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1.
Antibiotics (Basel) ; 13(4)2024 Apr 09.
Article in English | MEDLINE | ID: mdl-38667020

ABSTRACT

Background: As the anti-biofilm pharmacokinetic/pharmacodynamic (PK/PD) properties of antibiotics are not well-defined, we have evaluated the PK/PD indices for different regimens of ceftazidime (CAZ; with/without colistin) against Pseudomonas aeruginosa biofilm. Methods: We have used the Center for Disease Control and Prevention Biofilm Reactor with two susceptible (PAO1 and HUB-PAS) and one resistant (HUB-XDR) strains of P. aeruginosa. The regimens were CAZ monotherapies (mimicking a human dose of 2 g/8 h, CAZ-IB; 6 g/daily as continuous infusion at 50 mg/L, CAZ-CI50; and 9 g/daily at 70 mg/L, CAZ-CI70) and CAZ-colistin combinations. Efficacy was correlated with the CAZ PK/PD parameters. Results: CAZ-CI70 was the most effective monotherapy against CAZ-susceptible strains (Δlog CFU/mL 54-0 h = -4.15 ± 0.59 and -3.05 ± 0.5 for HUB-PAS and PAO1, respectively; p ≤ 0.007 vs. other monotherapies), and adding colistin improved the efficacy over CAZ monotherapy. CAZ monotherapies were ineffective against the HUB-XDR strain, and CAZ-CI50 plus colistin achieved higher efficacy than CAZ-IB with colistin. The PK/PD index that correlated best with anti-biofilm efficacy was fAUC0-24h/MIC (r2 = 0.78). Conclusions: CAZ exhibited dose-dependent anti-biofilm killing against P. aeruginosa, which was better explained by the fAUC0-24h/MIC index. CAZ-CI provided benefits compared to CAZ-IB, particularly when using higher doses and together with colistin. CAZ monotherapies were ineffective against the CAZ-resistant strain, independently of the optimized strategy and only CAZ-CI plus colistin appeared useful for clinical practice.

2.
Int J Antimicrob Agents ; 62(2): 106856, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37211260

ABSTRACT

INTRODUCTION: Device-related infections are difficult to treat due to biofilms. In this setting, optimizing antibiotic efficacy is difficult as most pharmacokinetic/pharmacdynamic (PK/PD) studies have been performed on planktonic cells, and therapies are limited when multi-drug-resistant bacteria are involved. This study aimed to analyse the PK/PD indices of meropenem predicting anti-biofilm efficacy against meropenem-susceptible and meropenem-resistant strains of Pseudomonas aeruginosa. MATERIALS AND METHODS: Pharmacodynamics of meropenem dosages mimicking those of clinical practice (intermittent bolus of 2 g every 8 h; extended infusion of 2 g over 4 h every 8 h), with and without colistin, were evaluated with the CDC Biofilm Reactor in-vitro model for susceptible (PAO1) and extensively-drug-resistant (XDR-HUB3) P. aeruginosa. Efficacy was correlated with the PK/PD indices for meropenem. RESULTS: For PAO1, both meropenem regimens were bactericidal, with higher killing for extended infusion [∆log10 colony-forming units (CFU)/mL 54-0h=-4.66±0.93 for extended infusion vs ∆log10 CFU/mL 54-0h=-3.4±0.41 for intermittent bolus; P<0.001]. For XDR-HUB3, the intermittent bolus regimen was non-active, but extended infusion showed bactericidal effect (∆log10 CFU/mL 54-0h=-3.65±0.29; P<0.001). Time above minimum inhibitory concentration (f%T>MIC) had the best correlation with efficacy for both strains. The addition of colistin always improved meropenem activity, and resistant strains did not emerge. CONCLUSION: f%T>MIC was the PK/PD index that best correlated with the anti-biofilm efficacy of meropenem; it was better optimized when using the extended infusion regimen, allowing recovery of bactericidal activity in monotherapy, including activity against meropenem-resistant P. aeruginosa. Combining meropenem by extended infusion with colistin offered the most effective therapy for both strains. Optimizing meropenem dosing by extended infusion should be encouraged when treating biofilm-related infections.


