Pharmacokinetics of fosfomycin in patients with prophylactic treatment for recurrent Escherichia coli urinary tract infection.

OBJECTIVES: To evaluate the pharmacokinetics and clinical effectiveness of IV and oral fosfomycin treatment in patients with recurrent urinary tract infection (rUTI) with Escherichia coli. PATIENTS AND METHODS: Patients with rUTI treated with 3 g of oral fosfomycin every 72 h for at least 14 days were included in a prospective open-label single-centre study. Serum samples were taken after oral and IV administration of fosfomycin. Urine was collected for 24 h on 3 consecutive days. Fosfomycin concentrations in serum and urine were analysed using validated LC-MS/MS. Pharmacokinetics were evaluated using a population model. EudraCT number 2018-000616-25. RESULTS: Twelve patients were included, of whom nine were also administered IV fosfomycin. Data were best described by a two-compartment model with linear elimination and a transit-absorption compartment. Median values for absolute bioavailability and serum half-life were 18% and 2.13 h, respectively. Geometric mean urine concentrations on Days 1, 2 and 3 were above an MIC of 8 mg/L after both oral and IV administration. Quality of life reported on a scale of 1-10 increased from 5.1 to 7.4 (P = 0.001). The average score of UTI symptoms decreased after fosfomycin dosing (by 3.1 points, 95% CI = -0.7 to 7.0, P = 0.10). CONCLUSIONS: Oral fosfomycin at 3 g every 72 h provides plasma and urine concentrations of fosfomycin above the MIC for E. coli. This pharmacokinetic model can be used to develop optimal dosing regimens of fosfomycin in patients with UTI.

The Oral Pheneticillin Absorption Test: An Accurate Method to Identify Patients with Inadequate Oral Pheneticillin Absorption.

Severe streptococcal infections are commonly treated with intravenous followed by oral penicillin (pheneticillin) therapy. However, switching from iv to oral therapy is complicated by the variability in oral pheneticillin absorption. We employed an Oral Absorption Test (OAT) for pheneticillin to identify patients in whom oral pheneticillin absorption is poor. Out of 84 patients 30 patients (36%) were identified as insufficient absorbers. Treatment failure due to pheneticillin malabsorption can be avoided by performing an OAT, and these patients should be treated by another antibiotic, which is known to be absorbed well.

Fosfomycin as a potential therapy for the treatment of systemic infections: a population pharmacokinetic model to simulate multiple dosing regimens.

Fosfomycin has emerged as a potential therapy for multidrug-resistant bacterial infections. In most European countries, the oral formulation is only approved as a 3 g single dose for treatment of uncomplicated cystitis. However, for the treatment of complicated systemic infections, this dose regimen is unlikely to reach efficacious serum and tissue concentrations. This study aims to investigate different fosfomycin-dosing regimens to evaluate its rationale for treatment of systemic infections. Serum concentration-time profiles of fosfomycin were simulated using a population pharmacokinetic model based on published pharmacokinetic parameter values, their uncertainty, inter-individual variability and covariates. The model was validated on published data and used to simulate a wide range of dosing regimens for oral and intravenous administration of fosfomycin. Finally, based on the minimum inhibitory concentration for E. coli, surrogate pharmacodynamic indices were calculated for each dosing regimen. This is the first population pharmacokinetic model to describe the oral pharmacokinetics of fosfomycin using data from different literature sources. The model and surrogate pharmacodynamic indices provide quantitative evidence that a dosing regimen of 6-12 g per day divided in 3 doses is required to obtain efficacious exposure and may serve as a first step in the treatment of systemic multi-drug-resistant bacterial infections.

Colistin methanesulfonate infusion solutions are stable over time and suitable for home administration.

The stability of colistin methanesulfonate (CMS) was determined in quadruplicate in elastomeric home infusion pumps containing 1, 2 or 3 MU CMS and in infusion bags with 2 MU CMS all in 100 mL normal saline. Infusions were stored at room temperature (20°C-24°C) with or without exposure to natural light or refrigerated (4°C-8°C) and protected from light up to 2 weeks. In the initial solution of 2 MU CMS in 100 mL saline sampled immediately after reconstitution and dilution, 1.5% of CMS was hydrolysed to colistin. When stored at room temperature and exposed to natural light, colistin concentration in elastomeric infusion pumps increased to 2.6% in 8 days and to 2.1% when stored at 4°C. CMS stability increases at lower temperatures and higher concentrations. Based on the current data, chemical stability of CMS infusion solution is sufficient for a shelf life of 7 days refrigerated plus 1 day at room temperature.

