A bibliometric study of scientific research conducted on second-generation antipsychotic drugs in Singapore.

INTRODUCTION: A bibliometric study was carried out to ascertain the volume and impact of scientific literature published on second-generation antipsychotic drugs (SGAs) in Singapore from 1997 to 2011. METHODS: A search of the EMBASE and MEDLINE databases was performed to identify articles originating from Singapore that included the descriptors 'atypic* antipsychotic*', 'second-generation antipsychotic*', 'clozapine', 'risperidone', 'olanzapine', 'ziprasidone', 'quetiapine', 'sertindole', 'aripiprazole', 'paliperidone', 'amisulpride', 'zotepine', 'asenapine', 'iloperidone', 'lurasidone', 'perospirone' and 'blonanserin' in the article titles. Certain bibliometric indicators of production and dispersion (e.g. Price's Law on the increase of scientific literature, and Bradford's Law) were applied, and the participation index of various countries was calculated. The bibliometric data was also correlated with some social and health data from Singapore, such as the total per capita expenditure on health and gross domestic expenditure on research and development. RESULTS: From 1997 to 2011, a total of 51 articles on SGAs in Singapore were published. Our results suggested non-fulfilment of Price's Law (r = 0.0648 after exponential adjustment vs. r = 0.2140 after linear adjustment). The most widely studied drugs were clozapine (21 articles), risperidone (16 articles) and olanzapine (8 articles). Division into Bradford zones yielded a nucleus occupied by the Journal of Clinical Psychopharmacology (6 articles) and the Singapore Medical Journal(4 articles). The analysed material was published in a total of 30 journals, with the majority from six journals. Four of these six journals have an impact factor greater than 2. CONCLUSION: Publications on SGAs in Singapore are still too few to confirm an exponential growth of scientific literature.

La investigación sobre fármacos antipsicóticos atípicos en España: una evaluación bibliométrica / Mapping the scientific research on atypical antipsychotic drugs in Spain: a bibliometric assessment

Objetivos: Se llevó a cabo un estudio bibliométrico de las publicaciones sobre fármacos antipsicóticos atípicos (AA) realizadas en España. Método: Se usaron las bases de datos EMBASE y MEDLINE y se aplicaron indicadores bibliométricos de productividad y dispersión de artículos (leyes de Price y de Bradford, respectivamente).También se calculó el índice de participación (IP)de los diferentes países y se buscaron correlaciones entre los datos bibliométricos y algunos datos sociales y de salud(gasto total per capita en salud y gasto interior bruto en investigación y desarrollo).Resultados: Se recopilaron 656 artículos originales publicados entre 1988 y 2011. Nuestros resultados constatan el cumplimiento de la ley de Price en la producción científica sobre AA, mostrando un crecimiento exponencial (coeficiente de correlación r = 0,9693 vs. r = 0,9177 después del ajuste lineal).Los fármacos más estudiados fueron la risperidona (181 artículos), la olanzapina (143), la clozapina (94) y la quetiapina (74). La división en zonas de Bradford dio lugar a un núcleo ocupado por las revistas European Psychiatry y European Neuropsychopharmacology (70 artículos). En total se publicaron artículos en 194 revistas diferentes, de las cuales 5de las 10 primeras tenían un factor de impacto mayor de 4.Conclusión: Las publicaciones sobre AA en España han experimentado un crecimiento exponencial en el período estudiado, sin evidencia de que se haya alcanzado un punto de saturación (AU)

Objectives: We carried out a bibliometric study on the scientific publications in relation to atypical antipsychotic drugs (AADs) in Spain. Methods: We used the EMBASE and MEDLINE databases and we applied some bibliometric indicators of paper production and dispersion (Price’s law and Bradford’s law, respectively). We also calculated the participation index of the different countries and correlated the bibliometric data with some social and health data (total per capita expenditure on health and gross domestic expenditure on research and development).Results: We collected 656 original papers published between 1988 and 2011. Our study results fulfilled Price’s law with scientific production on AADs showing exponential growth (correlation coefficient r = 0.9693, vs. r = 0.9177 after linear adjustment). The most widely studied drugs were risperidone (181 papers), olanzapine (143), clozapine (94),and quetiapine (74). Division into Bradford zones yielded a nucleus occupied by the European Psychiatry and European Neuropsychopharmacology (70 articles). Totally 194 different journals were published, with 5 of the first 10 usedj ournals having an impact factor being greater than 4.Conclusion: The publications on AADs in Spain have undergone exponential growth over the studied period, without evidence of reaching a saturation point (AU)

Mapping the scientific research on atypical antipsychotic drugs in Spain: a bibliometric assessment.

