Effectiveness and Pharmacokinetic evaluation of Geonistin® (Oxytetracyline and Nystatin) Vaginal Tablets for Unspecific and Mixed Vulvovaginal Infections (GENIE Study).

The GENIE study was performed to evaluate the effectiveness and systemic exposure to oxytetracycline in local treatment of unspecific and mixed vulvovaginal infections characterized by vaginal discharge with Geonistin® vaginal tablets (100 mg oxytetracycline and 100 000 IU nystatin). The total number of subjects enrolled was 189. The treatment had beneficial effects in 100% of the study population. According to the Nugent score, the treatment had a positive effect in 89.2% of participants. The microbiological cure rate was 78.8%. Oxytetracycline concentration levels were from 13.3 to 32.2 ng/mL in 11 out of 15 subjects, and in four subjects the levels were below 10 ng/mL. Geonistin® had a beneficial effect on the unspecific and mixed vulvovaginal infections characterized by vaginal discharge in all efficacy and safety outcomes. Microbiological and the Nugent score efficacy measures confirmed clinical effectiveness. Beneficial efficacy results were achieved with only a few non-serious adverse events.

Detection of sexually transmitted pathogens in patients with chronic prostatitis/chronic pelvic pain: a prospective clinical study.

In <10% of patients with prostatitis syndrome, a causative uropathogenic organism can be detected. It has been shown that certain organisms that cause sexually transmitted infections can also cause chronic bacterial prostatitis, which can be hard to diagnose and treat appropriately because prostatic samples obtained by prostatic massage are not routinely tested to detect them. We conducted a clinical study to determine the prevalence of Chlamydia, mycoplasma, and trichomonas infection in 254 patients that were previously diagnosed and treated for chronic prostatitis/chronic pelvic pain syndrome due to negative urethral swab, urine, and prostate samples. Urethral swabs and standard Meares-Stamey four-glass tests were done. Detailed microbiological analysis was conducted to detect the above organisms. Thirty-five (13.8%) patients had positive expressed prostatic secretions/VB3 samples, of which 22 (10.1%) were sexually transmitted organisms that were not detected on previous tests.

Antimicrobial Sensitivity Profile of Chlamydia trachomatis isolates from Croatia in McCoy Cell Culture System and Comparison with the Literature.

BACKGROUND: Chlamydia trachomatis (C. trachomatis) is the most common bacterial agent of sexually transmitted infections around the world, but susceptibility testing of this pathogen is rarely pursued due to its intracellular niche. The principal aims of this research were to determine in vitro sensitivity profile of urogenital chlamydial strains isolated from Croatian patients and to compare obtained concentration values of different antimicrobial drugs mutually and with the literature. METHODS: Forty strains of C. trachomatis isolated during 2010-2012 at the National Reference Laboratory for Chlamydia and two reference strains were subjected to susceptibility testing in 96-well microtiter plates containing McCoy cell monolayers. Minimal inhibitory concentration (MIC) and minimal chlamydicidal concentration (MCC) were determined for azithromycin, doxycycline, and levofloxacin. Briefly, strains were inoculated on McCoy cells, followed by addition of serially diluted antimicrobial drugs. Upon incubation, growth of C. trachomatis was detected using fluorescein-conjugated antibody to the lipopolysaccharide genus antigen under the inverted fluorescent microscope. RESULTS: All chlamydial strains were susceptible to the antibiotics tested (MIC < 4 pg/mL), thus the pattern of homotypic or heterotypic resistance has not been found. MCC values were equal or 1-5 dilutions higher than MIC values. Statistically significant differences in the effectiveness of antimicrobial agents in vitro have been proven. Significant correlation has been found for MCCs in the case of two antimicrobial pairs: azithromycin and levofloxacin, and doxycycline and levofloxacin. Comparison of medians for different clinical samples did not reveal any significant difference. CONCLUSIONS: Although resistant strains have not been found in this study, several literature reports of unsuccessfully treated genitourinary infections caused by C. trachomatis require our alertness for possible discovery of resistant strains. Considering the overall antibiotic burden worldwide, pursuing this kind of research is crucial in order to detect possible decreased susceptibility (or even resistance) of chlamydial strains, despite the laborious and time-consuming methodology.

Septic abortion caused by Campylobacter jejuni bacteraemia.

