Development of a method to quantify clindamycin in vitreous humor of rabbits' eyes by UPLC-MS/MS: application to a comparative pharmacokinetic study and in vivo ocular biocompatibility evaluation.

Ocular toxoplasmosis may result in uveitis in the posterior segment of the eye, leading to severe visual complications. Clindamycin-loaded poly(lactide-co-glycolide) (PLGA) implants could be applied to treat the ocular toxoplasmosis. In this study, the pharmacokinetic profiles of the drug administrated by PLGA implants and by intravitreal injections in rabbits' eyes were evaluated. The implant released the drug for 6 weeks while the drug administrated by intravitreal injections remained in the vitreous cavity for 2 weeks. Compared to the injected drug, the implants containing clindamycin had higher values of area under the curve (AUC) (39.2 vs 716.7 ng week mL(-1)) and maximum vitreous concentration (Cmax) (8.7 vs 13.83 ng mL(-1)). The implants prolonged the delivery of clindamycin and increased the contact of the drug with the eyes' tissues. Moreover, the in vivo ocular biocompatibility of the clindamycin-loaded PLGA implants was evaluated regarding to the clinical examination of the eyes and the measurement of the intraocular pressure (IOP) during 6 weeks. The implantable devices caused no ocular inflammatory process and induced the increase of the IOP in the fourth week of the study. The IOP augmentation could be related to the maximum concentration of clindamycin released from the implants. In conclusion, the PLGA implants based on clindamycin may be a therapeutic alternative to treat ocular toxoplasmosis.

Actividad de daptomicina, ciprofloxacino, clindamicina y cotrimoxazol frente a diferentes cepas de Staphylococcus coagulasa negativo con sensibilidad conservada y disminuida para vancomicina / Activity of daptomycin, ciprofloxacin, clindamycin and cotrimoxazole against coagulase-negative Staphylococcus strains with diminished susceptibility to vancomycin

Introducción. Los Staphylococcus coagulasa negativos(SCN) se han convertido en uno de los patógenos nosocomialesmás frecuentes y con una elevada tasa de mortalidad, debido ala mayor supervivencia de enfermos graves, estados deinmunosupresión prolongados y presencia de materialesextraños, como catéteres, prótesis, marcapasos, etc. Además,existe un importante aumento en las resistencias frente a losantimicrobianos, sobre todo betalactámicos, y se hadocumentado cómo el incremento en la CMI para vancomicinaconlleva una pérdida de su eficacia clínica, por lo que se buscannuevas alternativas terapéuticas, como daptomicina.El objetivo de este trabajo es estudiar la actividad dedaptomicina, ciprofloxacino, clindamicina y cotrimoxazol endos grupos de SCN clínicamente significativos, uno con CMI90para vancomicina ≤ 1 mg/L y el otro con CMI90 de 2 mg/L.Métodos. Se identificaron y estudiaron las CMI90 paraciprofloxacino, clindamicina y cotrimoxazol de 54 cepas de SCNclínicamente significativos mediante los paneles combo 22 deMicroScan (Dade behring, Siemens). La CMI90 para daptomicinase realizó mediante Etest (AB BioMèrieux, Solna, Suecia) enplacas de Mueller Hinton (BioMèrieux, Francia).Resultados. En el Grupo I (CMI90 para vancomicina ≤ 1mg/L) se estudiaron 19 cepas y en el Grupo II (CMI90 paravancomicina = 2 mg/L) se estudiaron 35 cepas. Expresadas enmg/L, los rangos de CMI90 para daptomicina fueron 0.047-0.5en el Grupo I y 0,064-0,5 en el Grupo II. Para ciprofloxacinohubo 8 cepas sensibles y 11 resistentes en el Grupo I y 10sensibles y 25 resistentes en el Grupo II. Para clindamicina hubo7 cepas sensibles y 12 resistentes en el Grupo I y 16 sensibles y19 resistentes en el Grupo II. Finalmente, Para cotrimoxazolhubo 10 cepas sensibles y 9 resistentes en el Grupo I y 19sensibles y 16 resistentes en el Grupo II...(AU)

