Therapeutic effect of rokitamycin in vitro and on experimental meningoencephalitis due to Naegleria fowleri.

Inhalation of freshwater containing the free-living amoeba Naegleria fowleri leads to a potentially fatal infection known as primary amoebic meningoencephalitis (PAME). Amphotericin B is the only agent with clinical efficacy in the treatment of PAME in humans, however this drug is often associated with adverse effects on the kidney and other organs. In an attempt to select other useful therapeutic agents for treating PAME, the amoebicidal activities of antibacterial agents including clarithromycin, erythromycin, hygromycin B, neomycin, rokitamycin, roxithromycin and zeocin were examined. Results showed that the growth of amoeba was effectively inhibited by treatment with hygromycin B, rokitamycin and roxithromycin. Notably, when N. fowleri trophozoites were treated with rokitamycin, the minimal inhibitory concentration was 6.25 microg/mL on Day 2. In the treatment of experimental meningoencephalitis due to N. fowleri, survival rates of mice treated with roxithromycin and rokitamycin were 25% and 80%, respectively, over 1 month. The mean time to death for roxithromycin and rokitamycin treatment was 16.2 days and 16.8 days, respectively, compared with 11.2 days for control mice. Finally, rokitamycin showed both in vitro and in vivo therapeutic efficacy against N. fowleri and may be a candidate drug for the treatment of PAME.

Generating signals of drug-adverse effects from prescription databases and application to the risk of arrhythmia associated with antibacterials.

BACKGROUND: Although it is well known that a variety of antibacterials may incidentally cause malignant arrhythmia, the list of drugs causing arrhythmia and the impact of these adverse effects are still uncertain. We investigated on this topic by using a large prescription database with different observational designs. METHODS: Prescription data on all incident users of several antibacterial and antiarrhythmic drugs over the period July 1997 through December 1999 were retrieved from the Drug Prescription Database (DPD) of the Italian Province of Varese. The association between the use of antibacterial and antiarrhythmic drugs was investigated by applying prescription sequence symmetry, cohort and nested case-control designs. RESULTS: Lower proarrhythmic effects were on an average obtained from prescription sequence symmetry approach with respect to both cohort and nested case-control. Evidence of association between exposure to drugs (erythromycin and ciprofloxacin) and the risk of arrhythmia was consistently found by the three approaches. No other signals were generated from the prescription sequence symmetry analysis. Two drugs (clarithromycin and levofloxacin) showed patterns compatible with an arrhythmic effect according to both cohort and nested case-control designs. CONCLUSIONS: Prescription databases are useful tools to explore drug safety through both conventional and emerging observational designs. In spite of its appealing features, prescription sequence symmetry design shows lower sensitivity with respect to conventional designs. Evidence about the association between the use of certain macrolides and fluoroquinolones and the onset of arrhythmia is confirmed by this study.

Development of macrolide resistance by ribosomal protein L4 mutation in Streptococcus pyogenes during miocamycin treatment of an eight-year-old Greek child with tonsillopharyngitis.

Streptococcus pyogenes isolates with the same pulsed-field patterns were recovered from the throat cultures of a child with tonsillopharyngitis before and after treatment with miocamycin, a 16-membered macrolide. The initial isolate was macrolide-susceptible, but the isolates after the treatment were resistant to 14 and 15-membered macrolides and had two amino acid (65WR66) deletions in ribosomal protein L4.

Treatment with rokitamycin suppresses the lethality in a murine model of Escherichia coli O157:H7 infection.