A 20-year-old female patient, 14 weeks pregnant, was admitted to hospital with anamnestic and clinical features of acute pyelonephritis. Clinical signs of septic abortion developed and after obstetric examination the therapy was changed to ampicillin, gentamicin and clindamycin. Campylobacter jejuni was isolated from blood cultures. Pathohistological findings confirmed diagnosis of purulent chorioamnionitis. After 2 weeks of ciprofloxacin administration the patient fully recovered. Campylobacter jejuni was not isolated from stool culture and no signs of acute enteritis were registered during the illness. Invasive forms of Campylobacter disease without enteritis are not unusual in immunocompromised hosts but they are restricted to C. fetus rather than C. jejuni isolates.

Platelet satellitism in infectious disease?

BACKGROUND: Platelet satellitism is a phenomenon of unknown etiology of aggregating platelets around polymorphonuclear neutrophils and other blood cells which causes pseudothrombocytopenia, visible by microscopic examination of blood smears. It has been observed so far in about a hundred cases in the world. CASE SUBJECT AND METHODS: Our case involves a 73-year-old female patient with a urinary infection. Biochemical serum analysis (CRP, glucose, AST, ALT, ALP, GGT, bilirubin, sodium, potassium, chloride, urea, creatinine) and blood cell count were performed with standard methods on autoanalyzers. Serum protein fractions were examined by electrophoresis and urinalysis with standard methods on autoanalyzer together with microscopic examination of urine sediment. Erythrocyte sedimentation rate, blood culture and urine culture tests were performed with standard methods. RESULTS: Due to typical pathological values for bacterial urinary infection, the patient was admitted to the hospital. Blood smear examination revealed phenomenon, which has persisted for three weeks after the disease has been cured. Blood smears with EDTA as an anticoagulant had platelet satellitism whereas the phenomenon was not observed in tubes with different anticoagulants (Na, Li-heparin) and capillary blood. DISCUSSION: We hypothesize that satellitism was induced by some immunological mechanism through formation of antibodies which have mediated platelets binding to neutrophil membranes and vice versa. Unfortunately we were unable to determine the putative trigger for this phenomenon. To our knowledge this is the second case of platelet satellitism ever described in Croatia.

The significance of Chlamydia trachomatis in prostatitis syndrome.

Research and publication expenses were supported in part by the Croatian Science Foundation and PLIVA Croatia Ltd. (project no. 04/30 'Research on the aetiology, epidemiology, diagnostics, and treatment of patients with prostatitis syndrome').

In vitro susceptibility of urogenital Chlamydia trachomatis strains in a country with high azithromycin consumption rate.

Although Chlamydia trachomatis resistance is not of great concern due to its excellent sensitivity to the currently recommended first-line antibiotics (azithromycin and doxycycline), clinical treatment failures have been reported and some of them were linked to laboratory proved resistance. The aim of this study was to determine in vitro susceptibility to azithromycin and doxycycline for 24 urogenital chlamydial strains isolated in Croatia-a country with the highest consumption of azithromycin in Europe and with very high antibiotic prescription rates. Fourteen isolates from cervical swabs, nine from male urethral swabs, and one isolate from expressed prostatic secretion were tested in McCoy cell culture system. All strains were susceptible to azithromycin and doxycycline with minimal inhibitory concentration for azithromycin and doxycycline ranging from 0.064 to 0.125 µg/mL and 0.016 to 0.064 µg/mL, and minimal chlamydicidal concentration ranging from 0.064 to 2.0 µg/mL and 0.032 to 1.0 µg/mL, respectively. Since we still lack information on whether C. trachomatis is evolving in vivo in response to antibiotic selection pressure, this kind of surveillance for resistance is essential in detecting shifts in antimicrobial susceptibilities.

Serum levels of metalloproteinases and their inhibitors during infection with pathogens having integrin receptor-mediated cellular entry.

