranges became sensitive to meropenem. For the MBL-producing isolates, the combination resulted in 40% of isolates becoming sensitive to meropenem. The meropenem regimens reached a PTA of ≥90% (MIC = 4 µg/ml) in 6 (32%) isolates when they were used as monotherapy and 13 (68%) isolates when they were combined with fosfomycin. None of the fosfomycin monotherapy regimens reached the PTA of ≥90% (MIC = 16 µg/ml). When combined with meropenem, the fosfomycin regimens reached the PTA of ≥90% in 14 (74%) isolates. The increase in pharmacodynamic activities resulting from the synergistic action of meropenem with fosfomycin demonstrates the potential relevance of this combination to fight infections caused by MDR and MBL-producing P. aeruginosa strains.
Assuntos
Antibacterianos/farmacologia , Fosfomicina/farmacologia , Meropeném/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , beta-Lactamases/genética , Adulto , Farmacorresistência Bacteriana Múltipla , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/enzimologiaRESUMO
Pseudomonas aeruginosa es un bacilo gramnegativo, capaz de adquirir genes que codifican la producción de metalo-β-lactamasas (MBL) haciéndose multirresistente, lo cual dificulta el tratamiento de las infecciones causadas por este microorganismo. Se evaluó la actividad in vitro de piperacilina-tazobactam, en combinación con aminoglucósidos y fluoroquinolonas, en 8 aislamientos de P. aeruginosa productoras de MBL, provenientes de cuatro hospitales del oriente y sur de Venezuela mediante el método epsilométrico. Las combinaciones de antimicrobianos que presentaron mayor efecto sinérgico fueron piperacilina-tazobactam/gentamicina y piperacilina-tazobactam/ciprofloxacina en 5/8 aislamientos. La combinación de piperacilina-tazobactam/amikacina presentó sinergia en 4 de los casos y adición en los otros 4, manifestando el menor índice de concentración inhibitoria fraccionada promedio. No hubo antagonismo en ninguna combinación de antimicrobianos. Los resultados de este estudio sugieren que piperacilina-tazobactam en combinación con gentamicina, amikacina o ciprofloxacina podrían ser utilizadas como alternativas terapéuticas en las infecciones por P. aeruginosa multirresistentes productoras de MBL en los hospitales del estado Bolívar, mientras que en los hospitales del oriente de Venezuela se sugiere la combinación piperacilina-tazobactam/amikacina.
Pseudomonas aeruginosa is a gram negative bacillus able to acquire genes which codify for production of metallo-β-lactamases (MBL) becoming multiresistant, which difficults the treatment of infections produced by this microorganism. The in vitro activity of piperacilline-tazobactam, in combination with aminoglycosides and fluoroquinonolones was evaluated in 8 P. aeruginosa MBL producers obtained at four hospitals of the west and south areas of Venezuela through an epsilometric method. The antimicrobial combinations which showed the greatest synergic effect were piperacillin-tazobactam/gentamicin and piperacillin-tazobactam/amikacin in 5/8 isolates. The piperacilline-tazobactam/amikacin combination showed synergy in 4 cases and addition in the other 4, with the lowest index of mean fractionated inhibitory concentration. There was no antagonism in any of the antimicrobial combinations. The results of this study suggest that piperacilline-tazobactam in combination with gentamicin, amikacin or ciprofloxacin, could be used as therapeutic alternatives in multiresistant P. aeruginosa MBL producers at all the hospitals of Bolivar State, while in hospitals located in the west of Venezuela, the piperacilline-tazobactan/amikacin combination is suggested.