The effects of rokitamycin (ROK) and levofloxacin (LEVX) were investigated in a murine model of enterohaemorrhagic Escherichia coli (EHEC) infection. After C3H/HeN mice were inoculated intragastrically with E. coli O157:H7, ROK (20mg/kg) or LEVX (1.2 mg/kg) was administered intragastrically. The death rate of the mice was noted and the faeces were collected to determine viable cell counts of EHEC and for Shiga-like toxins (SLTs) assays. After the mice were sacrificed, the kidneys and colons of some of the mice were removed for histopathological examination. The death rate of mice administered ROK (19%) was significantly lower than that of the control and LEVX-treated groups (80, 93%, respectively). Viable cell counts of EHEC in the faeces of the control and ROK-treated groups were 10(7) and 10(6) CFU/g at day 5 after the infection, respectively. LEVX reduced the bacterial count by less than 100 CFU/g at day 5. The level of SLTs in the faeces from the ROK group were lower than the LEVX-treated and control groups at day 5. The histopathological findings in the kidneys treated with LEVX showed necrotic tubular epithelial cells and those in the colon, inflammatory infiltrates. These were not seen in the ROK-treated group. These results suggested that ROK suppressed release of SLTs from the EHEC and could be useful in the treatment of EHEC infection.

[Epidemiological study of Chlamydia trachomatis infection in a sample of women requesting voluntary termination of pregnancy, treated with rokitamycin]. / Studio epidemiologico sull'infezione da Chlamydia trachomatis in un campione di donne che richiedono l'IVG trattate con rokitamicina.

BACKGROUND: Infection with Chlamydia trachomatis usually involves the cervix uteri, causing no symptoms, and may easily be unrecognised and untreated until troublesome symptoms arise, such as pelvic inflammatory disease, which can affect fertility and reproductive life. Therapies include the macrolide antibiotics, and in this class rokitamycin offers marked lipophilia, excellent intracellular penetration, and bactericidal activity at concentrations close to the MIC. The present study was therefore designed to establish the frequency of intracervical infection with Chlamydia trachomatis in women applying for termination of pregnancy, and to assess the efficacy and safety of this drug in this indication. METHODS: Women aged 18-40 years were admitted for termination of pregnancy, with a positive cervical swab for Chlamydia trachomatis. The study was conducted in accordance with the Declaration of Helsinki and amendments. Patients were given one oral tablet of 400 mg rokitamycin in the morning, and one in the evening, for two weeks. Treatment started ten days before the termination, within 48 h of taking the swab. Partners were to receive the same treatment. RESULTS: 292 women requiring termination of pregnancy, on average at the 9th week of pregnancy, were assessed. Of these, 24 (8.2%), mean (+/- SD) age 27.1 +/- 6.1 years, range 18-39, with a positive cervical swab for Chlamydia trachomatis, were treated with rokitamycin; 22 of their partners were treated too. Forty days after the start of treatment 22 patients (92%) gave negative results; these were all the cases whose partners had received treatment. No adverse events were reported and the acceptability of the treatment was considered good or excellent in 91% and fair in 9% of the cases. CONCLUSIONS: The findings confirm that rokitamycin is one of the most useful and effective macrolides for the treatment of infections caused by intracellular microorganisms; it is extremely well tolerated and has marked microbiological efficacy.

[Rokitamycin in the treatment of female genital Chlamydia and Mycoplasma infections. Comparative study vs josamycin ]. / Trattamento delle infezioni genitali da Chlamydia e Mycoplasma con rokitamicina. Studio controllato vs josamicina.