Subject(s)
Colistin , Pseudomonas Infections , Humans , Meropenem/pharmacology , Colistin/pharmacology , Colistin/therapeutic use , Pseudomonas aeruginosa , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Microbial Sensitivity Tests
3.
Int J Antimicrob Agents ; 60(4): 106664, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36002115

ABSTRACT

BACKGROUND: The anti-biofilm efficacy of dalbavancin (DAL) has been evaluated in static models. The comparative activity of DAL alone and with rifampicin (RIF) against biofilm-embedded methicillin-resistant Staphylococcus aureus (MRSA) was evaluated using an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. METHODS: Two MRSA strains (HUB-4, HUB-5) were evaluated with the Calgary Device System and the dynamic CDC-Biofilm Reactor over 144 h. Dosage regimens simulated the human PK of DAL (1500 mg, single dose), vancomycin (VAN) (1000 mg/12 h) and linezolid (LZD) (600 mg/12 h), alone and with RIF (600 mg/24 h). Efficacy was evaluated by assessing log10CFU/mL changes (ΔlogCFU/mL) and screening for resistance was conducted. RESULTS: The minimal biofilm inhibitory/eradication concentrations of DAL were 0.25/16 mg/L (HUB-4) and 0.25/8 mg/L (HUB-5). In the PK/PD analysis, DAL alone showed limited efficacy but no development of resistance. Adding RIF improved the activities of DAL, VAN, and LZD, but RIF-resistant strains appeared over time in all cases. DAL-RIF was bactericidal against HUB-4 in the absence of resistance at 72 h and 144 h (ΔlogCFU/mL: -3.54±0.83, -4.32±0.12, respectively), an effect that was only achieved by LZD-RIF at 144 h (-3.33 ± 0.66). DAL-RIF activity against HUB-5 was impaired by RIF resistance to a greater extent than other combinations and this combination had no bactericidal effect. CONCLUSIONS: The anti-biofilm efficacy of DAL was improved significantly by adding RIF. Although DAL resistance did not occur, RIF resistance appeared in all combination therapies and decreased their efficacy over time. DAL-RIF in vitro treatment appears to be a promising anti-biofilm therapy, but further studies are needed to evaluate the efficacy and risk of resistance in vivo.


Subject(s)
Methicillin-Resistant Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , Biofilms , Humans , Linezolid/pharmacology , Microbial Sensitivity Tests , Rifampin/pharmacology , Teicoplanin/analogs & derivatives , Vancomycin/pharmacology
4.
Antibiotics (Basel) ; 10(5)2021 Apr 30.
Article in English | MEDLINE | ID: mdl-33946290

ABSTRACT

Daptomycin is recommended for the treatment of Staphylococcus aureus infections due to its bactericidal activity. However, its mechanism of action is poorly understood. The involvement of reactive oxygen species (ROS) in the bactericidal activity of daptomycin has been proved against planktonic S. aureus, but not against the biofilm of S. aureus. Therefore, we evaluated if ROS contributes to the effect of daptomycin against biofilm of S. aureus. Biofilms of wild type, catalase deficient and daptomycin-resistant S. aureus strains were grown in microtiter-plates. After three days, the biofilms were exposed to daptomycin with or without thiourea in the presence of a ROS indicator. After overnight incubation, the amount of ROS and the percentage of surviving bacteria were determined. The bacterial survival was higher and the amount of ROS was lower in the wild type than in the catalase deficient biofilm, demonstrating a protective effect of catalase against daptomycin. The induction of cytotoxic ROS formation by daptomycin was verified by the addition of thiourea, which reduced the amount of ROS and protected the wild type biofilm against high concentrations of daptomycin. Accordingly, only the highest concentration of daptomycin reduced the bacterial survival and increased the ROS formation in the resistant biofilm. In conclusion, daptomycin induced the production of cytotoxic levels of endogenous ROS in S. aureus biofilm and the presence of catalase protected the biofilm against the lethality of the induced ROS.

