Biomedical subjects

Charles Knirsch

Publications and source records attributed to Charles Knirsch.

14 recordsLinked to original sources

PubMed2006

In vitro antimalarial activity of azithromycin, artesunate, and quinine in combination and correlation with clinical outcome.

Azithromycin when used in combination with faster-acting antimalarials has proven efficacious in treating Plasmodium falciparum malaria in phase 2 clinical trials. The aim of this study was to establish optimal combination ratios for azithromycin in combination with either dihydroartemisinin or quinine, to determine the clinical correlates of in vitro drug sensitivity for these compounds, and to assess the cross-sensitivity patterns. Seventy-three fresh P. falciparum isolates originating from patients from the western border regions of Thailand were successfully tested for their drug susceptibility in a histidine-rich protein 2 (HRP2) assay. With overall mean fractional inhibitory concentrations of 0.84 (95% confidence interval [CI]=0.77 to 1.08) and 0.78 (95% CI=0.72 to 0.98), the interactions between azithromycin and dihydroartemisinin, as well as quinine, were classified as additive, with a tendency toward synergism. The strongest tendency toward synergy was seen with a combination ratio of 1:547 for the combination with dihydroartemisinin and 1:44 with quinine. The geometric mean 50% inhibitory concentration (IC50) of azithromycin was 2,570.3 (95% CI=2,175.58 to 3,036.58) ng/ml. The IC50s for mefloquine, quinine, and chloroquine were 11.42, 64.4, and 54.4 ng/ml, respectively, suggesting a relatively high level of background resistance in this patient population. Distinct correlations (R=0.53; P=0.001) between quinine in vitro results and parasite clearance may indicate a compromised sensitivity to this drug. The correlation with dihydroartemisinin data was weaker (R=0.34; P=0.038), and no such correlation was observed for azithromycin. Our in vitro data confirm that azithromycin in combination with artemisinin derivatives or quinine exerts additive to synergistic interactions, shows no cross-sensitivity with traditional antimalarials, and has substantial antimalarial activity on its own.

Animals↗

PubMed2006

Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: a randomized, phase 2 clinical trial in Thailand.

BACKGROUND: Because antimalarial drug resistance is spreading, there is an urgent need for new combination treatments for malaria, which kills >1 million people every year. Azithromycin is a macrolide antibiotic that is particularly attractive as an antimalarial because of its safety in children and the extensive experience with its use during pregnancy. METHODS: We undertook a randomized, controlled, 28-day inpatient trial involving patients with acute, uncomplicated Plasmodium falciparum malaria. We compared the safety and efficacy of 2 azithromycin-artesunate combinations and 2 azithromycin-quinine regimens in adults with malaria. Treatments were as follows: cohort 1 received 3 days of azithromycin (750 mg twice daily) plus artesunate (100 mg twice daily), cohort 2 received 3 days of azithromycin (1000 mg once daily) plus artesunate (200 mg once daily), cohort 3 received 3 days of azithromycin (750 mg twice daily) plus quinine (10 mg/kg twice daily), and cohort 4 received 3 days of azithromycin (500 mg 3 times daily) plus quinine (10 mg/kg 3 times daily). The enrollment target was 25 evaluable subjects per group. RESULTS: The 28-day cure rates were similarly high in the artesunate and the standard-dose quinine cohorts: 92.0% (95% confidence interval [CI], 74.0%-99.0%), 88.9% (95% CI, 70.8%-97.6%), and 92.0% (95% CI, 74.0%-99.0%), for cohorts 1, 2, and 4, respectively. Late R1 treatment failures were seen in each of the artesunate and the standard-dose quinine cohorts. The cure rate for cohort 3 was 73.3% (95% CI, 44.9%-92.2%). In this cohort, 3 early treatment failures led to the termination of enrollment after 16 subjects had been enrolled. With mean parasite and fever clearance times (+/-SD) of 34+/-13 h and 20+/-20 h, the artesunate combinations were found to have led to a significantly (P<.001) faster clinical and parasitological improvement than occurred in the quinine cohorts (74+/-32 h and 43+/-37 h, respectively). Treatment-related adverse events were significantly more common in the quinine cohorts (P<.001). No deaths or drug-related serious adverse events were observed. In vitro results suggest that the treatment failures--particularly in the low-dose quinine cohort--were associated with decreased susceptibility to quinine, as well as with mefloquine cross-resistance. CONCLUSIONS: These data suggest that azithromycin-artesunate, even when given only once daily for 3 days, and azithromycin-quinine, given 3 times daily, are safe and efficacious combination treatments for uncomplicated falciparum malaria, and they deserve additional study in special patient populations.