OBJECTIVES: We carried out a bibliometric study on the scientific publications in relation to atypical antipsychotic drugs (AADs) in Spain. METHODS: We used the EMBASE and MEDLINE databases and we applied some bibliometric indicators of paper production and dispersion (Price's law and Bradford's law, respectively). We also calculated the participation index of the different countries and correlated the bibliometric data with some social and health data (total per capita expenditure on health and gross domestic expenditure on research and development). RESULTS: We collected 656 original papers published between 1988 and 2011. Our study results fulfilled Price's law with scientific production on AADs showing exponential growth (correlation coefficient r = 0.9693, vs. r = 0.9177 after linear adjustment). The most widely studied drugs were risperidone (181 papers), olanzapine (143), clozapine (94), and quetiapine (74). Division into Bradford zones yielded a nucleus occupied by the European Psychiatry and European Neuropsychopharmacology (70 articles). Totally 194 different journals were published, with 5 of the first 10 used journals having an impact factor being greater than 4. CONCLUSION: The publications on AADs in Spain have undergone exponential growth over the studied period, without evidence of reaching a saturation point.

The Australian contribution to the literature on atypical antipsychotic drugs: a bibliometric study.

OBJECTIVE: We performed a bibliometric study on scientific publications on atypical antipsychotic drugs (AADs) from Australia. METHODS: Using the EMBASE and MEDLINE databases, we chose those documents produced in Australia between 1993 and 2011, whose title included the descriptors atypic* (atypical*), antipsychotic*, second-generation antipsychotic*, clozapine, risperidone, olanzapine, ziprasidone, quetiapine, sertindole, aripiprazole, paliperidone, amisulpride, zotepine, asenapine, iloperidone, lurasidone, perospirone and blonanserin. We applied bibliometric indicators of production as well as dispersion. RESULTS: We identified 438 relevant publications. The most widely studied AADs were clozapine (162 documents), olanzapine (103), risperidone (77) and quetiapine (42). There was a lack of exponential growth in publications over time, indicated by non-fulfilment of Price's Law (correlation coefficient r=0.9195 after exponential adjustment vs. r=0.9253 after linear adjustment). Publications appeared in 148 different journals, with four of the top nine journals having an impact factor greater than 3; 84 of the articles appeared in the Australian and New Zealand Journal of Psychiatry. CONCLUSION: Despite Australian publications on AADs appearing in reasonably high impact journals, most were confined to a single Australian psychiatry journal and overall publications did not show exponential growth over the period studied. This might reflect, inter alia, the relative paucity of medication trials being performed in Australia.

Trends in scientific literature on atypical antipsychotics in South Korea: a bibliometric study.

OBJECTIVE: We have carried out a bibliometric study on the scientific publications in relation to atypical or second-generation antipsychotic drugs (SGAs) in South Korea. METHODS: With the EMBASE and MEDLINE databases, we selected those publications made in South Korea whose title included the descriptors atypic(*) (atypical(*)) antipsychotic(*), second-generation antipsychotic(*), clozapine, risperidone, olanzapine, ziprasidone, quetiapine, sertindole, aripiprazole, paliperidone, amisulpride, zotepine, asenapine, iloperidone, lurasidone, perospirone and blonanserin. We applied some bibliometric indicators of paper production and dispersion with Price's law and Bradford's law, respectively. We also calculated the participation index (PI) of the different countries, and correlated the bibliometric data with some social and health data from Korea (such as total per capita expenditure on health and gross domestic expenditure on research and development). RESULTS: We collected 326 original papers published between 1993 and 2011. Our results state fulfilment of fulfilled Price's law, with scientific production on SGAs showing exponential growth (correlation coefficient r=0.8978, as against an r=0.8149 after linear adjustment). The most widely studied drugs were risperidone (91 papers), aripiprazole (77), olanzapine (53), and clozapine (43). Division into Bradford zones yielded a nucleus occupied by the Progress in Neuro-Psychopharmacology and Biological Psychiatry (36 articles). A total of 86 different journals were published, with 4 of the first 10 used journals having an impact factor being greater than 4. CONCLUSION: The publications on SGAs in South Korea have undergone exponential growth over the studied period, without evidence of reaching a saturation point.