Neisseria Mucosa: A New Urinary Tract Pathogen?

The most common complication of vesicoureteral reflux is urinary tract infection. We report a case of a urinary tract infection in a child with severe vesicoureteral reflux, caused by Neisseria mucosa, usually considered to be a commensal inhabitant of the oro- or nasopharynx.

Colistin: Revival of an Old Polymyxin Antibiotic.

Colistin (polymyxin E) is a positively charged deca-peptide antibiotic that disrupts the integrity of the outer membrane of the cell wall of gram-negative bacteria by binding to the lipid A moiety of lipopolysaccharides, resulting in cell death. The endotoxic activity of lipopolysaccharides is simultaneously inhibited. Colistin is increasingly being prescribed as rescue treatment for infections with multidrug-resistant bacilli. Nephrotoxicity and, to a lesser degree, neurotoxicity occur often during systemic colistin therapy, and have severely limited its application in the past. However, these side effects are largely reversible and can be managed through close monitoring. The prodrug colistimethate sodium (CMS) is less toxic and is, therefore, the preferred formulation for parenteral administration. Importantly, resistance to colistin seems to emerge often unless it is combined with another antibiotic, but further studies into this phenomenon are necessary. Pharmacokinetic and pharmacodynamic properties have received little attention, partly because of the physicochemical peculiarities of polymyxin antibiotics, especially their propensity to stick to other molecules and surfaces. The ratio between the area under the curve of free colistin and the pathogen's Minimal Inhibitory Concentration (MIC) best predicts microbiological and clinical responses, but more studies are needed in this area. Likewise, further standardization is needed in production and labeling of colistin formulations, and in the way the susceptibility of bacteria to colistin is determined.

[Practical guideline for the use of colistin]. / Praktische leidraad voor gebruik van colistine.

Colistin (polymyxin E) binds to the cell wall of gram-negative bacteria, leading to osmotic destruction of the cell. Since its introduction in 1959, colistin has been little used parenterally due to a high incidence of reversible nephrotoxicity and, to a lesser extent, neurotoxicity. Colistin use remained limited to combating Pseudomonas aeruginosa in cystic fibrosis patients. In addition, oral colistin is part of the recently introduced regime of selective digestive tract decontamination in ICU patients. Intravenous administration of colistin is now increasingly prescribed for the control of multi-resistant microorganisms. Colistin monotherapy, however, rapidly selects resistant subpopulations. Therefore, only combination therapy is advised. The prodrug colistimethate sodium is less toxic and is hydrolyzed in vivo to active colistin; colistin is renally cleared. Clinical practice remains hampered by lack of uniformity and standardization of names, dosage units, dosing recommendations and methods of concentration and susceptibility testing.

Imported Armillifer pentastomiasis: report of a symptomatic infection in The Netherlands and mini-review.

We report a case of symptomatic visceral Armillifer pentastomiasis in a 23-year-old female Liberian immigrant to The Netherlands. The patient was referred to the gynecologist because of lower abdominal pain. During laparotomy, multiple adhesions were seen in the lower pelvis and a hydrosalpinx with an encapsulated Armillifer nymph, most likely Armillifer armillatus, was found. Key features of the parasite's cuticle which facilitate the diagnosis of pentastomiasis, are presented. Symptomatic pentastomiasis is uncommon, and most cases are diagnosed incidentally during surgery for other reasons, or at autopsy. With regard to increasing international migration, other imported pentastomiasis cases to Europe and North America are reviewed, and more cases are likely to be seen in the future.

A simplified oral flucloxacillin absorption test for patients requiring long-term treatment.