Introduction. Coagulase Negative Staphylococci (CNS)have become one of the most common nosocomial pathogensand it has a high mortality rate due to the increased ofseriously ill patients survival, long states immunosuppressionand presence of foreign bodies, such as catheters, prostheses,pacemakers, etc. In addition, there is a significant increase inresistance to antimicrobial drugs, especially beta-lactams, andthe increase in the MIC for vancomycin leads to a loss ofclinical efficacy. This necessitates the search for newtherapeutic alternatives, such as daptomycin.The aim of this paper is to study the activity ofdaptomycin, ciprofloxacin, clindamycin and cotrimoxazole intwo groups of clinically significant CNS. a MIC90 withvancomycin ≤ 1 mg/L and the other with MIC90 2 mg/L.Methods. We identified and studied MIC90 tociprofloxacin, clindamycin and cotrimoxazole from 54 strainsof clinically significant by the CNS Combo 22 Microscan panels(Dade Behring, Siemens). The MIC90 for daptomycin wasperformed using Etest (AB BioMérieux, Solna, Sweden) onMueller Hinton plates (BioMérieux, France).Results In Group I (vancomycin MIC90 ≤ 1 mg/L) were 19 strains whereas in Group II (vancomycin MIC90 = 2 mg/L) were35 strains. Expressed in mg/L, MIC90 ranges for daptomycinwere 0.047-0.5 in Group I and 0.064-0.5 in Group II. Forciprofloxacin were 8 sensitive strains and 11 resistant in GroupI and 10 sensitive and 25 resistant in Group II. For clindamycinwere 7 sensitive strains and 12 resistant in Group I and 16sensitive and 19 resistant in Group II. Finally, for cotrimoxazolewere 10 sensitive strains and 9 resistant in Group I and 19sensitive and 16 resistant in Group II...(AU)

Utilización de antimicrobianos en las infecciones odontogénicas en niños y adolescentes: análisis farmacocinético/farmacodinámico (PK/PD) / Antibiotic therapy in odontogenic infections in children and adolescents: pharmacokinetic/pharmacodynamic analysis

INTRODUCCIÓN. El objetivo de este estudio es evaluar la eficacia de los tratamientos más utilizados en infecciones odontogénicas en niños y adolescentes aplicando criterios farmacocinéticos/farmacodinámicos (PK/PD).MÉTODOS. Se han simulado las curvas de concentración plasmática libre-tiempo a partir de parámetros farmacocinéticos medios de amoxicilina, amoxicilina-ácido clavulánico, cefuroxima axetilo, espiramicina, clindamicina, azitromicina y metronidazol. Para los antibióticos con actividad dependiente del tiempo, se ha calculado el tiempo durante el cual las concentraciones permanecen por encima de la concentración inhibitoria mínima (CIM90)de los microorganismos (T > CIM). Para los antimicrobianos con actividad dependiente de la concentración, se ha calculado el cociente entre el área bajo la curva y la CIM90 (ABC/CIM90).RESULTADOS. Con amoxicilina-ácido clavulánico(80 mg/kg/día) se han obtenido índices de eficacia adecuados frente a los microorganismos estudiados(T > CIM > 40%), excepto para Veillonella spp. Clindamicina (40 mg/kg/día) también ha presentado índices PK/PD adecuados frente a la mayoría de los patógenos, excepto Lactobacillus, Actinobacillus actinomycetemcomitans, Peptostreptococcus resistente a penicilina y Eikenellacorrodens. Con dosis altas de amoxicilina los resultados nohan sido satisfactorios frente a varias especies bacterianas. Con azitromicina y metronidazol no se han alcanzado valores adecuados frente a la mayoría de patógenos (ABC/CIM90 < 25).CONCLUSIÓN. El tratamiento empírico más adecuado en infecciones odontogénicas en niños y adolescentes esamoxicilina-ácido clavulánico en altas dosis de amoxicilina, aunque se puede utilizar como alternativa clindamicina. Sería conveniente confirmar estos resultados mediante ensayos clínicos, para cuyo diseño y evaluación podría serde gran utilidad la aplicación de estudios PK/PD(AU)