5.
Clin Chem Lab Med ; 58(2): 240-250, 2020 01 28.
Article in English | MEDLINE | ID: mdl-31469649

ABSTRACT

Background Despite that measurement uncertainty data should facilitate an appropriate interpretation of measured values, there are actually few reported by clinical laboratories. We aimed to estimate the measurement uncertainty of some ß-lactam antibiotics (ß-LA), and to evaluate the impact of reporting the measurement uncertainty on clinicians' decisions while guiding antibiotic therapy. Methods Measurement uncertainty of ß-LA (aztreonam [ATM], cefepime [FEP], ceftazidime [CAZ], and piperacillin [PIP]) values, obtained by an UHPLC-MS/MS based-method, was estimated using the top-down approach called the single laboratory validation approach (EUROLAB guidelines). Main uncertainty sources considered were related to calibrators' assigned values, the intermediate precision, and the bias. As part of an institutional program, patients with osteoarticular infections are treated with ß-LA in continuous infusion and monitored to assure values at least 4 times over the minimal inhibitory concentration (4×MIC). We retrospectively evaluated the impact of two scenarios of laboratory reports on clinicians' expected decisions while monitoring the treatment: reports containing only the ß-LA values, or including the ß-LA coverage intervals (ß-LA values and their expanded measurement uncertainties). Results The relative expanded uncertainties for ATM, FEP, CAZ and PIP were lower than 26.7%, 26.4%, 28.8%, and 25.5%, respectively. Reporting the measurement uncertainty, we identified that clinicians may modify their decision especially in cases where 4×MIC values were within the ß-LA coverage intervals. Conclusions This study provides a simple method to estimate the measurement uncertainty of ß-LA values that can be easily applied in clinical laboratories. Further studies should confirm the potential impact of reporting measurement uncertainty on clinicians' decision-making while guiding antibiotic therapy.


Subject(s)
Anti-Bacterial Agents/blood , Drug Monitoring/methods , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Aztreonam/blood , Bone Diseases, Infectious/drug therapy , Cefepime/blood , Chromatography, High Pressure Liquid , Humans , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Retrospective Studies , Tandem Mass Spectrometry , Uncertainty
6.
Article in English | MEDLINE | ID: mdl-31481437

ABSTRACT

We compared the efficacies of meropenem alone and in combination with colistin against two strains of extended-spectrum-ß-lactamase-producing Klebsiella pneumoniae, using an in vitro pharmacodynamic model that mimicked two different biofilm conditions. Meropenem monotherapy achieved remarkable efficacy (even a bactericidal effect) under all conditions, whereas colistin was almost inactive and resistance emerged. The addition of colistin to meropenem produced no relevant benefits, in contrast to experiences with other microorganisms.


Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Colistin/pharmacology , Klebsiella pneumoniae/drug effects , Meropenem/pharmacology , beta-Lactamases/metabolism , Anti-Bacterial Agents/administration & dosage , Colistin/administration & dosage , Drug Resistance, Multiple, Bacterial , Drug Therapy, Combination , Klebsiella pneumoniae/enzymology , Klebsiella pneumoniae/ultrastructure , Meropenem/administration & dosage , Microscopy, Electron, Scanning , beta-Lactam Resistance
7.
Int J Antimicrob Agents ; 53(5): 612-619, 2019 May.
Article in English | MEDLINE | ID: mdl-30682497