BACKGROUND: The macrolides are among the most effective antibiotics against infections due to Chlamydia and Mycoplasma. The drug in such cases must have marked antibacterial activity, good oral bioavailability, and high intracellular diffusion--indispensable for instance with Chlamydia infection. Rokitamycin, a macrolide with a 16-atom lactone ring, has the features for use in the treatment of genital infections caused by Chlamydia or Mycoplasma, penetrating the cell and reaching considerably higher concentrations than other drugs of the same class. The aim of this trial was to gain further knowledge of rokitamycin in genital infections, including cases infected with Mycoplasma hominis, comparing the efficacy and safety of this drug with josamycin, another macrolide widely employed in clinical practice. METHODS: Patients of either sex, over the age of 18 years, with infections due to Chlamydia trachomatis and Mycoplasma hominis, were admitted. The trial was conducted in accordance with the Declaration of Helsinki and amendments. Fifteen patients were given rokitamycin, one 400 mg tablet every 12 h, and another fifteen received josamycin, one 500 mg tablet every 8 h, for 14 days. Before starting treatment, after the 14 days and after 42 days' follow-up the severity of the following symptoms was assessed: pruritus, burning, erythema, pollakiuria, dysuria, using a four-point rating scale (0 = absent, 1 = mild, 2 = moderate, 3 = strong). The presence or absence of leukorrhea was noted. Patients entered the severity of subjective symptoms daily in a diary. At the end of the trial overall assessments were made on the clinical response, microbiological outcome and efficacy. RESULTS: Thirty patients of both sexes were admitted, age 21-43 years, with genital infections due to Chlamydia trachomatis and/or Mycoplasma hominis. Fifteen were given rokitamycin, 800 mg/day, and 15 josamycin, 1500 mg/day, for 14 days. In 13 cases in each group an antibiotic was prescribed for the partner too. At the start of the trial microbiological samples were taken; in 13 cases a urethral swab was taken (six in the josamycin and seven in the rokitamycin group), and 17 cervical swabs were taken (respectively nine and eight). At the end of the trial 93% of patients gave a negative microbiological result. Mycoplasma hominis was isolated from one patient treated with rokitamycin, and Chlamydia trachomatis from one patient given josamycin. Symptoms improved at a similar rate in both groups, with no significant differences between the drugs. Safety was excellent in both groups, with no complaints of adverse reactions. CONCLUSIONS: This trial demonstrates the excellent activity of macrolide antibiotics against genital infections due to Mycoplasma hominis and Chlamydia trachomatis. Rokitamycin and josamycin both gave good or excellent clinical and microbiological outcomes in more than 90% of the cases. Both were extremely well tolerated. These findings confirm and extend the indications for rokitamycin, found in earlier trials to be extremely effective in the treatment of urethritis due to Chlamydia trachomatis and--as a whole--in infections caused by this microrganism.

Evaluación del antibiótico miocamicina en niños con infecciones bacterianas cutáneas / Evaluation of the miocarmycin antibiotic in children with bacterial skin infecctions

Se llevó a cabo un ensayo clínico prospectivo abierto con 42 niños que sufrían de enfermedades de la piel, para verificar la eficacia y tolerancia de la Miocamicina, un nuevo antibiótico-macrólido. Se incluyeron 31 casos con impétigo, 5 forunculosis y 6 foliculitis con edades comprendidas entre 1 mes hasta 12 años de edad. De éstos, 27 fueron niñas y 15 niños, promedio de edad 3,3 años. La duración del tratamiento fue de 10 días, a una dosis oral de 30-50 mg/Kg/día. la suspensión de Miocamicina contenía 200 mg/5 ml. Se encontraron 30 aislados bacterianos con alta sensibilidad a la Miocamicina, 2 casos de sensibilidad intermedia y 10 casos con mediana resistencia, la mayoría de los cuales fueron Staphylococcus aureus. Los resultados clínicos mostraron porcentaje de éxito terapéutico equivalente a 90,32 por ciento dentro del grupo de 31 pacientes con impétigo. Asi mismo curaron completamente 3 forunculosis de un grupo de 6 casos, en tanto que 2 mejoraron parcialmente. Por su parte, se logró exito terapéutico total en 50 por ciento de los casos de foliculitis. Del grupo total de 42 pacientes, en 2 no se modificó la patología y 4 empeoraron. Estos datos totalizan un promedio de curación completa, para las 3 piodermias indicadas, equivalente a 85,71 por ciento. Los efectos secundarios se presentaron sólo en 2 casos y consistieron en diarrea ligera y pérdida de apetito, hecho que nos da una tolerancia del 95,23 por ciento

Uso y eficacia de la miocamicina en infecciones de piel y tejido blando en niños / Use and efficacy of miocamycin in skin and soft tissue infections in children