Adherence of Streptococcus pneumoniae to polystyrene plates and epithelial cells and the antiadhesive potential of albumin and xylitol.

Aimed to prevent Streptococcus pneumoniae biofilm infections, we studied the adherence of nine pneumococcal strains to polystyrene plates and on epithelial cells and the antiadhesive effect of albumin and xylitol. The adherence was variable among strains, but there was a good correlation between their adherent ability and binding to abiotic material and cells. Strains of serotypes 6B and 23F were the most adherent organisms, whereas serotype 3 strains were the least adherent. Human serum albumin (HSA) enhanced bacterial growth at low concentrations (0.5-2.5%) but inhibited it at 10%. Xylitol inhibited bacterial growth of all strains at concentrations ranging from 5 to 15%. Exposure to 0.5-5% HSA in solubilized form and to 5% HSA precoating of plates diminished adherence to polystyrene >80% for all strains, except for serotype 3 strains. Contrarily, 0.5 and 5% xylitol did not diminish significantly pneumococcal adherence to polystyrene plates or on epithelial cells. Our results suggest that 1) the potential application of HSA coatings on medical devices to inhibit pneumococcal adherence and 2) the possible beneficial effect of xylitol in preventing some pneumococcal infections could be because of its antimicrobial activity rather than to an antiadhesive effect.

Comparative efficacy of novobiocin and amoxicillin in experimental sepsis caused by beta-lactam-susceptible and highly resistant pneumococci.

Therapeutic alternatives are needed against infections caused by highly multidrug-resistant Streptococcus pneumoniae. Novobiocin, an old antibiotic, was tested in vitro and in a murine sepsis model against one amoxicillin-susceptible and three amoxicillin-resistant strains [minimum inhibitory concentrations (MICs) 8-64 mg/L]. Novobiocin MICs for all strains were 0.25-0.5 mg/L. In sepsis, novobiocin and amoxicillin were evaluated at 25, 50, 100 and 200 mg/kg given at 1, 5, 24 and 48 h post bacterial challenge. The most effective regimens in animals infected with the amoxicillin-susceptible strain were 200 mg/kg novobiocin and 25 mg/kg amoxicillin, achieving 100% survival and undetectable organisms in the peritoneum. Among mice infected with amoxicillin-resistant S. pneumoniae, 200 mg/kg novobiocin gave the highest protection (90-100% survivors), followed by 200mg/kg amoxicillin (60-100%), 100 mg/kg novobiocin (50-87.5%) and 50 mg/kg amoxicillin (14.3-25%). The killing effect of antibiotics in the peritoneum (mean Deltalog(10) colony-forming units/mL between treated and control mice) was as follows: 200 mg/kg novobiocin (-6.6)>200 mg/kg amoxicillin (-5.6)>100 mg/kg novobiocin (-3.7) > 50 mg/kg amoxicillin (-0.7). Total plasma and ultrafiltrate pharmacokinetics of novobiocin (200 mg/kg, single dose) in non-infected mice showed, respectively, half-lives of 151 min and 215 min, area under the concentration-time curves (AUCs) of 945.0 mgh/L and 136.6 mgh/L and maximal concentrations of 147 mg/L and 18 mg/L. Novobiocin may be a promising agent for therapy of highly beta-lactam-resistant pneumococcal infections.

Antimicrobial susceptibility of multidrug-resistant Streptococcus pneumoniae strains with penicillin MICs of 8 to 32 mg/L.

The in vitro activity of 22 antibiotics (including novobiocin) and beta-lactam/gentamicin combinations was assessed against 11 multidrug-resistant pneumococcal strains. Among orally administered drugs, only telithromycin, levofloxacin, and linezolid were active against all isolates, but their use is not indicated in pediatrics. Novobiocin could be a potential therapeutic alternative.

Antimicrobial susceptibility of Streptococcus pyogenes in Central, Eastern, and Baltic European Countries, 2005 to 2006: the cefditoren surveillance program.