ABSTRACT

OBJECTIVES: Ceftolozane/tazobactam is a potential tool for infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa (P. aeruginosa), but its efficacy against some difficult-to-treat infections has not been well defined. METHODS: Using an in vitro pharmacodynamic biofilm model, this study evaluated the comparative efficacy of ceftolozane/tazobactam against MDR/extensively drug-resistant (XDR) P. aeruginosa strains, alone and in combination with colistin. Simulated regimens of ceftolozane/tazobactam (2 g/1 g every 8 h), meropenem (2 g every 8 h) and ceftazidime (2 g every 8 h), alone and in combination with colistin (continuous infusion) were evaluated against three colistin-susceptible and ceftazidime-resistant strains: MDR-HUB1, ceftolozane/tazobactam-susceptible and meropenem-susceptible; XDR-HUB2, ceftolozane/tazobactam-susceptible and meropenem-resistant; MDR-HUB3, ceftolozane/tazobactam-resistant and meropenem-susceptible. Antibiotic efficacy was evaluated by decreases in bacterial counts (Δlog CFU/mL) from biofilm-embedded bacteria over 54 h. Resistance emergence was screened. RESULTS: Among monotherapies, ceftolozane/tazobactam had low killing but no resistance appeared, ceftazidime was ineffective, colistin was initially effective but regrowth and resistance occurred, and meropenem was bactericidal against carbapenem-susceptible strains. Ceftolozane/tazobactam plus colistin was the most effective combination against the meropenem-resistant XDR-HUB2 strain (Δlog CFU/mL 54-0 h = -4.42 vs. -3.54 for meropenem-colistin; P = 0.002), whereas this combination against MDR-HUB1 (-4.36) was less effective than meropenem-colistin (-6.25; P < 0.001). Ceftolozane/tazobactam plus colistin was ineffective against the ceftolozane/tazobactam-resistant strain; meropenem plus colistin was the most bactericidal therapy (-6.37; P < 0.001 vs. others). Combinations of active beta-lactams plus colistin prevented the emergence of colistin-resistant strains. CONCLUSIONS: Combinations of colistin plus ceftolozane/tazobactam and meropenem were the most appropriate treatments for biofilm-related infections caused by XDR and MDR P. aeruginosa strains, respectively. These combinations could be considered as potential treatment options for these difficult to treat infections.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Biofilms/drug effects , Cephalosporins/administration & dosage , Colistin/administration & dosage , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Tazobactam/administration & dosage , beta-Lactamase Inhibitors/administration & dosage , Biofilms/growth & development , Drug Resistance, Bacterial , Drug Therapy, Combination/methods , Humans , Models, Theoretical , Pseudomonas aeruginosa/growth & development
8.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 36(6): 362-365, jun.-jul. 2018. tab
Article in English | IBECS | ID: ibc-176587

ABSTRACT

INTRODUCTION: The anti-staphylococcal efficacy of cotrimoxazole in the setting of difficult-to-treat infections seems to be compromised by large amounts of pus and devitalized tissue, and, therefore, high levels of thymidine. Our objective was to evaluate the activity of cotrimoxazole against a staphylococcal foreign-body infection experimental model, which also yields significant quantities of thymidine. MATERIAL AND METHODS: We used a rat tissue-cage model of infection (with high inherent thymidine levels) caused by a strain of methicillin-susceptible Staphylococcus aureus (MSSA; ATCC 29213). MIC values were determined (microdilution method) and compared in the presence or absence of tissue-cage fluid samples. RESULTS: The inefficacy of cotrimoxazole was found to be similar to that of the control group. The MIC of cotrimoxazole was 4-8 fold higher in the presence of rat tissue-cage fluid. CONCLUSIONS: The inefficacy of cotrimoxazole in our foreign-body infection model by MSSA, and the probable negative impact of the presence of thymidine on its efficacy, challenge the use of this drug in acute phases of foreign-body infections. It should be reserved as an alternative treatment when the infection is more controlled


INTRODUCCIÓN: La eficacia antiestafilocócica del cotrimoxazol en el marco de las infecciones de difícil tratamiento parece alterarse por la presencia de grandes cantidades de pus y tejido desvitalizado que condicionan unos niveles elevados de timidina. Nuestro objetivo fue evaluar la actividad de cotrimoxazol en un modelo experimental de infección estafilocócica por cuerpo extraño, que también produce grandes cantidades de timidina. MATERIAL Y MÉTODOS: Utilizamos un modelo de infección de caja subcutánea en rata (con elevados niveles inherentes de timidina) producida por una cepa de S. aureus sensible a meticilina (SASM; ATCC29213). Se determinaron los valores de CMI (método de microdilución) y se compararon en presencia del líquido de las cajas o sin él. RESULTADOS: Cotrimoxazol mostró una ineficacia similar a la de un grupo control. El valor de su CMI aumentó de 4 a 8 veces en presencia del líquido de las cajas. CONCLUSIONES: La ineficacia de cotrimoxazol en nuestro modelo de infección de cuerpo extraño por SASM y el probable impacto negativo de la presencia de timidina en su eficacia, cuestionan el uso de este antibiótico en las fases agudas de estas. Por todo ello, cotrimoxazol debería reservarse como tratamiento alternativo cuando la infección esté ya más controlada