Se realizó un estudio clínico, abierto, no comparativo para evaluar la eficacia y seguridad de miocamicina, en infecciones de piel y tejido blando. Para este propósito se evaluaron treinta y dos (32) pacientes, entre 2 y 14 años con relación clínica y bacteriológica de afecciones de piel y tejido blando, que podían ser manejadas ambulatoriamente. La dosis utilizada fue de 30 mg/kg/día V.O. mediante dos tomas al día por 10 días; con evaluaciones clínicas a los tres, siete y/o diez días posteriores al comienzo del tratamiento. En veintisiete (27) pacientes se aisló el germen causal, los gérmenees aislados con mayor frecuencia fueron estafilococo coagulasa positivo en 14 casos (43 por ciento) y luego 3 Streptococus piógenes en 7 casos (21,8 por ciento). El porcentaje de curación fue del 94 por ciento y la tolerancia Streptococcus pyogenes considererada como excelente o buena en el 98 por ciento de los casos. Se presentaron efectos adversos gastrointestinales transitorios en cinco casos, siendo los más frecuentes: dolor abdominal, náuseas y vómitos. Ninguno de los casos requirió la interrupción del tratamiento

Miocamycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential.

Miocamycin is an orally administered 16-membered macrolide antimicrobial drug. It has a spectrum of in vitro activity similar to that of erythromycin, inhibiting a range of Gram-positive and Gram-negative organisms, atypical microbes and some anaerobes. Importantly, miocamycin demonstrates greater in vitro potency than erythromycin against several pathogens including Legionella pneumophila, Mycoplasma hominis, and Ureaplasma urealyticum. Equally noteworthy is its activity against erythromycin-resistant staphylococcal and streptococcal species expressing inducible-type resistance. Miocamycin possesses poor overall activity against Haemophilus influenzae and is inactive against Enterobacteriaceae. Penetration of miocamycin into body tissues and fluids is both rapid and extensive. The 3 major metabolites of miocamycin possess antimicrobial activity and may contribute to the therapeutic efficacy of the drug. Clinical data indicate that miocamycin is useful in the treatment of upper and lower respiratory tract infections in both adult and paediatric patients. Miocamycin is also effective in the treatment of urogenital tract infections caused by Chlamydia trachomatis or U. urealyticum. Several studies suggest that miocamycin is at least as effective as erythromycin in these indications; however, comparisons with newer macrolide agents have yet to be performed. In other studies, miocamycin proved to be a useful agent in the treatment of periodontal infections and as anti-infective prophylaxis in dental surgery. Miocamycin appears to have a tolerability profile qualitatively similar to that of other macrolides, with gastrointestinal and skin disorders being the most commonly reported adverse events. Current data suggest that the potential for drug interactions with miocamycin is low, with the possible exceptions of carbamazepine and cyclosporin. Thus, although further confirmation and elaboration of various aspects of its efficacy and tolerability profile is needed, at this stage miocamycin offers a useful alternative oral therapy to erythromycin for the treatment of uncomplicated community-acquired respiratory tract infections and nongonococcal urethritis.

Clinical efficacy of dirithromycin versus miocamycin in tonsillopharyngitis.

A single-blind, randomized, parallel-group study was conducted to compare the efficacy and safety of dirithromycin with miocamycin in the treatment of streptococcal pharyngitis/tonsillitis caused by Group A streptococci. The study population consisted of 60 patients: 30 were randomized to receive 500 mg dirithromycin od and 30 to receive 600 mg miocamycin bd. All 30 dirithromycin-treated patients were eligible for efficacy analysis. A favourable clinical response was observed in 100% of these patients at the post-therapy visit. In the miocamycin-treated group, 28 of 30 (93.3%) patients were eligible for efficacy analysis; a favourable clinical response was observed in 100%. Bacteriological cure of evaluable dirithromycin- and miocamycin-treated patients was 96.7% and 92.9%, respectively. No statistically significant post-therapy differences in clinical or bacteriological response rates were noted between the two groups. Adverse event analysis showed no significant differences between treatment groups. There were no serious adverse events during the study. Two miocamycin-treated patients were prematurely withdrawn from the study due to adverse events (diarrhoea). Analysis of clinical laboratory data revealed no statistically significant differences between the treatment groups that were considered to be drug related. The results of this study suggest that dirithromycin has comparable safety and efficacy to miocamycin in the treatment of streptococcal pharyngitis/tonsillitis infections caused by Group A streptococci.

