Eradication of methicillin-resistant Staphylococcus aureus (MRSA) throat carriage: a randomised trial comparing topical treatment with rifampicin-based systemic therapy.

Eradication of methicillin-resistant Staphylococcus aureus (MRSA) colonisation may prevent transmission of strains between patients and reduces the risk of clinical infection. Colonisation of the throat is associated with prolonged carriage and is more difficult to eradicate. An open randomised study was conducted to evaluate two eradication protocols. Patients with pharyngeal carriage of MRSA were enrolled at six Swedish centres during 4 years. One treatment group received oral rifampicin and either clindamycin or trimethoprim/sulfamethoxazole (SXT) for 7 days in combination with nasal mupirocin. Patients in the other group were treated with nasal mupirocin only. Patients in the same household were randomised together. Both groups followed a hygiene protocol including chlorhexidine washing. Cultures from the nares, perineum and throat were taken at baseline and then at 2 weeks, 2 months and 6 months after the end of treatment. A total of 28 patients received rifampicin-based systemic antibiotics and 24 subjects received mupirocin only. At follow-up 6 months after the end of treatment, 61% of patients and 50% of households in the systemic antibiotics group had culture results negative for MRSA. Significantly less patients (12%) and households (10%) became decolonised in the group receiving topical treatment only. A combination of rifampicin and either clindamycin or SXT was more effective in eliminating pharyngeal MRSA carriage compared with topical treatment with mupirocin only.

The modified Cincinnati procedure: combined conjunctival limbal autografts and keratolimbal allografts for severe unilateral ocular surface failure.

PURPOSE: To describe the technique and present the outcomes of combined conjunctival limbal autografts (CLAU) and keratolimbal allografts (KLAL) for the treatment of unilateral severe ocular surface failure. METHODS: Interventional case series. Eleven eyes of 11 patients who sustained chemical burns (4 alkali and 2 acid) and combined chemical/thermal burns (5 eyes) from firework explosions had combined CLAU/KLAL surgery. Keratoplasty was performed subsequently for residual corneal stromal scarring limiting visual acuity. Inclusion criteria included eyes with severe unilateral total ocular surface failure, controlled glaucoma, and reasonable eyelid apposition with no exposure. Exclusion criteria included patients with any ocular surface abnormality in the fellow eye and those with contraindications to systemic immunosuppression (SI). Outcome measures included Snellen best-corrected visual acuity (BCVA), ocular surface stability, SI exposure, and complications. RESULTS: Preoperative BCVA was 20/400 or worse in all eyes. At the final follow-up (mean, 35.8 months; range, 12.1-105.9 months), 73% (8 of 11) eyes had BCVA of 20/80 or better (range, 20/25 to counting fingers), and ocular surface was stable in 82% (9 of 11). Ninety-one percent (10 of 11) had additional penetrating keratoplasty (PK) with a 60% (6 of 10 eyes) success rate. Three cases had subsequent Boston type 1 keratoprosthesis implantation after PK failure, and the fourth patient, at the time of his last follow-up visit, did not want further intervention for his edematous PK, which was a result of noncompliance-related corneal rejection. In eyes with more than 2 years of follow-up, SI was tapered at a mean of 16 months (range, 8-28 months). There were no intraoperative complications. No secondary tumors, cardiac events, or deaths occurred while patients were on SI. One patient developed secondary glaucoma refractory to medical management after subsequent PK, requiring cyclodiode laser. CONCLUSIONS: Combined CLAU/KLAL and staged keratoplasty is effective in improving vision and maintaining long-term ocular surface stability in patients with severe unilateral ocular surface disease and conjunctival deficiency.

[Of bugs and joints. Oligoarthritis caused by Tropheryma whipplei]. / Oligoarthritis durch Tropheryma whipplei. "Of bugs and joints".