Subject(s)
Animals , Rats , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use , Foreign Bodies/drug therapy , Staphylococcal Infections/drug therapy , Disease Models, Animal
9.
Front Microbiol ; 9: 919, 2018.
Article in English | MEDLINE | ID: mdl-29867830

ABSTRACT

The rate of invasive group B Streptococcus (GBS) infections is steadily increasing, particularly in older persons and in adults with diabetes and other comorbidities. This population includes persons with a foreign body (e.g., who have undergone arthroplasty). In a rat tissue cage model, we evaluated the efficacy of adjunctive gentamicin (GEN) administered systemically (5 mg/kg body weight) every 24 h, or locally (12.5 mg/L tissue cage concentration) every 24 or 72 h, in combination with penicillin (PEN) administered systemically (250,000 IU/kg body weight three times per day). The efficacy was evaluated on two different sessile forms of GBS: transition (i.e., in between planktonic and biofilm) and biofilm. After 3 days of treatment, the mean bacterial load reduction of transition-form GBS was greater in all PEN-GEN combination groups than in the PEN monotherapy group (P ≤ 0.03). The 6-day regimen decreased the bacterial load significantly in comparison to the 3-day regimen, irrespective of growth form and adjunctive GEN (P < 0.01). After 6 days of treatment, the mean reduction in transition-form GBS was greater with PEN plus GEN administered locally every 24 h than with PEN monotherapy (P = 0.03). These results were not confirmed with biofilm GBS. The difference in mean bacterial load reduction between all PEN-GEN and PEN monotherapy groups was <100 CFU/mL. Hence, synergy criteria were not fulfilled. Adjunctive systemic GEN consists of potential side effects and showed poor efficacy in this study. Combining systemic PEN and local GEN has a potential application in the treatment of streptococcal implant-associated infections.

10.
Int J Antimicrob Agents ; 51(6): 854-861, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29374577

ABSTRACT

Combinations of linezolid (LZD) or trimethoprim/sulfamethoxazole (SXT) plus rifampicin (RIF) are alternative oral treatments for staphylococcal prosthetic joint infections (PJIs) when fluoroquinolones are not possible to use, but there is limited evidence regarding their activity. This study evaluated the efficacy of LZD and SXT, alone and in combination with RIF, against Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic biofilm model. Using the CDC Biofilm Reactor® system, simulated regimens of LZD (600 mg every 12 h), SXT (160/800 mg every 8 h) and levofloxacin (LVX) (750 mg/day), alone and in combination with RIF (600 mg/day), were evaluated against one methicillin-susceptible S. aureus (MSSA) and one methicillin-resistant S. aureus (MRSA) strain. Antibiotic efficacy was evaluated by the decrease in planktonic bacterial counts from medium and biofilm-embedded bacteria from coupons over 56 h. Resistant strains were screened. In both strains, SXT alone was ineffective and LZD presented low activity, but no resistance emerged. Combinations with RIF significantly increased the antibiofilm efficacy against MSSA (Δlog CFU/mL 56h-0h: SXT + RIF, -2.9 and LZD + RIF, -3.1), but RIF-resistant strains appeared with SXT + RIF. Against MRSA, LZD + RIF (-3.1) protected against the emergence of resistance and was more effective than SXT + RIF (-0.6; P <0.05), in which RIF-resistant strains were again detected. LVX + RIF confirmed its high efficacy against biofilm-embedded bacteria, this being the most effective therapy (-5.1 against MSSA). The emergence of RIF-resistant strains with SXT + RIF poses serious concerns for its use in clinical practice. Interestingly, LZD + RIF appears to be an appropriate alternative for PJI caused by LVX-resistant S. aureus.


Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/growth & development , Linezolid/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Rifampin/pharmacology , Sulfamethizole/pharmacology , Trimethoprim/pharmacology , Biofilms/drug effects , Drug Combinations , Humans , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Microbial Sensitivity Tests , Prosthesis-Related Infections/drug therapy , Prosthesis-Related Infections/microbiology
11.
Article in English, Spanish | MEDLINE | ID: mdl-28818482

ABSTRACT

INTRODUCTION: The anti-staphylococcal efficacy of cotrimoxazole in the setting of difficult-to-treat infections seems to be compromised by large amounts of pus and devitalized tissue, and, therefore, high levels of thymidine. Our objective was to evaluate the activity of cotrimoxazole against a staphylococcal foreign-body infection experimental model, which also yields significant quantities of thymidine. MATERIAL AND METHODS: We used a rat tissue-cage model of infection (with high inherent thymidine levels) caused by a strain of methicillin-susceptible Staphylococcus aureus (MSSA; ATCC 29213). MIC values were determined (microdilution method) and compared in the presence or absence of tissue-cage fluid samples. RESULTS: The inefficacy of cotrimoxazole was found to be similar to that of the control group. The MIC of cotrimoxazole was 4-8 fold higher in the presence of rat tissue-cage fluid. CONCLUSIONS: The inefficacy of cotrimoxazole in our foreign-body infection model by MSSA, and the probable negative impact of the presence of thymidine on its efficacy, challenge the use of this drug in acute phases of foreign-body infections. It should be reserved as an alternative treatment when the infection is more controlled.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Foreign Bodies/complications , Staphylococcal Infections/drug therapy , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use , Wound Infection/drug therapy , Animals , Anti-Bacterial Agents/pharmacokinetics , Bacterial Load , Diffusion Chambers, Culture , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Rats , Staphylococcal Infections/microbiology , Thymidine/analysis , Treatment Failure , Trimethoprim, Sulfamethoxazole Drug Combination/pharmacokinetics , Wound Infection/etiology , Wound Infection/metabolism
12.
Enferm Infecc Microbiol Clin ; 35 Suppl 1: 28-32, 2017 Jan.
Article in Spanish | MEDLINE | ID: mdl-28129818

ABSTRACT

Multiresistant Gram-positive infections continue to pose a major clinical challenge and the development of new antibiotics is always desirable. Dalbavancin is a lipoglycopeptide with a prolonged half-life that allows long dosing intervals. In experimental models, its activity has been evaluated in distinct models and microorganisms, which limits the conclusions that can be drawn; however, the largest number of studies have been conducted in Staphylococcus aureus infection. Overall, dalbavancin has shown concentration-dependent efficacy and the parameters best explaining its activity are maximal pharmacodynamic concentration/minimal inhibitory concentration and the area under the curve/minimal inhibitory concentration. In these experimental models, dalbavancin has shown good distribution, a prolonged half-life in all animal species and efficacy that is mostly similar to that of previous glycopeptides but with lower doses and with longer dosing intervals. Of note, the efficacy of dalbavancin is not altered by methicillin resistance or the glycopeptide sensitivity of S. aureus. In the case of difficult-to-treat staphylococcal infections (eg, endocarditis, foreign body infections), an adequate dosing interval and high dosage seem to play an important role in the efficacy of the drug. All in all, experimental models can still provide greater knowledge of this new antibiotic to guide clinical research and determine its role in the treatment of distinct infections produced by Gram-positive microorganisms.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Gram-Positive Bacterial Infections/drug therapy , Teicoplanin/analogs & derivatives , Animals , Disease Models, Animal , Teicoplanin/therapeutic use
13.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 35(supl.1): 28-32, ene. 2017. tab
Article in Spanish | IBECS | ID: ibc-170731