The in vitro activity of penicillin, ampicillin, cefditoren, cefotaxime, erythromycin, clarithromycin, and levofloxacin against 763 clinical isolates of Streptococcus pyogenes was determined. Clinically significant isolates collected from November 2005 to December 2006 in the Czech Republic, Slovakia, Hungary, Poland, Romania, Estonia, Latvia, and Lithuania (the latter 3 analyzed as Baltic countries) were studied. No resistance to beta-lactams and levofloxacin was found. The rate of erythromycin resistance in S. pyogenes varied among countries, being low (<10%) in Romania and Baltic countries, intermediate (10-20%) in Poland and Czech Republic, and high (>25%) in Hungary and Slovakia. The predominant (75.0%) erythromycin-resistant phenotype among S. pyogenes isolates was MLS(B). The identification of the prevalence of erythromycin resistance mechanism could have impact on the choice of empiric antibiotic therapy for the clinicians in such countries.

In vitro activity of ciprofloxacin, moxifloxacin, vancomycin and erythromycin against planktonic and biofilm forms of Corynebacterium urealyticum.

OBJECTIVES: To study the ability of Corynebacterium urealyticum to produce biofilms and to compare the in vitro activity of antimicrobials against planktonic and biofilm-associated organisms. METHODS: Biofilm formation on polystyrene plates by three C. urealyticum strains was studied in artificial urine under static conditions. The bactericidal activities of ciprofloxacin, moxifloxacin, vancomycin and erythromycin were studied against biofilm-associated organisms, and the results were compared with those obtained against planktonic organisms. Persister biofilm-associated organisms of each strain exposed to antibiotics were retested to determine the MIC of the same antibiotic. RESULTS: The three strains tested consistently produced biofilms. Planktonic organisms was susceptible to ciprofloxacin, moxifloxacin and vancomycin, and their MBC values were two to eight times higher than their corresponding MICs. Bactericidal effect on biofilm-associated organisms required very high antibiotic concentrations; the minimum biofilm bactericidal concentrations for ciprofloxacin, moxifloxacin and vancomycin ranged from 128 to > or =1024 times their respective MBCs for planktonic organisms. Erythromycin was not bactericidal against either planktonic or biofilm-associated organisms for the single susceptible strain tested. Persister biofilm-associated organisms exposed to erythromycin increased their MIC by a factor >8000, but no changes in susceptibility were observed with the other compounds. CONCLUSIONS: This work demonstrates that C. urealyticum produces biofilms on polystyrene plates and biofilm-associated organisms are much less susceptible to the bactericidal effect of the antibiotics; and the exposure of C. urealyticum to erythromycin may favour resistance selection. Overall, these results may explain the difficulties for bacterial eradication in chronic infections caused by C. urealyticum.

Correlation between virulence factors and in vitro biofilm formation by Escherichia coli strains.

The ability of 15 Escherichia coli strains to form biofilms on polystirene plates was studied. The strains were serotyped, and their phenotypic expression of surface virulence factors (VFs), and antibiotic susceptibility was also determined. Moreover, 30 VFs-associated genes were analysed, including 15 adhesins (papC, papG and its three alleles, sfa/focDE, sfaS, focG, afa/draBC, iha, bmaE, gafD, nfaE, fimH, fimAvMT78, agn43, F9 fimbriae and type 3 fimbriae-encoding gene clusters), four toxins (hlyA, cnf1, sat and tsh), four siderophore (iron, fyuA, iutA and iucD), five proctetins/invasion-encoding genes (kpsM II, kpsMT III, K1 kps variant- neuC, traT and ibeA), and the pathogenicity island malX and cvaC. Morphological appearance and thickness of biofilms of two strong and three weak biofilm producers were also studied by confocal laser scanning microscopy (CLSM). Seven strains were classified as strong biofilm producers and the remaining eight strains were regarded as weak biofilm producers. Mannose-resistant haemagglutination was the only phenotypically expressed surface virulence factor more frequently found in the strong biofilm group. Five virulence-associated genes were more common (p<0.05) in strong biofilm producers: papC and papG alleles, sfa/focDE, focG, hlyA and cnf1. CLSM images showed irregular biofilms with projections at the top mainly in strong biofilm.