Whipple's disease is a rare, chronic infection caused by Tropheryma whipplei, an ubiquitary gram positive bacterium. The disease is associated with a high mortality in absence of an antibiotic treatment. The disease can be detected in affected tissues and body fluids by light and electron microscopy, as well as by polymerase chain reaction (PCR). Musculoskeletal symptoms such as arthralgia and arthritis frequently represent the first manifestation of this multi-system disease; typical subsequent symptoms are weight loss, diarrhea, and abdominal pain. Symptoms of central nervous system involvement are present in 10-40% of cases. We report on a 67 year-old male with a history of migratory oligoarthritis over three decades in whom the causative agent was detected by PCR in synovial fluid only. This case illustrates that searches for the characteristic PAS-positive macrophages and PCR in biopsies from the duodenum may be insufficient and that diagnostic efforts should be complemented with PCR assays from affected tissues or body fluids. It is recommended that antibiotic treatment be carried out with an agent that penetrates well into the cerebrospinal fluid, e.g. ceftriaxone, followed by cotrimoxazole. Antibiotics should be maintained over several months to years. It is prudent to document the disappearance of the pathogen in the affected compartments prior to the discontinuation of the antibiotic therapy.

Pivmecillinam versus sulfamethizole for short-term treatment of uncomplicated acute cystitis in general practice: a randomized controlled trial.

OBJECTIVE: To investigate whether short-term treatment with pivmecillinam was more effective than sulfamethizole in patients with acute uncomplicated urinary tract infection (UTI). DESIGN: Randomized controlled trial. SETTING: General practice, Denmark. SUBJECTS: Patients (n = 167) with uncomplicated UTI confirmed by positive urine phase-contrast microscopy. MAIN OUTCOME MEASURES: Drug efficacy based on clinical and bacteriological cure. RESULTS: Urinary symptoms disappeared first in patients treated with pivmecillinam, but after five days there was no significant difference in clinical cure rate between the two antibiotics. At the follow-up visit 7-10 days after initiation of treatment, 95.4% of patients treated with pivmecillinam and 92.6% of patients treated with sulfamethizole had no persistent cystitis symptoms (difference 2.8%, CI -4.5%; 10.0%). Bacteriological cure was observed in 68.8% of patients randomized to pivmecillinam and in 77.9% randomized to sulfamethizole (difference -9.2%, CI -24.7%; 6.3%). Some 26.8% of patients randomized to pivmecillinam experienced a new UTI within 6 months after treatment compared with 18.4% of patients randomized to sulfamethizole (difference 8.4%, CI -4.5%;21.4%). No patients developed septicaemia with urinary pathogens within one year after initial treatment. CONCLUSION: Patients treated with a three-day regime of pivmecillinam experienced faster relief of symptoms compared with patients treated with a three-day regime of sulfamethizole. Five days after initiation of treatment there was no significant difference in clinical and bacteriological cure between the two antibiotic regimes.

[A case of Salmonella paratyphi A infection in Poland]. / Przypadek zawleczenia paraduru typu A do Polski.

Paratyphoid fever is an acute infection caused by Salmonella paratyphi A, B or C. The disease is transmitted from person to person by fecal-oral way. Typical for typhoid fever are splenomegaly, bradycardia, fever, constipation or mild diarrhoea oftten associated with abdominal tenderness. We present the case of patient who was infected by Salmonella paratyphi C while his travelling in Asia.

Urinary concentrations and urine ex-vivo effect of mecillinam and sulphamethizole.

Healthy adult volunteers received 1 g of sulphamethizole orally (n = 10) and later 400 mg of pivmecillinam (274 mg of mecillinam) (n = 9). All urine was collected in defined periods over 24 h, and the drug concentrations in urine were determined. For sulphamethizole, the maximum urine concentration for seven subjects was reached in 0-3 h, and for the remaining three in 3-6 h. For mecillinam, eight of the nine subjects attained a maximum urine concentration in 0-3 h, after which the concentration declined rapidly for six subjects in 3-6 h. Strains of Escherichia coli with different MICs for sulphamethizole and mecillinam were exposed to collected urine for 2.5 h and 5 h. The results indicated that a sensitive E. coli population should be suppressed by sulphamethizole in urine for two-thirds of the time (with 1 g twice-daily) and by mecillinam in urine throughout the 24-h period (with 400 mg three times a day). There was a slight but significant correlation between the ex-vivo effect (Delta log10 CFU/mL) and the log10 concentration/MIC ratio after exposure to sulphamethizole for 5 h (r2 = 0.27, p < 0.0001), and a significant correlation between the variables with mecillinam (r2 = 0.66, p < 0.0001).