ABSTRACT

Las infecciones producidas por microorganismos Gram positivos multirresistentes siguen siendo un problema clínico de gran relevancia, por lo que la incorporación de nuevos antibióticos en este ámbito es siempre deseable. Dalbavancina es un lipoglucopéptido con una prolongada vida media que permite largos intervalos entre sus dosificaciones. A nivel experimental, su actividad ha sido evaluada con una miscelánea de modelos y de microorganismos, hecho que limita las conclusiones que pueden extraerse, si bien la mayor experiencia se ha obtenido en la infección producida por Staphylococcus aureus. Globalmente, dalbavancina ha mostrado una eficacia dependiente de la concentración, y los parámetros farmacodinámicos concentración máxima/concentración mínima inhibitoria y área bajo la curva/concentración mínima inhibitoria son los que mejor explican su actividad. En estos modelos experimentales, dalbavancina ha presentado una buena difusión, una prolongada vida media en todas las especies animales y una eficacia mayoritariamente similar a los glucopéptidos previos mediante el uso de dosis menores con intervalos de administración alargados. De forma destacable, la eficacia de dalbavancina no se ha visto alterada por el grado de resistencia a meticilina o de sensibilidad a glucopéptidos de S. aureus. En el caso particular de las infecciones estafilocócicas consideradas de "difícil tratamiento" (p. ej., endocarditis, infecciones de cuerpo extraño), un intervalo adecuado entre las administraciones y una dosificación elevada parecen tener un papel relevante en la eficacia de dalbavancina. Con todo, los modelos experimentales aún deberían aportar un mayor conocimiento de este nuevo antibiótico, para orientar la investigación clínica y determinar el papel que dalbavancina debe tener en el tratamiento de distintas infecciones y microorganismos Gram positivos (AU)


Multiresistant Gram-positive infections continue to pose a major clinical challenge and the development of new antibiotics is always desirable. Dalbavancin is a lipoglycopeptide with a prolonged half-life that allows long dosing intervals. In experimental models, its activity has been evaluated in distinct models and microorganisms, which limits the conclusions that can be drawn; however, the largest number of studies have been conducted in Staphylococcus aureus infection. Overall, dalbavancin has shown concentration dependent efficacy and the parameters best explaining its activity are maximal pharmacodynamic concentration/minimal inhibitory concentration and the area under the curve/minimal inhibitory concentration. In these experimental models, dalbavancin has shown good distribution, a prolonged halflife in all animal species and efficacy that is mostly similar to that of previous glycopeptides but with lower doses and with longer dosing intervals. Of note, the efficacy of dalbavancin is not altered by methicillin resistance or the glycopeptide sensitivity of S. aureus. In the case of difficult-to-treat staphylococcal infections (eg, endocarditis, foreign body infections), an adequate dosing interval and high dosage seem to play an important role in the efficacy of the drug. All in all, experimental models can still provide greater knowledge of this new antibiotic to guide clinical research and determine its role in the treatment of distinct infections produced by Gram-positive microorganisms (AU)


Subject(s)
Animals , Glycopeptides/therapeutic use , Models, Animal , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/veterinary , Methicillin-Resistant Staphylococcus aureus , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Staphylococcus aureus , Staphylococcus aureus/isolation & purification , Streptococcus pneumoniae , Streptococcus pneumoniae/isolation & purification
14.
Med Microbiol Immunol ; 206(1): 31-39, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27639707

ABSTRACT

Using a tissue cage infection rat model, we test the anti-biofilm effect of clarithromycin on the efficacy of daptomycin and a daptomycin + rifampicin combination against methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). In vitro: kill curves, daptomycin exposure studies and clarithromycin activity against biofilm were studied. In vivo: the efficacies of clarithromycin, daptomycin or daptomycin + clarithromycin, daptomycin + rifampicin and daptomycin + rifampicin + clarithromycin combinations were evaluated. In vitro: the addition of clarithromycin to daptomycin improved its activity only against one MRSA strain. Changes in daptomycin MIC values appeared more quickly in MSSA than in MRSA strain, and this was not modified by clarithromycin. Clarithromycin prevented biofilm formation but did not eradicate it. In vivo: the daptomycin + rifampicin combination was the most effective treatment and was not improved by the addition of clarithromycin. Daptomycin and daptomycin + clarithromycin had similar effectiveness; the combination protected against the appearance of daptomycin resistance only in one MRSA strain. Using a staphylococcal foreign-body infection model, we observed a slight effect with the addition of clarithromycin to daptomycin, which resulted in protection against the appearance of daptomycin-resistant strains. However, efficacy was not improved. Overall, our findings do not support a relevant clinical role for macrolides in treating device-related staphylococcal infections based on their anti-biofilm effect.


Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Clarithromycin/administration & dosage , Foreign Bodies/complications , Staphylococcal Infections/prevention & control , Staphylococcus aureus/drug effects , Animals , Biofilms/growth & development , Clarithromycin/pharmacology , Daptomycin/administration & dosage , Daptomycin/pharmacology , Disease Models, Animal , Drug Interactions , Drug Therapy, Combination/methods , Microbial Sensitivity Tests , Microbial Viability/drug effects , Rats , Rifampin/administration & dosage , Rifampin/pharmacology , Staphylococcus aureus/physiology , Treatment Outcome
15.
Int J Antimicrob Agents ; 46(2): 189-95, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26051988

ABSTRACT

Whilst levofloxacin (LVX) in combination with rifampicin (RIF) is considered the optimal treatment for prosthetic joint infection (PJI) caused by meticillin-susceptible Staphylococcus aureus (MSSA), no therapeutic alternatives have been accurately evaluated. Based on the high effectiveness of the combination of daptomycin (DAP) plus RIF against meticillin-resistant S. aureus (MRSA) in this setting, in this study the efficacy of DAP+RIF and DAP+LVX combinations was tested as alternative therapies for foreign-body infections (FBIs) caused by MSSA. A tissue-cage infection model was performed using an MSSA strain. Male Wistar rats were treated for 7 days with LVX, DAP, RIF or the combinations LVX+RIF, DAP+RIF and DAP+LVX. Antibiotic efficacy was evaluated by bacterial counts from tissue cage fluid (TCF) and the cure rate was determined from adhered bacteria. Resistance was screened. Monotherapies were less effective than combinations (P<0.05), and resistance to DAP and RIF emerged. DAP+RIF (decrease in bacterial counts in TCF, -4.9logCFU/mL; cure rate, 92%) was the most effective therapy (P<0.05). There were no differences between LVX+RIF (-3.4logCFU/mL; 11%) and DAP+LVX (-3.3logCFU/mL; 47%). No resistant strains appeared with combined therapies. In conclusion, the combinations DAP+RIF and DAP+LVX showed good efficacy and prevented resistance. DAP+RIF provided higher efficacy than LVX+RIF. These DAP combinations were efficacious alternatives therapies for MSSA FBI. Further studies should confirm whether DAP+RIF may be useful as a first-line therapy in the setting of PJI caused by MSSA.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Complementary Therapies/methods , Daptomycin/administration & dosage , Foreign Bodies/complications , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Animals , Colony Count, Microbial , Disease Models, Animal , Drug Therapy, Combination/methods , Levofloxacin/administration & dosage , Male , Rats, Wistar , Rifampin/administration & dosage , Treatment Outcome
16.
Antimicrob Agents Chemother ; 58(9): 5576-80, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24957833

ABSTRACT

We compared the efficacies of daptomycin (doses equivalent to 8 to 10 mg/kg of body weight/day in humans) and cloxacillin alone with those of cloxacillin-rifampin and cloxacillin-daptomycin combinations, using a tissue cage methicillin-susceptible Staphylococcus aureus (MSSA) infection model. Monotherapies were less effective than combinations (P<0.05), and daptomycin resistance emerged. Cloxacillin-daptomycin proved as effective as cloxacillin-rifampin and prevented the appearance of resistance; this combination may be an alternative anti-MSSA therapy, which may offer greater benefits in the early treatment of prosthetic joint infections (PJI).


Subject(s)
Cloxacillin/therapeutic use , Daptomycin/therapeutic use , Rifampin/therapeutic use , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/therapeutic use , Cloxacillin/pharmacokinetics , Daptomycin/pharmacokinetics , Drug Combinations , Microbial Sensitivity Tests , Rats , Rats, Wistar , Rifampin/pharmacokinetics
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