In vitro interactions of LytA, the major pneumococcal autolysin, with two bacteriophage lytic enzymes (Cpl-1 and Pal), cefotaxime and moxifloxacin against antibiotic-susceptible and -resistant Streptococcus pneumoniae strains.

OBJECTIVES: In an innovative therapeutic exploitation against antibiotic-resistant Streptococcus pneumoniae, here we have evaluated the in vitro activity of a purified bacterially-encoded cell wall lytic enzyme, LytA (the major pneumococcal autolysin), and compared it with those of Cpl-1 and Pal (pneumococcal phage lytic enzymes) and two antibiotics versus four pneumococcal strains. METHODS: Two serotype 3, penicillin-susceptible strains and two penicillin-resistant (serotypes 19F and 19A, respectively) S. pneumoniae clinical isolates were used. The effect of several combinations of lytic enzymes and antibiotics (cefotaxime and moxifloxacin) was studied by chequerboard and time-kill assays, the latter at concentrations of 0.25 x MIC. RESULTS: LytA was more active than Cpl-1 and Pal. By the chequerboard technique, the combination of LytA and cefotaxime was synergistic for one of the two cefotaxime-resistant strains studied. The combined use of Cpl-1 and Pal was synergistic for three of the four strains, as was Cpl-1 with antibiotics for two of the three strains studied. In the time-kill assays, after 5 h of exposure to LytA, Cpl-1 or Pal, the mean differences in colony counts versus controls were -3.55, -2.66 and -2.71 log(10) cfu/mL, respectively. The combination of LytA/Pal reduced the bacterial inoculum >2 log units for three of the four strains. LytA combined with cefotaxime or moxifloxacin achieved >3 log units decrease for the strains tested. Particularly, a strong synergism was observed with LytA/cefotaxime for one cefotaxime-resistant meningeal strain. LytA/moxifloxacin was synergistic for the quinolone-resistant strain when tested by time-kill methodology, and just close to synergistic (fractional inhibitory concentration index of 0.58) by the chequerboard technique. Antagonism was not observed for any combination when assayed by either method. CONCLUSIONS: LytA, Cpl-1 or Pal, alone or in combination, might prove to be effective in combination therapy, as well as in monotherapy against S. pneumoniae. These results suggest avenues of research to study the cell wall lytic enzymes as anti-pneumococcal therapeutic agents.

Pneumococcal LytA autolysin, a potent therapeutic agent in experimental peritonitis-sepsis caused by highly beta-lactam-resistant Streptococcus pneumoniae.

The in vitro and in vivo antipneumococcal activities of the main pneumococcal autolysin (LytA) and Cpl-1, a lysozyme encoded by phage Cp-1, were studied. Intraperitoneal therapy with LytA or high-dose Cpl-1 remarkably reduced peritoneal bacterial counts (>5 log(10) CFU/ml) compared with those for the controls. After intravenous injection, LytA was the most effective treatment.

Adherence of Streptococcus pneumoniae to polystyrene plates, effect of serum on adhesion, and virulence in the gerbil otitis media model.

The adherence of 11 pneumococcal strains to polystyrene was studied and expressed as the number of colony-forming units (CFU) recovered per 10(6)CFU of initial inoculum. Three strains were considered as strong adherent (>100CFU/10(6)), three as medium adherent (10-100CFU/10(6)), and five as low adherent (<10CFU/10(6)). All serotype 3 strains were low adherent whilst serotypes 23F and 19F behaved as strong or medium adherent. The impact of gerbil sera on adherence of six selected pneumococcal strains (one strong adherent, one medium adherent, and four low adherents) to abiotic material was also studied under two experimental conditions. In the presence of sera, the adherence ability of the strong, medium, and one low adherent strains decreased significantly. On the other hand, the adherence significantly increased in all strains when sera were removed following preincubation of bacteria exposed to sera, although such increase was statistically significant for five of them. Finally, the ability of two (one strong adherent and one low adherent) strains to induce otitis media in gerbils was also evaluated; the strong adherent strain behaved significantly more virulent than the less adherent in terms of ear damage and animal weight loss.

Impact of ibuprofen therapy in the outcome of experimental pneumococcal acute otitis media treated with amoxicillin or erythromycin.