INTRODUCTION. The objective of this study was to evaluate the efficacy of the most commonly used antimicrobial treatments in odontogenic infections in children and adolescents on the basis of pharmacokinetic/pharmacodynamic (PK/PD) criteria. METHODS. Unbound drug plasma concentration-time curves were simulated with mean population pharmacokinetic parameters of amoxicillin, co-amoxiclav, cefuroxime axetil, spiramycin, clindamycin, azithromycin, and metronidazole. For drugs showing time-dependent antibacterial killing, the time above MIC90 of the pathogens studied was calculated (T > MIC). For drugs with concentration dependent bactericidal activity, the area under the concentration-time curve (AUC)/MIC90 ratio was calculated. RESULTS. Adequate efficacy indexes (T > MIC > 40%) against all the microorganisms examined with the exception of Veillonella spp. were obtained with co-amoxiclav(80 mg/kg/day). Clindamycin (40 mg/kg/day) obtained ad equate PK/PD indexes except for Lactobacillus, Actinobacillus actinomy cetemcomitans, penicillin-resistant Peptostreptococcus, and Eikenella corrodens. High-dose amoxicillin yielded unsatisfactory results against many bacterial species. Azithromycin and metronidazole showed inadequate efficacy indexes against the majority of pathogens studied (AUC/MIC90 < 25).CONCLUSION. When antibiotic therapy is needed for odontogenic infections in children and adolescents, the most active empirical therapeutic choice is co-amoxiclav with high doses of amoxicillin. Clindamycin can be used as an alternative option. These results should be confirmed inclinical trials, in which the PK/PD approach could be useful for the design and assessment of results (AU)

[Pharmacokinetics and pharmacodynamics of antimicrobial therapy used in child osteoarticular infections]. / Pharmacocinétique et pharmacodynamique sériques des antibiotiques utilisés dans les infections ostéoarticulaires de l'enfant.

The progress in the knowledge of antibiotic action mechanisms have led to determine phamacodynamic/pharmacokinetic (PK/PD) parameters predictive of antibiotic efficacy in bacterial infections. According to the antibiotic compound, the implicated bacterial specie, the localization of the infection, the severity of the disease, these parameters could vary. The PK/PD parameters described in this paper focus only on blood compartment and S. aureus, (main bacteria implicated in bone and joint tissue infections). All beta-lactamase resistant beta-lactam compounds given by IV route, if they are prescribed at the good dosage and frequency, fulfill these PK/PD parameters. In contrast, by oral route, M penicillins and cefuroxime-axetil should not be considered as acceptable regimens. Only amoxicillin-clavulanate and some first generation cephalosporin compounds fulfill the PK/PD parameters predictive of clinical efficacy if S. aureus strains are methicillin susceptible and dosages of cephalosporins are increased. Clindamycin is a very interesting alternative, if the strains are susceptible to macrolides.

[Pharmacokinetic/pharmacodynamic analysis of antibiotic therapy in dentistry and stomatology]. / Análisis farmacocinético/farmacodinámico (PK/PD) de la antibioterapia en odontoestomatología.

INTRODUCTION: This study evaluates the efficacy of various antimicrobial treatments for orofacial infections on the basis of pharmacokinetic/pharmacodynamic (PK/PD) criteria. METHODS: A complete a literature search was undertaken to establish the MIC90 values of the five microorganisms most frequently isolated in odontogenic infections and the pharmacokinetic parameters of 13 antibiotics used in these infections. Pharmacokinetic simulations were then carried out with mean population parameters and efficacy indexes were calculated for the 47 treatment regimens analyzed. For drugs showing time-dependent antibacterial killing, the time above MIC (t > MIC) was calculated. For drugs with concentration-dependent bactericidal activity, the AUC/MIC was calculated. RESULTS: Amoxicillin-clavulanic (500 mg/8 h or 1000 mg/12 h) and clindamycin (300 mg/6 h) in the time-dependent killing group and moxifloxacin (400 mg/24 h) in the concentration-dependent group showed adequate efficacy indexes against the five pathogens considered to be the most commonly implicated in odontogenic infections. The spiramycin plus metronidazole combination, present in the commercial formulation Rhodogyl, did not reach satisfactory PK/PD indexes. CONCLUSION: PK/PD indexes, which are useful predictors of the potential efficacy of antibacterial therapy, were used with ontogenic infections in the present study. The PK/PD simulations showed that amoxicillin-clavulanic, clindamycin and moxifloxacin were the most suitable antibiotics for this kind of infection. Clinical trials are required to confirm that this methodology is useful in these pathologic processes.

Adsorption and release of antibiotics from morselized cancellous bone. In vitro studies of 8 antibiotics.