BACKGROUND: Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes with numerous roles in the normal immune response to infection. However, excess MMP activity following infection may lead to immunopathological processes that cause tissue damage. Their activity in normal tissues is subject to tight control, which is regulated by its specific endogenous tissue inhibitors (TIMPs). It is known that MMPs bind to cell surface proteins (e.g. integrins) and that such interactions can have modulatory effects on MMP functionality. The objective of this study was to determine whether there are differences in MMP and TIMP production during the acute phase of infection with different pathogens that use ß-integrins as their receptors for cell entry. METHODS: We measured the total amounts of soluble MMP-2, MMP-9, TIMP-1, and TIMP-2 in the sera from patients infected with Dobrava virus (DOBV), Coxiella burnetii, or uropathogenic Escherichia coli. Statistical analyses were used to correlate MMP/TIMP serum levels with different clinical laboratory parameters. RESULTS: The results showed that both of the bacterial infections generally manifested the stronger effect on MMP production, while in contrast, viral infection introduced stronger changes to metalloproteinase inhibitors. MMPs and TIMPs were significantly correlated with some of the clinical laboratory parameters in both bacterial infections, but no correlations were found for DOBV infection. CONCLUSIONS: These findings suggest diverse mechanisms by which MMP activity could be implicated in the pathology of these 2 bacterial infections versus the viral DOBV infection, despite the type of their cellular entry receptors.

Fluoroquinolone-macrolide combination therapy for chronic bacterial prostatitis: retrospective analysis of pathogen eradication rates, inflammatory findings and sexual dysfunction.

We previously demonstrated the safety and efficacy of fluoroquinolone-macrolide combination therapy in category II chronic bacterial prostatitis (CBP). The aim of this study is to retrospectively compare the microbiological and clinical findings of two treatment schemes for CBP based on the combination of azithromycin (500 mg, thrice-weekly) with a once-daily 500- or 750-mg dose of ciprofloxacin (Cipro-500 or Cipro-750 cohort, respectively). Combined administration of azithromycin (1500 mg week(-1)) with ciprofloxacin at the rate of 750 mg day(-1) for 4 weeks rather than at 500 mg day(-1) for 6 weeks increased the eradication rates from 62.35% to 77.32% and the total bacteriological success from 71.76% to 85.57%. A significant decrease in pain and voiding signs/symptoms and a significant reduction in inflammatory leukocyte counts and serum prostate-specific antigen (PSA) were sustained throughout an 18-month follow-up period in both groups. Ejaculatory pain, haemospermia and premature ejaculation were significantly attenuated on microbiological eradication in both groups, but the latter subsided more promptly in the Cipro-750 cohort. In total, 59 Cipro-750 patients showed mild-to-severe erectile dysfunction (ED) at baseline, while 22 patients had no ED on microbiological eradication and throughout the follow-up period. In conclusion fluoroquinolone-macrolide therapy resulted in pathogen eradication and CBP symptom attenuation, including pain, voiding disturbances and sexual dysfunction. A once-daily 750-mg dose of ciprofloxacin for 4 weeks showed enhanced eradication rates and lower inflammatory white blood cell counts compared to the 500-mg dose for 6 weeks. Our results are open to further prospective validation.

Critical issues in chronic prostatitis.

In the last decade, an impressive amount of clinical research data has shed new light on pathogenesis and management of the chronic prostatitis syndrome. A new classification and a validated symptom score have enabled urologists worldwide to speak a "common language", thus greatly improving the amount and quality of focused research in this field. In Europe, a large number of groups and experts have been actively involved in this research, and have developed in many cases a genuine view on prostatitis and chronic pelvic pain etiology, diagnosis and treatment. The present paper, written by a panel of researchers from Europe and Far East Russia, reviews the most recent findings, discusses the most controversial contemporary topics on prostatitis syndromes, and highlights a number of unresolved issues requiring further research and study.

[Urogenital infections--antimicrobial treatment]. / Urogenitalne infekcije--antimikrobno lijecenje.

Urogenital infections are among the most common infectious diseases of humans in the world. They are one of the leading causes of acute diseases, chronic health impairment and mortality. Sexually transmitted infections are important public health problem due to their epidemic spread, numerous complications leaving permanent consequences on the human health as well as large expenses that health care systems and individuals have to pay for their detection, prevention and treatment. Urinary tract infections are the most common bacterial infections in humans and the most common reason for justified antibiotic prescriptions. Prostatitis syndrome is the most common urological problem in males younger than 50 years of age and third most common urological problem in older men. This paper does not deal with all existing problems regarding antimicrobial treatment of sexually transmitted infections, urinary tract infections and prostatitis syndrome, however basic guidelines that cover the majority of conditions are presented.

[Determining antimicrobial resistance to Chlamydia trachomatis and applying present findings in daily practice]. / Odredivanje antimikrobne rezistencije Chlamydia trachomatis i primjena dosadasnjih spoznaja u svakodnevnoj praksi.