Case report: Nocardia asteroides mycetoma.

Primary cutaneous infections with Nocardia asteroides are rare and have been reported in immunocompromised patients. Herein, we report a case of primary cutaneous Nocardia asteroides mycetoma of the skin in an immunocompetent individual. The infection was treated successfully with trimethoprim-sulfamethoxazole. Because a prolonged incubation time is required for the cultures and since additional biochemical tests are necessary for identification of this species, the clinician should alert the microbiology laboratory when such an infection is suspected clinically.

Clinical efficacy of trimethoprim/sulfadiazine and procaine penicillin G in a Streptococcus equi subsp. zooepidemicus infection model in ponies.

Tissue chambers, implanted subcutaneously on both sides of the neck in eight ponies, were inoculated with Streptococcus equi subsp. zooepidemicus in order to compare the clinical efficacy of trimethoprim/sulfadiazine (TMP/SDZ) and penicillin G treatment in a purulent infection. The TMP/SDZ treatment consisted of one intravenous (i.v.) injection of 5 mg/kg TMP and 25 mg/kg SDZ and the same dose of TMP/SDZ per os (p.o.), both given 20 h after inoculation. The oral dose was then repeated every 12 h for 21 days. The penicillin treatment consisted of one i.v. injection of 20 000 IU/kg sodium penicillin G and intramuscular (i.m.) injection of 20 000 IU/kg procaine penicillin G, both given 20 h after infection. The i.m. dose was then repeated every 24 h for 21 days. Eight ponies, each with two tissue chambers, were used in a cross over design; in the first experiment the left tissue chamber (TC) was infected and in the second experiment the right. TMP/SDZ treatment resulted in a limited reduction of viable bacteria in the TC but did not eliminate the infection, resulting in abscessation in 10-42 days in all eight ponies. However, penicillin treatment eliminated the streptococci in seven of eight ponies, and only one pony suffered abscessation on day 10. This constitutes a significantly better efficacy of the penicillin treatment in this model. The most probable cause of the failure of TMP/SDZ to eliminate the streptococci is inhibition of the action of TMP/SDZ in the purulent TCF. Therefore, TMP/SDZ should not be used to treat purulent infections in secluded sites in horses.

Effects of antimicrobials and weaning on porcine serum insulin-like growth factor binding protein levels.

The effects of subtherapeutic antimicrobial supplementation and weaning on serum levels of IGF-I and insulin-like growth factor binding proteins (IGFBP)-2, -3 and -4 were determined in crossbred weanling pigs. At weaning, pigs were allotted to a diet containing 21.8% crude protein and 1.15% lysine with or without Aureozol (110 mg/kg of Aureomycin chlortetracycline, 110 mg/kg of sulfathiazole, and 55 mg/kg of penicillin) for 4 wk. Insulin-like growth factor-binding proteins and IGF-I analyses were performed on blood samples that were drawn weekly. Weaning decreased serum IGFBP-3 levels in both control and Aureozol-treated groups on d 6 and d 14 (P < 0.05) relative to preweaning levels. The IGFBP-3 values returned to preweaning levels by d 21. Although the circulating levels of both the 43-kDa and the 39-kDa glycosylation variants of IGFBP-3 were affected by weaning, the level of the 39-kDa IGFBP-3 was affected relatively more than that of the 43-kDa IGFBP-3 (P < 0.05). Compared with circulating IGFBP-3 levels in control pigs, Aureozol-treated pigs had higher circulating IGFBP-3 levels on d 21 (43%, P < 0.05) and d 27 (46%, P < 0.05). In direct contrast to the effect of weaning on serum IGFBP-3 level, serum IGFBP-2 levels increased on d 6 and d 14 after weaning (P < 0.05) and decreased to preweaning levels by d 21. The IGFBP-2 levels continued to decline and were less than preweaning levels by d 27 (P < 0.05). Aureozol treatment had no effect on serum IGFBP-2 levels at any time. Serum levels of nonglycosylated IGFBP-4 were not affected by either weaning or Aureozol supplementation. Weaning decreased circulating IGF-I concentration on d 6 in both control and Aureozol-treated pigs (76 and 73%, respectively, P < 0.05) and on d 14 (62%, P < 0.05) and d 21 (32%, P < 0.05) in control pigs. Aureozol-supplemented pigs had higher serum IGF-I concentrations than control pigs on d 14 (82%, P < 0.05), d 21 (55%, P < 0.05), and d 27 (36%, P < 0.05). The Aureozol-fed pigs had a 14.2% increase in BW gain (P < 0.05) and a 59.6% increase in ADG (P < 0.05) compared with pigs fed the control diet. Both Aureozol-supplementation and weaning cause changes in serum IGFBP levels and IGF-I concentrations that might be involved in regulating rate and efficiency of growth.