We studied the basic release patterns of antibiotics from cancellous bone in vitro. Antibiotic-impregnated bone was compressed into a wire-mesh cylinder and the release of antibiotic was assessed by two different in vitro methods: agar diffusion and broth elution. The zones of inhibition were measured on seeded agar and the amounts of antibiotics released in elution tubes were assessed by a bioassay. The study continued for 21 days with daily transfer of the cylinders. The results indicated that benzylpenicillin, dicloxacillin, cephalotin, netilmicin, clindamycin, vancomycin, ciprofloxacin and rifampicin were adsorbed to cancellous bone in vitro. Compared to broth elution, agar diffusion showed a prolonged period of release, owing to the small amounts of antibiotic leaking out of the cylinder into the agar. The betalactams had antibacterial activity in broth for a shorter time than the other antibiotics. The release patterns of the betalactams were similar, in spite of their differences in thermal stability. Only rifampicin showed a concentration higher than MIC for longer than 21 days.

Serum concentrations and ex vivo inhibitory/bactericidal activity of clindamycin after administration of two oral dosages.

Two dosages of clindamycin, 300 and 600 mg, were given orally to 10 patients each. The patients were admitted for minor elective surgery. Their mean age was 39.3 years; mean weight was 67.5 kg. None of them had taken antibiotics for at least 1 month. After administration of a single dose, blood samples were obtained at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h after dosing. Drug levels were determined by the bioassay method using Micrococcus luteus as test organism. Serum inhibitory and bactericidal activities against five isolates each of Staphylococcus aureus and Streptococcus pyogenes were determined by the microdilution method according to the National Committee for Clinical Laboratory Standards guidelines. The mean peak serum level was 3.4 mg/l for the 300-mg dose and 4.8 mg/l for the 600-mg dose. The mean reciprocal peak inhibitory titers for the 300-/600-mg doses were 13.7/23.8 and 15.2/34.7 against S. aureus and S. pyogenes, respectively. Most serum samples did not show bactericidal activity against S. aureus.

Antibiotic-impregnated heart valve sewing rings for treatment and prophylaxis of bacterial endocarditis.

Prosthetic heart valve sewing rings were impregnated with gentamicin crobefat (EMD 46217), a poorly soluble gentamicin salt, gentamicin sulfate, and clindamycin palmitate to prevent early prosthetic endocarditis. MICs and MBCs of gentamicin and/or clindamycin were tested against several pathogens of early prosthetic endocarditis. The combination of gentamicin and clindamycin was found to be effective against most relevant bacterial pathogens. With an in vitro pharmacokinetic model, the antibacterial activity of gentamicin and clindamycin was tested against Staphylococcus aureus and Escherichia coli. High gentamicin levels over the first 24 h were required for a strong reduction of bacterial counts of both strains. Equal amounts of gentamicin and clindamycin sustained the antibacterial effect and prevented regrowth. The most effective release curves of gentamicin and clindamycin found with an in vitro model were used for monitoring release profiles of these antibiotics from impregnated sewing rings by investigating combinations of gentamicin sulfate, gentamicin crobefat, and clindamycin palmitate. Sewing rings impregnated with 4 mg of gentamicin sulfate, 14 mg of gentamicin crobefat, and 20 mg of clindamycin palmitate gave an initial gentamicin burst and afterwards yielded a lower sustained release of gentamicin and clindamycin palmitate. These in vitro release kinetics were confirmed in vivo by pharmacokinetic analysis after intramuscular implantation of impregnated sewing ring segments. Gentamicin and active clindamycin palmitate metabolites were obtained at the implantation site for at least 2 weeks in concentrations of 3 and 5 micrograms per g of muscle, respectively. The investigated method of impregnation holds promise for revision implants after prosthetic valve endocarditis. It may also serve as a prophylactic tool for routine use against this disease.

[Antibacterial action of clindamycin in chronic, recurrent tonsillitis]. / Antibakterielle Wirksamkeit von Clindamycin bei chronisch-rezidivierender Tonsillitis.