Chlamydia trachomatis (C. trachomatis) is the most common bacterial causative agent of sexually transmitted diseases today. Treatment outcome will depend on the choice of antimicrobial drug. Therefore, it is very important to know antimicrobial sensitivity of this pathogen. Cultivation in cell culture is a method of choice for diagnosis of C. trachomatis infection, in terms of medico-legal investigations and follow-up after completed therapy, but also serves for determining the antimicrobial sensitivity of C. trachomatis. Tetracyclines, macrolides and kinolones are commonly used in the treatment of the C. trachomatis infection. Resistance to these antibiotics was described for strains isolated from unsuccessfully treated patients. All described resistant clinical strains demonstrated in vitro heterotypic resistance. To date no homotypic resistance was described for human isolates. An evaluation of antimicrobial resistance and treatment outcome in C. trachomatis infection is complicated by the lack of standardized tests, as well as by the fact that in vitro resistance does not correlate with clinical outcome. In case of any suspicion of unsuccessful treatment of genitourinary infection caused by C. trachomatis isolation should be attempted and isolated strains forwarded to a specialized laboratory.

[ISKRA guidelines on antimicrobial treatment and prophylaxis of urinary tract infections--Croatian national guidelines]. / ISKRA smjernice antimikrobnog lijecenja i profilakse infekcija mokracnog sustava--hrvatske nacionalne smjernice.

These guidelines refer to diagnosis, antimicrobial treatment and prophylaxis of urinary tract infections in adults and children older than 12 years of age and cover lower urinary tract in females, uncomplicated pyelonephritis, complicated UTI with or without pyelonephritis, asymptomatic bacteriuria and recurrent UTI. These guidelines do not cover sexually transmitted diseases. The guidelines are primarily intended for use by general practitioners and specialists working in primary health care and hospitals. The members of the Working Group for the development of guidelines on antimicrobial treatment and prophylaxis of urinary tract infections were appointed by the Croatian Ministry of Health and Social Welfare. The project was financially supported by the Dutch government and professional assistance was provided by international consultants. The evidence for this guidelines is based on a systematic review of the literature, local antibiotic resistance data, the existing clinical protocols on the treatment and prophylaxis of UTIs, as well as suggestions and comments made by colleagues physicians during more than 50 continuous medical education courses held in the last three years on antimicrobial treatment and prophylaxis of UTIs. Draft version of the guidelines was available for comments on the web site http://iskra.bfm.hr and during the two-month piloting period the guidelines were widely presented to general practitioners, specialists working in primary care and hospitals--urologists, gynecologists, infectious disease specialists, nephrologists. The final version of the guidelines was approved by the Intersectoral Coordination Mechanism for the Control of Antimicrobial Resistance (ISKRA) Board.

Research of urinary tract infections in family medicine physicians' offices--empiric antimicrobial therapy of urinary tract infections--Croatian experience.

In the period between October 1st and November 30th, 2006, we investigated a total of 3188 episodes of UTI (802 among males; 2386 among females) recorded in 108 family medicine offices in 20 cities in Croatia. The most common UTIs in women were acute uncomplicated cystitis (62%), complicated UTIs - cystitis and pyelonephritis (14%), urethritis (9%), acute uncomplicated pyelonephritis (6%), recurrent cystitis (5%), asymptomatic bacteriuria (3%) and recurrent pyelonephritis. The most common UTIs in men were complicated UTIs - cystitis and pyelonephritis (48%), urethritis (25%), prostatitis (24%) and asymptomatic bacteriuria (3%). Etiological diagnosis was made in 999 (31%) UTI episodes before antimicrobial therapy was given. The most frequently isolated causative pathogens were Escherichia coli (77%), Enterococcus faecalis (9%), Proteus mirabilis (5%), Klebsiella spp (3%), Streptococcus agalactiae (3%) and Enterobacter (1%). Antimicrobial drug was administered in 2939 (92.19%) UTI episodes, in 1940 (66.01%) as empirical therapy, and in 999 (34%) as targeted antimicrobial therapy. The most commonly administered drug in empirical therapy for acute uncomplicated cystitis, recurrent cystitis and urethritis in women was cephalexin, for acute uncomplicated pyelonephritis and complicated UTIs in women co-amoxiclav, and for UTIs in males ciprofloxacin. The results of this research of 3188 UTI episodes in family medicine physicians' offices provide a confirmatory answer to question whether empirical antimicrobial therapy of UTI prescribed by Croatian family practitioners is in accordance with the national guidelines.