Evaluation and preparation of controlled release lipid micropheres of sulphamethizole by a congealable disperse phase encapsulation method.

A congealable disperse phase encapsulation method was used to prepare controlled release lipid microspheres of sulphamethizole as a model drug. Hydrogenated cotton seed oil (HCSO) and stearic acid were employed as the lipid matrix materials. Tween 60 was the droplet stabilizer used to form microspheres. In in vitro dissolution tests, the drug release was found to be affected by the type of lipid material depending on hydrophilicity. Generally, an initial rapid release followed by a slower release of the drug from the lipid microspheres was observed. Lipid microspheres were also compressed in the tablet form to prevent the initial rapid release of the drug. But the drug release drastically decreased. To achieve a controlled release of the drug. Eudragit L as a channeling agent was added internally to HCSO-microspheres. Although the drug release increased, the controlled release pattern was not achieved. The external addition of polyethyleneglycole 4000 to HCSO-microspheres before compressing tablets, did not produce an affirmative change in the release profile. The lipid microspheres prepared by stearic acid released all of the drug within 1 h. Upon compression, the drug release was very low. Therefore, stearic acid-microspheres were compressed in the tablet form adding disintegrating agents, sodium alginate and Ac-Di-Sol (cross-linked sodium carboxymethylcellulose). A pH-dependent drug release was obtained from the tablets containing sodium alginate. With the tablets of stearic acid-microspheres containing Ac-Di-Sol, the controlled release could be achieved due to gradual disintegration from the tablet to aggregates, and to individual microspheres. Furthermore, in vivo study on 6 healthy volunteers confirmed the controlled release pattern of this dosage form.

Sulfamethizole capsules containing contrast medium for assessment of gastric emptying in functional dyspepsia patients.

The usefulness of sulfamethizole capsules containing contrast medium in gastric emptying tests for functional dyspepsia was evaluated in five healthy volunteers and nine patients with dysmotility-like symptoms. Each subject swallowed 15 capsules with a liquid, food, and at 0, 15, 30, 45, 60, 90, and 120 min, the capsule position and size were monitored fluoroscopically for 30 sec and radiograms were obtained. Blood sulfamethizole concentrations were also measured at the same time. Visualized capsule movement from the proximal to distal stomach up to 60 min was faster in the patients, whereas in the later digestion period, proximal stomach emptying in the patients was delayed significantly (P < 0.05), and the number of capsules remaining in the distal stomach at 120 min was significantly larger in the patients (P < 0.05). This test method was evaluated as being useful in monitoring solid emptying in normal and pathophysiologic conditions.

N-acetyl-L-gamma-glutamyl derivatives of p-nitroaniline, sulphamethoxazole and sulphamethizole for kidney-specific drug delivery in rats.