After oral administration of 300 mg Sobelin, the efficacy and pharmacological kinetics of clindamycin (CAS 18323-44-9) were analysed in 35 patients with recurrent tonsillitis. Minimal inhibitor concentration (MIC) and minimal bactericidal concentration (MBC) have been evaluated for 120 strains. MIC and MBC for 91.7% of the strains amounted to 0.25 micrograms/ml. Concentrations of antibiotics in the serum were higher than 0.25 micrograms/ml after 12 h, i.e. higher than the minimal inhibitory concentration. The established free and efficient portion of clindamycin in the serum which is not bound to plasma proteins shows that a clear bacteriostatic effect is achieved up to 6 h after application of the antibiotic. The concentration in the tissue of the tonsils was 0.6-0.8 micrograms/g after 7-9 h indicating that sufficient MIC values were achieved. The free portion of the antibiotic in the tissues after 9 h also reached the MIC of germs. Hence clindamycin is considered to be an efficient antibiotic in the management of acute exacerbation of recurrent tonsillitis. Due to serum- and tissue levels of the tonsils administration of 300 mg of the test drug is indicated three times daily.

Antibiotic penetration of experimental intra-abdominal abscesses.

Intra-abdominal abscess is seldom adequately treated by systemic antibiotics alone and often requires surgical or computed tomography-guided drainage for resolution. Abscess penetration of six currently used antibiotics was examined in a murine intra-abdominal abscess model. Ampicillin/sulbactam, cefmetazole, clindamycin, and trospectomycin penetrated intra-abdominal abscesses to a greater degree than cefoxitin and ceftriaxone. Abscess pus antibiotic levels were not significantly higher after multiple doses than after a single dose. Pus antibiotic levels below the MIC90 for Bacteroides and E. coli within intra-abdominal abscess were observed for most antibiotics with the doses used in this study. Selection of antibiotics with a greater ability to penetrate abscess may be important in optimally treating patients with abdominal infection.

Comparison of cefoperazone plus sulbactam with clindamycin plus gentamicin as treatment for intra-abdominal infections.

This study compared the safety and efficacy of cefoperazone plus sulbactam with that of clindamycin plus gentamicin in the treatment of intra-abdominal infection. Seventy-six patients were included in the analysis of an open, randomized, comparative, single-site trial. Forty-seven patients received cefoperazone-sulbactam, and 29 patients received clindamycin plus gentamicin. Thirty-three patients (70%) who received cefoperazone-sulbactam and 15 patients (52%) who received clindamycin plus gentamicin were cured of infection, did not suffer a relapse within one month after the end of treatment, and did not receive any other antibiotics during the follow-up period (P = 0.17). In patients treated with cefoperazone-sulbactam there were four cases of superinfection, one patient had a prolonged prothrombin time, six patients had a poor response, two patients received antibiotics during follow-up, and one patient died during follow-up because of cancer. Treatment with clindamycin plus gentamicin was associated with five cases of superinfection, four patients had a poor response, four patients had a drug reaction, and one patient required antibiotics in the follow-up period. Serum levels of cefoperazone-sulbactam measured at one and three hours after dosing were consistent with earlier findings in normal volunteers. Two hundred and one pathogens were isolated, and 17 of 122 aerobic isolates (14%) were resistant to cefoperazone-sulbactam, and 17 of 122 (14%) were resistant to both clindamycin and gentamicin. Eleven of 79 (14%) anaerobic isolates were resistant to cefoperazone, none was resistant to cefoperazone-sulbactam, and 10 of 79 (13%) were resistant to clindamycin. The results of this study show that cefoperazone-sulbactam is an effective and safe alternative to clindamycin plus gentamicin in the treatment of intra-abdominal infections.

Comparative efficacy of clindamycin, erythromycin and spiramycin against Staphylococcus aureus in the rat croton oil pouch model.

Spiramycin, a macrolide antibiotic, has inferior in-vitro activity to erythromycin, but superior tissue penetration. Recent publications have suggested that the in-vivo activity of spiramycin should be re-assessed. The efficacy of clindamycin, erythromycin and spiramycin was compared against Staphylococcus aureus infections in the rat croton oil pouch model. The concentration of spiramycin in the pouch fluid was lower than the concentration of clindamycin or erythromycin after single or multiple intraperitoneal injections. In contrast, the concentration of spiramycin in the pouch wall (73.3 +/- 14.5 micrograms/g) was markedly higher than that of erythromycin (less than 7.5 micrograms/g). Multiple doses of spiramycin had no significant effect upon bacterial growth in the pouch, whereas clindamycin and erythromycin had a significant bactericidal effect. The results suggest that spiramycin is bound to tissues, diffuses poorly into tissue fluid and may therefore be ineffective against infections in large collections of tissue fluid.