BACKGROUND: Patients with severe methicillin-sensitive Staphylococcus aureus infections are effectively treated with initial continuous intravenous (iv) flucloxacillin followed by oral maintenance therapy. As the absorption of oral flucloxacillin is variable, an oral absorption test (OAT) is used to ensure efficacious therapy. The classical OAT (test A) requires overnight fasting, interruption of iv therapy, and is laborious. We designed a simplified OAT (test B) in which iv therapy is continued and oral dosing is performed after a 1-hour fast. METHODS: In 43 hospitalized patients on iv flucloxacillin, either test A or test B was performed. In each variant, 1 g of oral flucloxacillin was given, and blood samples were taken before and at 1 and 2 hours after dosing. Flucloxacillin concentration was determined by high-performance liquid chromatography. Adequate absorption was defined as a ≥ 10 mg/L increase in flucloxacillin concentration at 1 or 2 hours after dosing. RESULTS: In a population of 43 patients (18F/25M), test A was done in 19 patients and test B in 24 patients. The groups had similar baseline characteristics such as age, renal function, gender, diagnoses, or comedication. All the patients tolerated the test without problems. The absorption was highly variable between patients. The average (SD; range) maximal increase for test A was 22.3 (11.6; 7-50) mg/L and 26.5 (12.6; 8-53) mg/L for test B. There was no significant difference between the 2 tests (P = 0.23), and 10% of the patients were poor absorbers (increase <10 mg/L). There was no influence of serum creatinine, age, or pretest flucloxacillin concentration. No clinical condition or drug use that may have impaired flucloxacillin absorption could be identified. CONCLUSIONS: We designed a simplified OAT that performs well and can be implemented easily. This test may be helpful to rationally and effectively treat patients with severe methicillin-sensitive S. aureus infections with an orally administered small-spectrum antibiotic.

Parvovirus B19 in pregnancy: prenatal diagnosis and management of fetal complications.

PURPOSE OF REVIEW: Parvovirus B19 infection is often considered a mild and self-limiting disease of minor clinical importance. This review aims to raise awareness of recently discovered potentially devastating consequences of this infection in pregnancy, and provides updated guidelines on diagnosis and management. RECENT FINDINGS: In contrast to previous beliefs, parvovirus B19 infection during any stage of pregnancy may not only cause fetal death, but may also result in severe and irreversible neurological sequelae in survivors. Improved diagnostic techniques allow more reliable and earlier diagnosis of fetal disease. SUMMARY: Clinicians need to be aware of the risk of adverse outcome of parvovirus B19 infection in pregnancy, and sometimes the long interval between exposure and fetal symptoms. Accurate diagnosis using PCR and weekly ultrasound checks ups with Doppler measurement of middle cerebral artery flow velocity up to 20 weeks postexposure may improve detection of fetal disease. More timely treatment likely results in improved outcome.

Clinically important interaction between tedisamil and verapamil.

Tedisamil, a class III antiarrhythmic drug, is a P-glycoprotein substrate. Tedisamil treatment may implicate coadministration with class IV antiarrhythmics such as verapamil, a P-glycoprotein inhibitor. Pharmacokinetic and pharmacodynamic interactions between tedisamil and verapamil were evaluated in a double-blind, crossover study. Twelve healthy volunteers received a 3-day treatment of tedisamil (100 mg bid), verapamil (180 mg bid), a combination of these drugs, or placebo. Blood pressure and electrocardiograms were assessed daily and cardiac output and pharmacokinetics on day 3. Combination of tedisamil and verapamil increased tedisamil plasma concentrations (AUC(0-12 h): +77%, CI(90%): +51% to +108%; C(max): +78%, CI(90%): +57% to +102%) compared to tedisamil monotreatment but decreased plasma concentrations of verapamil (AUC(0-12 h): -21%, CI(90%): -32% to -8%; C(max): -28%, CI(90%): -39% to -14%) and norverapamil (AUC(0-12 h): -17%, CI(90%): -28% to -6%; C(max): -20%, CI(90%):-29% to -10%) compared to verapamil monotreatment. Compared to placebo, verapamil and the combination treatment increased PR by 23.5 (CI(95%): 17.9 to 29.2) ms and 12.2 (5.7 to 17.0) ms, respectively. Compared to placebo, tedisamil and the combination treatment increased QTc by 27.8 (15.8 to 39.8) ms and 45.7 (33.7 to 57.7) ms, respectively. Thus, concomitant use of tedisamil with P-glycoprotein inhibitors likely results in clinically significant drug interactions.