Kidney-specific delivery of p-nitroaniline, sulphamethoxazole and sulphamethizole after either intravenous administration of the L-gamma-glutamyl or N-acetyl-L-gamma-glutamyl derivatives or the parent drugs has been examined in a rat model. All L-gamma-glutamyl derivatives were converted to the corresponding parent drugs within 60 min whereas the N-acetyl-L-gamma-glutamyl derivatives were fairly stable in the systemic circulation after parenteral administration. Concentrations of p-nitroaniline and sulphamethoxazole 20 min after administration of the parent drugs were somewhat higher in the kidney than in the liver and lung. The concentration of sulphamethizole in the kidney was dramatically higher than those in the hepatic and pulmonary tissue. Kidney-specific delivery of the drugs of interest was evaluated by determining the tissue concentrations of the released parent drug and the total drug levels (i.e. drug levels after hydrolysis of all conjugate to the parent drug). For L-gamma-glutamyl-p-nitroaniline released renal levels of p-nitroaniline and total p-nitroaniline concentrations were both higher than those obtained after p-nitroaniline dosing. Use of L-gamma-glutamylsulphamethoxazole resulted in higher total sulphamethoxazole concentrations in the kidney, but did not lead to an increase in released (unconjugated) sulphamethoxazole levels. In contrast, no kidney-selective distribution was observed for L-gamma-glutamylsulphamethizole. Markedly increased kidney distribution was observed for both N-acetyl-L-gamma-glutamyl-p-nitroaniline and N-acetyl-L-gamma-glutamylsulphamethoxazole and the liver and lung concentrations were correspondingly reduced in comparison with parent drug dosing. Use of the N-acetyl-L-gamma-glutamyl-p-nitroaniline conjugate increased the concentration of p-nitroaniline in the kidney to the same extent as did L-gamma-glutamyl-p-nitroaniline. In conclusion, N-acetyl-L-gamma-glutamyl derivatization of certain compounds seems to be useful for kidney-specific drug delivery and preliminary data suggests that lipophilic drugs are better substrates than hydrophilic compounds. Results related to the selectivity of tissue distribution of the derivatives and species differences are discussed.

Sulfamethizole capsule method. A new method for assessing gastric emptying of solids.

We have developed a new method that is capable of assessing gastric emptying in humans. This method is based on the rapid absorption of sulfamethizole in the upper small intestine. Sulfamethizole capsules are gelatin capsules that are filled with a solid composed of egg albumin and sulfamethizole. After subjects ingested of 15 capsules with ham and bread, blood concentrations of sulfamethizole were measured and the areas under the sulfamethizole concentration-time curve (AUC) were calculated as an index of gastric emptying. After ingestion of 99mTc-labeled sulfamethizole capsules, there was a statistically significant correlation between the percentage of radioactivity remaining in the stomach at 120 min and AUC for 120 min (r = -0.82, P < 0.01). This method yielded a reliable value for gastric emptying of a solid meal as estimated by AUC. This method can be considered safe and is easily applicable to human subjects for assessment of gastric emptying.

Evaluation of enteric coated tablet sensitive to pancreatic lipase. II. In vivo evaluation.

Plain tablets containing a model drug, sulfamethizole (SMZ), were coated with triolein (TO), trilaurin (TL) and ethylcellulose (EC). The biological behavior of the coated tablets (TOTL-Tab), which are pH independent and sensitive to pancreatic lipase, was investigated in humans. Results of the administration of the tablets with or without an antacid, under fasting and non-fasting conditions, and at 0.5 h before and 0.5 h after meals, were examined. A comparison of the in vivo behavior of SMZ after the administration of these tablets was done using the following data: the lag time of urinary excretion (Ulag), the total urinary recovery percentage (X infinity u), and the mean residence time after Ulag (MRTaf). A typical pH-sensitive tablet coated by cellulose acetate phthalate (CAP-Tab) was used as a reference. For the administration of a CAP-Tab alone, the Ulag obtained under both the non-fasting and fasting condition was longer than that of the plain tablet. However, Ulag after the administration of a CAP-Tab with an antacid became considerably shorter. This lag time was about the same as that obtained from the plain tablet, regardless of food ingestion. The obtained CAP-Tab MRTaf and X infinity u values were not significantly different in comparison to the plain tablets. Under the non-fasting condition, Ulag, MRTaf and X infinity u of TOTL-Tab were not affected by the co-administration of an antacid, and these values were virtually the same as those obtained from a CAP-Tab without an antacid. The urinary excretion data obtained after the administration of TOTL-Tab alone under fasting was analogues to the non-fasting case.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of deacetylated gellan gum (Gelrite) for the production of sulphamethizole containing beads.

Deacetylated gellan gum (Gelrite) was used to produce a bead formulation containing sulphamethizole by a hot extrusion process into chilled ethylacetate. The spherical dried beads recovered had a porous surface which could be reduced in porosity by increasing the Gelrite concentration. Energy dispersive analysis showed the drug to be uniformly distributed throughout the beads. Dissolution studies confirmed that the drug was slowly released from the beads, the retardation of which could be extended by the use of increasing Gelrite concentration or by post-treatment of dried beads with either a waxy sealant or gamma irradiation. In-vivo studies in dogs confirmed that dried beads prepared by extruding a suspension of 10 per cent w/w sulphamethizole in 3 per cent aqueous Gelrite dispersion had effective sustained properties on oral dosing in comparison to a conventional capsule formulation but had a possible small loss in relative bioavailability.