Adult↗

PubMed2006

Using discordance to improve classification in narrative clinical databases: an application to community-acquired pneumonia.

Data mining in electronic medical records may facilitate clinical research, but much of the structured data may be miscoded, incomplete, or non-specific. The exploitation of narrative data using natural language processing may help, although nesting, varying granularity, and repetition remain challenges. In a study of community-acquired pneumonia using electronic records, these issues led to poor classification. Limiting queries to accurate, complete records led to vastly reduced, possibly biased samples. We exploited knowledge latent in the electronic records to improve classification. A similarity metric was used to cluster cases. We defined discordance as the degree to which cases within a cluster give different answers for some query that addresses a classification task of interest. Cases with higher discordance are more likely to be incorrectly classified, and can be reviewed manually to adjust the classification, improve the query, or estimate the likely accuracy of the query. In a study of pneumonia--in which the ICD9-CM coding was found to be very poor--the discordance measure was statistically significantly correlated with classification correctness (.45; 95% CI .15-.62).

Adult↗

PubMed2006

Effective treatment of uncomplicated Plasmodium falciparum malaria with azithromycin-quinine combinations: a randomized, dose-ranging study.

Azithromycin, the most potent antimalarial macrolide antibiotic, is synergistic with quinine against Plasmodium falciparum in vitro. We assessed combinations of azithromycin and quinine against uncomplicated P. falciparum malaria at the Armed Forces Research Institute of Medical Sciences-Kwai River Clinical Center along the Thailand-Myanmar border, an area with a high prevalence of multidrug-resistant P. falciparum. Four regimens were assessed in an open-label dose-ranging design involving 61 volunteers. All received oral quinine (Q; 30 mg/kg/day divided every 8 hours for 3 days) with oral azithromycin (Az; 500 mg twice a day for 3 days, 500 mg twice a day for 5 days, or 500 mg three times a day for 3 days). A comparator group received quinine and doxycycline (Dx; 100 mg twice a day for 7 days). Study observation was 28 days per protocol. Sixty volunteers completed the study. Seven days of QDx cured 100% of the volunteers. One failure occurred in the lowest QAz regimen (on day 28) and none occurred in either of the two higher Az regimens. Cinchonism occurred in nearly all subjects. Overall, the azithromycin regimens were well tolerated, and no volunteers discontinued therapy. Three- and five-day azithromycin-quinine combination therapy appears safe, well tolerated, and effective in curing drug-resistant P. falciparum malaria. Further evaluation, especially in pediatric and obstetric populations, is warranted.

Administration, Oral↗

PubMed2005

Azithromycin for the secondary prevention of coronary events.

BACKGROUND: Epidemiologic, laboratory, animal, and clinical studies suggest that there is an association between Chlamydia pneumoniae infection and atherogenesis. We evaluated the efficacy of one year of azithromycin treatment for the secondary prevention of coronary events. METHODS: In this randomized, prospective trial, we assigned 4012 patients with documented stable coronary artery disease to receive either 600 mg of azithromycin or placebo weekly for one year. The participants were followed for a mean of 3.9 years at 28 clinical centers throughout the United States. RESULTS: The primary end point, a composite of death due to coronary heart disease, nonfatal myocardial infarction, coronary revascularization, or hospitalization for unstable angina, occurred in 446 of the participants who had been randomly assigned to receive azithromycin and 449 of those who had been randomly assigned to receive placebo. There was no significant risk reduction in the azithromycin group as compared with the placebo group with regard to the primary end point (risk reduction, 1 percent [95 percent confidence interval, -13 to 13 percent]). There were also no significant risk reductions with regard to any of the components of the primary end point, death from any cause, or stroke. The results did not differ when the participants were stratified according to sex, age, smoking status, presence or absence of diabetes mellitus, or C. pneumoniae serologic status at baseline. CONCLUSIONS: A one-year course of weekly azithromycin did not alter the risk of cardiac events among patients with stable coronary artery disease.