Clinical efficacy of dirithromycin versus miocamycin in the treatment of acute bronchitis or acute exacerbations of chronic bronchitis.

A multicentre trial was carried out to compare the efficacy and safety of dirithromycin with miocamycin in the treatment of patients with acute bronchitis or acute exacerbations of chronic bronchitis. The study was a single-blind, randomized, parallel-group study. Dirithromycin was administered orally at a dosage of 500 mg once daily and miocamycin was administered orally at a dosage of 600 mg twice daily; the duration of therapy was five to seven days for both drugs. The results, in 161 assessable patients (78 taking dirithromycin; 83 taking miocamycin), show that dirithromycin and miocamycin have comparable efficacy and safety in the treatment of bronchitis caused by susceptible bacterial pathogens.

Dirithromycin in the treatment of skin and skin structure infections.

The efficacy and safety of dirithromycin were compared with those of erythromycin or miocamycin for the treatment of skin and/or skin structure infections in two double-blind, double-dummy, randomized, parallel group, multicentre studies conducted in North America and in Europe, and one single-blind, randomized, parallel group study conducted in Italy. The US and European study patients, in which bacterial infection was confirmed by culture, received either dirithromycin 500 mg once daily or erythromycin base 250 mg four times daily for seven days. Patients in the Italian trial were treated with either 500 mg dirithromycin once daily or with 600 mg miocamycin twice daily for seven days. A total of 156 of the 304 US patients treated with dirithromycin and 127 of the 274 patients treated with erythromycin qualified for efficacy analysis post-therapy. At the post-therapy evaluation, 112 (71.8%) dirithromycin-treated patients were cured and 34 (21.8%) improved compared with 94 (74.0%) and 25 (19.7%) patients treated with erythromycin. The pathogen was eliminated or presumably eliminated in 136 (87.2%) and 110 (86.6%) dirithromycin- and erythromycin-treated patients, respectively. A total of 100 of the 193 dirithromycin-treated patients qualified for efficacy analysis, as did 99 of the 198 erythromycin-treated patients in the European study at post-therapy. Favourable clinical responses (cure or improvement) at the post-therapy visit were recorded in 96 (96.0%) dirithromycin- and 98 (99%) erythromycin-treated patients, and pathogens were eliminated or presumed to have been eliminated in 87 (87.0%) and 88 (88.9%) patients respectively, in the dirithromycin and erythromycin treatment groups. Efficacy analysis was performed in 56 of the 70 Italian patients treated with dirithromycin and in 62 of the 71 patients treated with miocamycin. At post-therapy evaluation, a favourable clinical response was observed in 98.2% of the dirithromycin-treated patients compared with 95.1% of miocamycin-treated patients, whereas a favourable bacteriological response was observed in 52 (92.9%) dirithromycin- and 52 (83.9%) miocamycin-treated patients respectively. In all studies no serious treatment-related events were noted. Events most frequently reported were gastrointestinal in nature. Overall in the three studies, no statistically significant differences were observed between two treatment groups in the clinical and bacteriological outcomes.

Recovery of Chlamydia pneumoniae, in six patients with otitis media with effusion.

Six cases of otitis media with effusion associated with Chlamydia pneumoniae, a currently recognized respiratory tract pathogen, are presented. The organism was isolated from the middle ear fluids and serological evidence confirmed it as the infectious agent. The study population is small; however, these reports suggest C. pneumoniae as a causative agent of middle ear diseases.

[A clinical experience of rokitamycin on Campylobacter enteritis. Research Group of Rokitamycin on Infectious Enteritis].