Kinetic studies on drug disposition in rabbits. II. Dose dependent pharmacokinetics of sulfamethizole.

In order to evaluate dose-dependent sulfamethizole (SMZ) kinetics, 100, 300 and 1000 mg of SMZ was constantly infused over 5 min in rabbits and thereafter plasma and urine samples were collected at convenient intervals. When a dose of 100 mg was given, the time course of total plasma concentration followed a biexponential characteristic. For higher doses, plasma decay curves revealed a convex descending feature after the distribution phase. The respective unbound fraction in plasma (fp) at the total plasma concentrations of 200 and 100 micrograms/ml were 0.41 and 0.19. The corresponding total body clearances were 2.6 and 2.2 l/h, indicating that the drug elimination did not contribute to the convex-descending plasma curves. A physiologically based pharmacokinetic model was adapted to various tissue levels of SMZ. No saturable tissue binding was observed and the apparent volume of distribution of SMZ at steady state with a rabbit of 3.3 kg, Vss (1), calculated by tissue volumes and partition coefficients of tissue to unbound plasma was expressed as follows: Vss = 0.14 + 1.86fp. From this relationship, it was shown that the apparent volume of distribution of SMZ was significantly affected by the unbound fraction in plasma and the dose-dependent kinetics after intravenous administration was due to the decrease of the apparent volume of distribution with time. The tissue distribution study contributed significantly to the understanding of the dose-dependent drug kinetics.

Single-dose versus six-day therapy with sulfamethizole for asymptomatic bacteriuria during pregnancy. A prospective randomised study.

Single-dose versus conventional six-day therapy with sulfamethizole for asymptomatic urinary tract infection in pregnant women was investigated in a prospective, randomised open study. During a nine-month period 4,274 pregnant women were screened for significant bacteriuria, which was found in 123 (2.9%), of whom only five had symptoms of urinary tract infection. Seventy-nine of the patients had a second urine culture performed, revealing significant counts of the same bacteria in only 41. These 41 patients were randomly allocated to one of the two treatment groups. Control urine cultures one week and 4-6 weeks after start of treatment revealed the same cure rates of approximately 50% in both groups. Single-dose treatment is not inferior to conventional therapy; future study is needed to find the best single-dose regimen.

Role of parenteral antibiotherapy in gastrointestinal tract flora suppression. A study in children treated with high-dose chemotherapy and autologous bone marrow transplantation.

In order to determine the effect of parenteral antibiotherapy on the fecal flora in patients with profound and prolonged granulocytopenia, we initiated a prospective study of 62 cases of autologous bone marrow transplantation following high-dose chemotherapy. All patients were children from 2 to 18 years old, isolated in a protective environment, receiving a diet low in viable microbial content but no oral non-absorbable prophylactic antibiotics to decontaminate the gastrointestinal tract. Bacteriological analysis of fecal flora was conducted at least once a week before and during parenteral antibiotherapy, administered at the first greater than 38 degrees C febrile episode in these granulocytopenic patients (granulocyte count less than 0.5 X 10(9)/l). The 58 evaluable patients fell into three groups with regard to the systemic antibiotherapy: group A (n = 16): moxalactam + mezlocillin; group B (n = 15): moxalactam + tobramycin; and group C (n = 27): cefotaxime plus gentamicin. Fecal flora suppression was observed in 51/58 cases (88%) (group A: 15/16, group B: 13/15, group C: 23/27). It always occurred within 5 days of initiating parenteral antibiotherapy and persisted in 88% of the 51 patients over the whole period of systemic antibiotherapy. During the latter, fecal recolonization was observed in seven cases (12%), always by Enterobacteriaceae sensitive to the prescribed systemic antibiotherapy, never responsible for septicemia. Since parenteral antibiotherapy alone was able to suppress the gastrointestinal tract flora, the effects of this treatment should be considered in all trials of digestive tract decontamination.