Aged↗

PubMed2005

Pharmacokinetics of intravenously administered azithromycin in pediatric patients.

BACKGROUND: The objective of this study was to characterize the pharmacokinetics and tolerance of a single intravenous (IV) azithromycin dose in children. METHODS: Subjects were stratified into 4 age groups: 0.5-2 years; >2-<6 years; 6-<12 years; and 12-<16 years. Each subject received a single 10 mg/kg dose (500 mg maximum) infused in 1 hour. Serial venous blood samples were obtained for a 168-hour period, and laboratory safety evaluations were performed immediately preceding azithromycin administration and at the conclusion of the study. Serum azithromycin concentrations were quantified with a validated high performance liquid chromatography method with mass spectrometric detection. Pharmacokinetic indices were calculated for each subject by noncompartmental techniques. RESULTS: Thirty-two subjects (6.7 +/- 5.0 years, 11 boys) participated. Mean serum concentration-time data were comparable for the 4 age groups. For all subjects with evaluable data, the mean area under the curve from 0 to 72 hours (AUC0-72) was 8.2 microg . h/mL (n = 26), the maximum concentration (Cmax) was 2.4 microg/mL and the elimination half-life (t1/2) was 65.2 hours (n = 25). The AUC0-72 and Cmax were not associated with age. The dose was well-tolerated with no serious adverse events. CONCLUSION: The disposition of azithromycin after a single 10-mg/kg IV dose (maximum labeled adult dose of 500 mg) is comparable in pediatric patients between 0.5 and 16 years of age. These pharmacokinetic data can be used to guide dose selection for future therapeutic trials of IV azithromycin in pediatric patients.

Adolescent↗

PubMed2005

Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections.

Skin and soft tissue infections (SSTIs) are a common cause of morbidity in both the community and the hospital. An SSTI is classified as complicated if the infection has spread to the deeper soft tissues, if surgical intervention is necessary, or if the patient has a comorbid condition hindering treatment response (e.g., diabetes mellitus or human immunodeficiency virus). The purpose of this study was to compare linezolid to vancomycin in the treatment of suspected or proven methicillin-resistant gram-positive complicated SSTIs (CSSTIs) requiring hospitalization. This was a randomized, open-label, comparator-controlled, multicenter, multinational study that included patients with suspected or proven methicillin-resistant Staphylococcus aureus (MRSA) infections that involved substantial areas of skin or deeper soft tissues, such as cellulitis, abscesses, infected ulcers, or burns (<10% of total body surface area). Patients were randomized (1:1) to receive linezolid (600 mg) every 12 h either intravenously (i.v.) or orally or vancomycin (1 g) every 12 h i.v. In the intent-to-treat population, 92.2% and 88.5% of patients treated with linezolid and vancomycin, respectively, were clinically cured at the test-of-cure (TOC) visit (P=0.057). Linezolid outcomes (124/140 patients or 88.6%) were superior to vancomycin outcomes (97/145 patients or 66.9%) at the TOC visit for patients with MRSA infections (P<0.001). Drug-related adverse events were reported in similar numbers in both the linezolid and the vancomycin arms of the trial. The results of this study demonstrate that linezolid therapy is well tolerated, equivalent to vancomycin in treating CSSTIs, and superior to vancomycin in the treatment of CSSTIs due to MRSA.

Acetamides↗

PubMed2004

Short-course azithromycin for the treatment of uncomplicated typhoid fever in children and adolescents.