Comparison of clinical symptoms scored according to the National Institutes of Health chronic prostatitis symptoms index and assessment of antimicrobial treatment in patients with chronic prostatitis syndrome.

We examined a total of 194 patients over 18 years of age with chronic prostatitis syndrome and no evidence of structural or functional lower genitourinary tract abnormalities. The following data were obtained for each patient: clinical history--the severity of chronic prostatitis symptoms scored by a Croatian translation of the NiH CPSI questionnaire, clinical status including digitorectal examination, urethral swab specimens, and selective samples of urine and expressed prostatic secretion, according to the 4-glass localization test (meares and Stamey localization technique). Patients were treated orally with antimicrobial agents in doses and duration according to clinical practice in Croatia. An infectious etiology was determined in 169 (87%) patients. Chlamydia trachomatis was the causative pathogen in 38 (20%), Trichomonas vaginalis in 35 (18%), Enterococcus in 36 (19%) and Escherichia coli in 35 (18%) patients. In the remaining 25 patients the following causative pathogens were found: Ureaplasma urealyticum, Proteus mirabilis, Klebsiella pneumoniae, Streptococcus agalactiae and Pseudomonas aeruginosa. Comparison of symptoms scores and effect on quality of life has shown that the most severe clinical presentation of disease was recorded in patients with chronic bacterial prostatitis caused by E. coli and Enterococcus (p<0.001). Clinical success was paralleled by bacteriological eradication in chronic bacterial prostatitis caused by C. trachomatis, Enterococcus and E. coli (kappa >0.2<0.5), but not in inflammatory chronic pelvic pain syndrome caused by T. vaginalis.

The significance of Chlamydia trachomatis in urethritis and prostatitis - differences in therapeutic approach - Croatian experience.

We examined a total of 1014 patients over 18 years of age; 252 with urethritis and 762 with chronic prostatitis syndrome. the mean age of patients with urethritis was 32.7 and with prostatitis syndrome 37.6 years. Clinical symptoms of urethritis were present from a few days to several months. in patients with chronic prostatitis syndrome, symptoms were present for at least 3 months. Chlamydia trachomatis alone was confirmed in 26 (10%) and in combination with Ureaplasma urealyticum in 6 (2%) patients with urethritis. in 171 (68%) patients with urethritis neither C. trachomatis nor U. urealyticum or Mycoplasma hominis were found. C. trachomatis alone was confirmed in 70 (9%), and in combination with other microorganisms in 7 (1%) patients with chronic prostatitis syndrome. in Croatia, the frequency of chronic chlamydial prostatitis has not significantly changed in the last 10 years, while the frequency of infections among adolescents decreased. the recommended regimen for acute chlamydial urethritis in Croatia is azithromycin 1.0 g as a single dose, and a total dose of 4-4.5 g azithromycin for chronic chlamydial prostatitis.

The role of Chlamydia trachomatis in prostatitis syndrome--our experience in diagnosis and treatment.

Since the beginning of 1999, over 1500 patients with symptoms of chronic prostatitis were examined at Dr. Fran Mihaljevic University Hospital for Infectious Diseases in Zagreb. In almost all of these patients urethral swabs and quantitative segmented bacteriologic cultures and microscopy of expressed prostatic secretion (EPS) or voided bladder urine3 (VB3) were performed as described by Meares and Stamey. Urethral swabs, EPS or VB3 were examined for the presence of Chlamydia (C.) trachomatis by McCoy culture and Lugol stain or by immunofluorescent typing with monoclonal antibodies. In the majority of patients C. trachomatis was demonstrated in parallel in EPS or VB3 by DNA/RNA hybridization method. Normal white blood cell count viewed per high power field<10 was found in 362 (68%) of 536 patients with symptoms of chronic prostatitis and C. trachomatis detected in EPS or VB3. These findings additionally suggest that C. trachomatis can be suspected as a causative pathogen in all categories of chronic prostatitis syndrome. Furthermore, this paper summarizes the results of five previously published clinical studies on the efficacy and tolerability of various treatment schemes for chronic chlamydial prostatitis, conducted from the beginning of 1999 until the end of 2003.