The impact of ibuprofen combined with amoxicillin or erythromycin for therapy of penicillin-resistant pneumococcal acute otitis media (AOM) was evaluated in a gerbil model. Ibuprofen (at 2.5 or 7.5 mg/kg, orally) and/or amoxicillin or erythromycin (5 mg/kg each, s.c.) were administered at 5 h (early therapy, as single-dose regimen) or at 18 h (delayed therapy, five doses) postinoculation (PI). Each antibiotic alone and combined with ibuprofen was more effective administered as early regimen than as delayed treatment when evaluating the presence of otorrhea, otoscopic aspect, culture-positive and bacterial counts in middle ear (ME) samples, and loss of body weight. There was a trend for a better bacteriological outcome in animals receiving amoxicillin or erythromycin and ibuprofen, especially with the high dose. Such a dose of ibuprofen, associated with each antibiotic regimen, also preserved the animal well-being, avoiding a great weight loss in comparison to those receiving the antibiotic alone but a statistically significant difference was only observed for animals receiving delayed therapy with erythromycin and high-dose ibuprofen. In conclusion, ibuprofen combined with antibiotics seemed to improve the outcome of this experimental pneumococcal AOM.

Correlation between in vitro and in vivo activity of levofloxacin and moxifloxacin against pneumococcal strains with different susceptibilities to fluoroquinolones.

In vitro and in vivo models were developed to evaluate the efficacy of levofloxacin and moxifloxacin against three serotype 3 pneumococcal strains with different susceptibilities to fluoroquinolones (wild-type, parC mutant, and parC, parE and gyrA mutant). Levofloxacin and moxifloxacin reduced the bacterial burden in the in vitro pharmacodynamic and animal models for the wild-type strain but had very little activity against the fully resistant strain (parC, parE and gyrA mutant). Levofloxacin showed very little activity both in the in vitro pharmacodynamic model and in the animal model for the strain having a mutation in parC (levofloxacin and moxifloxacin minimum inhibitory concentrations, 2mg/L and 0.25mg/L, respectively). However, moxifloxacin still had a significant in vitro and in vivo activity against this strain.

Effect of erythromycin treatment delay on therapeutic outcome of experimental acute otitis media caused by Streptococcus pneumoniae.

OBJECTIVE: To evaluate the effect of delayed administration of erythromycin in the course of acute otitis media caused by an erythromycin-susceptible Streptococcus pneumoniae strain in the gerbil model. METHODS: The bacterium was inoculated by transbullar challenge in the middle ear (ME) and antibiotic treatment at different doses was administered at various times thereafter. RESULTS: When 2.5 mg/kg of erythromycin was administered as a single dose 2, 5, 18 or 21 h post-inoculation (pi) the bacterial eradication rate was 55, 40, 0 and 0%, respectively. A higher dose (5 mg/kg) administered also as a single dose 2, 5, 18 and 21 h pi achieved bacterial eradication rates of 62.5, 43.8, 0 and 0%, respectively. Using a very high dose (50 mg/kg) repeated three times at 3 h intervals (total dose 150 mg/kg) and starting the treatment 21 h pi only achieved bacterial eradication in 25% of cases. The concentration of erythromycin achieved in the ME 90 min after administration of 5 mg/kg 5 or 21 h pi was very similar (0.74 and 0.79 mg/L) but the ME half-life was longer (98.2 min) with the early administration as compared with the delayed form (47.5 min), which could partially explain the different results. Further experiments showed that the failures observed with the delayed administration were not related to the time elapsed from antibiotic administration to ME sampling or selection of antibiotic-resistant mutants. CONCLUSION: Bacteriological and clinical efficacies were significantly diminished if antibiotic administration was delayed.

Urinary concentrations and bactericidal activity against amoxicillin-nonsusceptible strains of Escherichia coli with single-dose, oral, sustained-release amoxicillin/clavulanic acid: a phase I, open-label, noncomparative clinical trial in healthy volunteers.