We studied 149 children and adolescents 3-17 years of age with clinical typhoid fever who were treated with either oral azithromycin (20 mg/kg per day; maximum dose, 1000 mg/day) or intravenous ceftriaxone (75 mg/day; maximum dose, 2.5 g/day) daily for 5 days. Blood and stool specimens were obtained for culture before the initiation of therapy and were repeated on days 4 and 8 of treatment. Isolation of Salmonella enterica serovar Typhi or S. enterica serovar Paratyphi from the initial culture was required for inclusion in the final analysis. S. Typhi was isolated from 68 patients, 32 of whom were receiving azithromycin. Cure was achieved in 30 (94%) of 32 patients in the azithromycin group and in 35 (97%) of 36 patients in the ceftriaxone group (P=NS). Mean time to clearance of bacteremia was longer in the azithromycin group than in the ceftriaxone group. No patient who received azithromycin had a relapse, compared with 6 patients who received ceftriaxone. A 5-day course of azithromycin was found to be an effective treatment for uncomplicated typhoid fever in children and adolescents.

Adolescent↗

PubMed2003

Azithromycin in the treatment of Legionella pneumonia requiring hospitalization.

Azithromycin is highly active against Legionella pneumophila and has been shown to be efficacious in animal models and in clinical studies of patients with legionnaires disease. This open, prospective, multicenter trial evaluated azithromycin for the treatment of legionnaires disease. Twenty-five hospitalized patients with community-acquired pneumonia and a positive result of a L. pneumophila serogroup 1 urinary antigen assay received monotherapy with intravenous azithromycin (500 mg/day) for 2-7 days, followed by oral azithromycin (1500 mg administered over the course of 3 or 5 days). The mean total duration of intravenous plus oral therapy was 7.92 days. The overall cure rate among clinically evaluable patients was 95% (20 of 21 patients) at 10-14 days after therapy and 96% (22 of 23 patients) at 4-6 weeks after therapy. The results of this study support previously reported data demonstrating that azithromycin is both safe and efficacious for the treatment of hospitalized patients with legionnaires disease.

Adult↗

PubMed2003

Azithromycin found to be comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico.

Increased drug resistance among enteropathogens is an emergent problem in travelers' diarrhea. This randomized, double-blind trial was conducted in Guadalajara, Mexico, during the summers of 1999-2001 to compare azithromycin with levofloxacin for the treatment of travelers' diarrhea. A total of 217 US adults were randomized to receive a single oral dose of azithromycin (1000 mg; 108 persons) or levofloxacin (500 mg; 109 persons), with a follow-up period of 4 days. Three patients in each group dropped out of the study. The median time between initiation of therapy and passage of the last unformed stool (azithromycin group, 22.3 h; levofloxacin group, 21.5 h) and the number of unformed stools passed during the 4-day follow-up period (azithromycin group, 6.5; levofloxacin group, 5.5) were similar. Treatment failure occurred in 10 patients (9.5%) receiving azithromycin and 8 patients (7.5%) receiving levofloxacin. Possible minor, self-limiting adverse events occurred in 57 patients in each treatment group. Azithromycin was found to be a safe and effective alternative to levofloxacin for the treatment of acute travelers' diarrhea in US adult travelers to Mexico.

Adult↗

PubMed2003

Impact of azithromycin administration for trachoma control on the carriage of antibiotic-resistant Streptococcus pneumoniae.

Community distribution of azithromycin has an important role to play in trachoma control. Previous studies have suggested that this may increase the prevalence of macrolide-resistant Streptococcus pneumoniae. S. pneumoniae was isolated from children under 7 years of age in Rombo District, northern Tanzania, before and 2 and 6 months after community-wide administration of azithromycin. Overall carriage rates were 11, 12, and 7%, respectively. Only one macrolide-resistant isolate carrying the mef gene was obtained 6 months after azithromycin administration. This contrasted with cotrimoxazole and penicillin resistance, both of which were common (cotrimoxazole resistance, 42, 43, and 47%, and penicillin resistance, 21, 17, and 16% at baseline, 2 months, and 6 months, respectively). There was a significant association between cotrimoxazole and penicillin resistance (P < 0.0001, Fisher's exact). These data suggest that in communities where macrolide resistance is rare, azithromycin distribution for trachoma control is unlikely to increase the prevalence of resistant organisms.

Anti-Bacterial Agents↗

PubMed2002

Relation of antibiotic use to risk of myocardial infarction in the general population.