Rokitamycin, a newly developed macrolide, was administered to a total of 107 cases, 16 years old or more, in order to evaluate its clinical efficacy, safety and usefulness on Campylobacter enteritis. Daily dosage of 600 mg of rokitamycin was administered orally in three divided doses for 5 days. Bacteriological and clinical efficacies were judged by the attending doctors from the evaluation criteria made by the committee and from the days required for improvement of diarrhea, defervescence and so on, respectively. Antibacterial activities against the isolates were tested of rokitamycin (RKM), erythromycin (EM), josamycin (JM) and ofloxacin (OFLX). The results were as follows; 41 symptomatic patients and 5 carriers were evaluated. Clinical efficacy (n = 41) was 100% (excellent; 34.1%, good; 65.9%). Bacteriological efficacy (n = 41) was 97.6%. Eight of the 9 cases with consecutive stool cultures were free of the bacteria on and after one day of the drug administration. Clinical usefulness (n = 46) was 97.8%. Slight epigastric pain was seen in only one as a side effect. The items of abnormal laboratory findings were 4 elevated GPT and/or GOT and one increased number of WBC in 4 cases. MIC90 of RKM, EM, JM and OFLX against 41 clinical isolates of C. jejuni were 1.56, 3.13, 3.13 and 0.78 micrograms/ml, respectively. Rokitamycin was considered clinically useful to treat Campylobacter enteritis.

[Comparison of clinical efficacy of rokitamycin (RKM) and ofloxacin (OFLX) for the treatment of Campylobacter enteritis by a double-blind method. The Research Committee for the Effect of Rokitamycin, Research Group for Infectious Enteritis].

The clinical efficacy, safety and usefulness of Rokitamycin (RKM), a new macrolide antibiotic, were compared with those of Ofloxacin (OFLX) for the treatment of Campylobacter enteritis by a double blind method. The daily dose level of RKM or OFLX was 600 mg. They were orally administered in three divided doses for 5 days. Of 223 cases studied, 106 cases were diagnosed as Campylobacter enteritis. Ninety cases (RKM group: 50, OFLX group: 40) except for 16 excluded or drop-out cases were analysed. There was no significant difference between the two groups in any background factors. The effectiveness and usefulness was evaluated in 88 cases (RKM group: 48, OFLX group: 40). The results obtained were as follows: 1. In a total of 82 strains of Campylobacter jejuni/coli (RKM group: 42, OFLX group: 40), the bacteriological efficacy rate of RKM (95.2%) was superior to that of OFLX (70.0%) with a significant difference (p = 0.006). 2. In 76 symptomatic patients (RKM group: 42, OFLX group: 34) on the day of the beginning of drug administration, the clinical efficacy rate was 97.6% in the RKM group and 85.3% in the OFLX group with no significant difference between the two groups. 3. In 88 evaluable patients, the global clinical efficacy rate of RKM (95.8%) was superior to that of OFLX (67.5%) with a significant difference (p = 0.001). 4. Side effect was observed in 1 (1.9%) of the 54 patients in the RKM group and none of the 44 patients in the OFLX group. Slightly abnormal laboratory findings were seen in 4 (10.8%) of the 37 patients treated with RKM and 3 (9.7%) of the 31 patients treated with OFLX, but there was no significant difference between the two groups. 5. In 88 evaluable patients, the clinical usefulness of RKM (91.7%) was superior to that of OFLX (67.5%) with a significant difference (p = 0.01). From these results, RKM is considered to be a very useful agent for the treatment of Campylobacter enteritis.

Antibióticos macrolídicos - retorno à vista? / Macrolide antibiotics, a return in sight?

O autor apresenta as perspectivas de progressos, no campo da terapêutica antimicrobiana, representadas pelo aparecimento de novos antibióticos macrolídicos com propriedades que os diferenciam, e muitas vezes os tornam mais atraentes, relativamente aos membros mais antigos da família. Compara esses novos antibióticos com a eritromicina, destacando as diferenças de propriedades farmacocinéticas e de espectro antimicrobiano. Por fim, apresenta as indicaçöes terapêuticas especiais que esses medicamentos poderäo vir a ter