BACKGROUND: Urinary tract infections (UTIs) account for 5 to 6 million medical consultations in the United States each year. Worldwide, an estimated 20% to 30% of women aged 20 to 40 years have at least 1 episode of the most common type of UTI (uncomplicated cystitis) in their lifetime, with Escherichia coli being the causative pathogen in 80% of cases. Antibacterial activity in urine has been shown to be correlated with outcomes of uncomplicated cystitis. OBJECTIVE: The objectives of this study were to determine urinary concentrations and ex vivo bactericidal activity of sustained-release (SR) amoxicillin/clavulanic acid 2000/125 mg against intermediately resistant and resistant strains of E coli over 72 hours and compare them with those of a susceptible strain. This study also investigated whether urinary concentrations obtained after dosing cover E coli strains categorized as intermediately resistant and resistant based on current Clinical and Laboratory Standards Institute (formerly NCCLS) breakpoints in uncomplicated cystitis. METHODS: This Phase I, open-label, noncomparative study in healthy male volunteers was conducted at the Pharmacology Unit, Autónoma University, Madrid, Spain. Subjects received a single oral dose of amoxicillin/clavulanic acid 2000/125 mg SR. The amoxicillin/clavulanic acid MICs were 8/4 microg/mL (susceptible), 16/8 microg/mL (intermediately resistant), and 32/16 and 64/32 microg/mL (resistant). Urine samples were collected before (baseline; time 0) and at the following intervals: 0-2, 2-4, 4-8, 8-12, 12-16, 16-24, 24-36, 36-48, 48-60, and 60-72 hours after dosing. Killing curves with urine samples were performed with initial inocula of approximately 10(7) colony-forming units (CFU)/mL, and bactericidal activity (defined as >3 log(10) CFU/mL and >99.9% reduction in bacterial counts) was calculated as the difference between log(10) initial inoculum and log(10) CFU/mL after 4 hours of incubation of each sample. RESULTS: Twelve volunteers were included (mean [SD] age, 24.83 [5.64] years; mean [SD] height, 175.75 [7.56] cm; and mean [SD] weight, 73.55 [9.19] kg). No statistically significant differences between the activities in the 12-16-hour interval compared with baseline were found in any of the strains tested. Bactericidal activity against the susceptible and intermediately resistant strains (MICs 8/4 and 16/8 g/mL, respectively) was obtained up to 8 hours after dosing. Bactericidal activity against the resistant strains (MICs 32/16 and 64/32 microg/mL) was obtained in the 2-4-hour interval. CONCLUSIONS: In this Phase I study in healthy volunteers, urinary concentrations after dosing with amoxicillin/clavulanic acid 2000/125 mg SR showed bactericidal activity against the amoxicillin-susceptible and intermediately resistant strains of E coli.

Pulmonary damage and bacterial load in assessment of the efficacy of simulated human treatment-like amoxicillin (2,000 milligrams) therapy of experimental pneumococcal pneumonia caused by strains for which amoxicillin MICs differ.

An experimental rat pneumonia model using two amoxicillin-susceptible (MICs, < or =0.015 and 2 microg/ml) and two non-amoxicillin-susceptible (MIC, 4 microg/ml) Streptococcus pneumoniae strains was developed for testing the efficacy of amoxicillin administered to simulate human serum kinetics after treatment with amoxicillin-clavulanate (2,000 and 125 mg, respectively, twice a day, for 2.5 days). The end points for efficacy were reductions in bacterial loads in the lungs and reductions in levels of pulmonary damage. For the amoxicillin-susceptible strains (serotypes 23F and 14), a decrease greater than 4.5 log(10) CFU/pair of lungs was obtained, and the time for which the serum antibiotic concentration (SAC) was higher than the MIC (T(S)(A)(C)(>)(MIC)) was greater than 60% of the dosing interval. For non-amoxicillin-susceptible strains, the decrease in bacterial load was 1.34 to 1.75 log(10) CFU/pair of lungs, with a T(S)(A)(C)(>)(MIC) of 46.7% of the dosing interval. An in vitro study showed that serotype 9V non-amoxicillin-susceptible strains behaved as tolerant-like to concentrations similar to those in the in vivo model. The high and maintained SACs (T(S)(A)(C)(>)(MIC), >46% for all strains) significantly diminished lung injury (affected area of the lung and lung weight), compared to that in controls, by all strains, regardless of the MIC, bactericidal behavior in in vitro killing curves, or the serotype of the infecting strain. These results show the importance of host therapeutic end points in the evaluation of antibiotic efficacy. The antibiotic was more efficacious, for one nonsusceptible strain tested, when the treatment was started early (1 h postinoculation [p.i.]) than when treatment was delayed (24 h p.i.).