There are conflicting reports of an association between Chlamydia pneumoniae (C. pneumoniae) infection and coronary artery disease (CAD); randomized trials of antibiotics for the secondary prevention of CAD are currently underway. Physicians may be tempted to believe that their choice of antibiotic class in treating any infection may alter the risk of CAD. Our objective was to determine if the use of antibiotics with antichlamydial activity in the general population reduces the risk of myocardial infarction. A healthcare claims database with 354,258 patients with continuous health and pharmacy coverage for at least 2 years between January 1, 1991 and December 31, 1997 was used for the analyses. Hazard ratios were derived from proportional hazards models with time-dependent covariates, relating antibiotic prescription to first claim related to incident first myocardial infarction during the observation period, adjusting for previous CAD, age, sex, diabetes, hypertension, hyperlipidemia, and chronic obstructive pulmonary disease. There were a total of 1,684,091 person-years of observation and 16,139 incident myocardial infarctions. The adjusted hazard ratios were 1.10 (95% confidence intervals [CI] 1.04 to 1.16) for macrolides, 1.20 (95% CI 1.13 to 1.26) for quinolones, 1.10 (95% CI 0.96 to 1.21) for cephalosporins, 1.00 (95% CI 0.96 to 1.06) for tetracyclines, 1.01 (95% CI 0.96 to 1.06) for penicillins, and 1.13 (95% CI 0.98 to 1.30) for trimetroprim-sulfamethoxazole. The hazard ratios for individual antibiotics with activity against C. pneumoniae within each group were similar. Use of antibiotics with activity against C. pneumoniae does not reduce the risk of myocardial infarction in the general population.

Anti-Bacterial Agents↗

PubMed2002

Synergistic activities of macrolide antibiotics against Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans isolated from patients with cystic fibrosis.

Azithromycin and clarithromycin were paired with other antibiotics to test synergistic activity against 300 multidrug-resistant pathogens isolated from cystic fibrosis (CF) patients. Clarithromycin-tobramycin was most active against Pseudomonas aeruginosa and inhibited 58% of strains. Azithromycin-trimethoprim-sulfamethoxazole, azithromycin-ceftazidime, and azithromycin-doxycycline or azithromycin-trimethoprim-sulfamethoxazole inhibited 40, 20, and 22% of Stenotrophomonas maltophilia, Burkholderia cepacia complex, and Achromobacter (Alcaligenes) xylosoxidans strains, respectively.

Alcaligenes↗

PubMed2002

Assessment of azithromycin in combination with other antimalarial drugs against Plasmodium falciparum in vitro.

Initial field malaria prophylaxis trials with azithromycin revealed insufficient efficacy against falciparum malaria to develop azithromycin as a single agent. The objective of this in vitro study was to determine the best drug combination(s) to evaluate for future malaria treatment and prophylaxis field trials. In vitro, azithromycin was tested in combination with chloroquine against 10 representative Plasmodium falciparum isolates. Azithromycin was also assessed in combination with eight additional antimalarial agents against two or three multidrug-resistant P. falciparum isolates. Parasite susceptibility testing was carried out with a modification of the semiautomated microdilution technique. The incubation period was extended from the usual 48 h to 68 h. Fifty percent inhibitory concentrations (IC(50)s) were calculated for each drug alone and for drugs in fixed combinations of their respective IC(50)s (1:1, 3:1, 1:3, 4:1, 1:4, and 5:1). These data were used to calculate fractional inhibitory concentrations and isobolograms. Chloroquine-azithromycin studies revealed a range of activity from additive to synergistic interactions for the eight chloroquine-resistant isolates tested, while an additive response was seen for the two chloroquine-sensitive isolates. Quinine, tafenoquine, and primaquine were additive to synergistic with azithromycin, while dihydroartemisinin was additive with a trend toward antagonism. The remaining interactions appeared to be additive. These results suggest that a chloroquine-azithromycin combination should be evaluated for malaria prophylaxis and that a quinine-azithromycin combination should be evaluated for malaria treatment in areas of drug resistance.

Animals↗