Evaluation of the antiviral response to zanamivir administered intravenously for treatment of critically ill patients with pandemic influenza A (H1N1) infection.

A retrospective nationwide study on the use of intravenous (IV) zanamivir in patients receiving intensive care who were pretreated with oseltamivir in the Netherlands was performed. In 6 of 13 patients with a sustained reduction of the viral load, the median time to start IV zanamivir was 9 days (range, 4-11 days) compared with 14 days (range, 6-21 days) in 7 patients without viral load reduction (P = .052). Viral load response did not influence mortality. We conclude that IV zanamivir as late add-on therapy has limited effectiveness. The effect of an immediate start with IV zanamivir monotherapy or in combination with other drugs need to be evaluated.

One-year follow-up of patients of the ongoing Dutch Q fever outbreak: clinical, serological and echocardiographic findings.

PURPOSE: In 2007, a large goat-farming-associated Q fever outbreak occurred in the Netherlands. Data on the clinical outcome of Dutch Q fever patients are lacking. The current advocated follow-up strategy includes serological follow-up to detect evolution to chronic disease and cardiac screening at baseline to identify and prophylactically treat Q fever patients in case of valvulopathy. However, serological follow-up using commercially available tests is complicated by the lack of validated cut-off values. Furthermore, cardiac screening in the setting of a large outbreak has not been implemented previously. Therefore, we report here the clinical outcome, serological follow-up and cardiac screening data of the Q fever patients of the current ongoing outbreak. METHODS: The implementation of a protocol including clinical and serological follow-up at baseline and 3, 6 and 12 months after acute Q fever and screening echocardiography at baseline. RESULTS: Eighty-five patients with acute Q fever were identified (male 62%, female 38%). An aspecific, flu-like illness was the most common clinical presentation. Persistent symptoms after acute Q fever were reported by 59% of patients at 6 months and 30% at 12 months follow-up. We observed a typical serological response to Coxiella burnetii infection in both anti-phase I and anti-phase II IgG antibodies, with an increase in antibody titres up to 3 months and a subsequent decrease in the following 9 months. Screening echocardiography was available for 66 (78%) out of 85 Q fever patients. Cardiac valvulopathy was present in 39 (59%) patients. None of the 85 patients developed chronic Q fever. CONCLUSIONS: Clinical, serological and echocardiographic data of the current ongoing Dutch Q fever outbreak cohort are presented. Screening echocardiography is no longer part of the standard work-up of Q fever patients in the Netherlands.

Molecular typing of a suspected cluster of Nocardia farcinica infections by use of randomly amplified polymorphic DNA, pulsed-field gel electrophoresis, and amplified fragment length polymorphism analyses.

Randomly amplified polymorphic DNA (RAPD), pulsed-field gelelectrophoresis (PFGE), and amplified fragment length polymorphism (AFLP) analyses were used to investigate a possible outbreak of Nocardia farcinica. RAPD and PFGE analyses yielded irreproducible and unsatisfactory results, respectively. AFLP analysis seem to be a promising and welcome addition for molecular analysis of Nocardia isolates.

Baseline human papillomavirus status of women with abnormal smears in cervical screening: a 5-year follow-up study in The Netherlands.

OBJECTIVE: To determine in a screening population the human papillomavirus (HPV) status in those with cytological abnormalities and to evaluate the presence of high-risk (HR) HPV with a minimum of 5-year follow up. DESIGN: Retrospective examination of HPV status on prospectively collected and cytologically screened cervical smears. SETTING: Canisius-Wilhelmina Hospital in Nijmegen, The Netherlands. POPULATION: Three hundred and fifty-seven women aged 30-60 years, from the population screened. METHODS: Three hundred and fifty-seven women with borderline or higher cytological abnormalities were retrospectively examined for HPV with DNA microarray typing. Follow up was through the nationwide Dutch Pathology database (PALGA). MAIN OUTCOME MEASURES: For the cytological abnormalities, the CISOE-A classification was used. HPV was scored as negative or positive. In case of positive HPV polymerase chain reaction, the HPV genotype was determined. The occurrence of cervical intraepithelial neoplasia lesions of grade 3 or higher was considered as endpoint for follow up. RESULTS: The majority of the women with borderline cytology in this study were HPV negative (87%). Among the HPV-positive women in borderline cytology group, 74% had HR-HPV or probable high-risk types. The overall percentage of HR-HPV types increased with progressive cytological abnormalities. The cytological classifications of borderline dyskaryosis and moderate dyskaryosis contain all types of HPVs, e.g. low risk, HR and unknown risk. The samples with severe dyskaryosis or higher contain only HR types. The negative predictive value for HR-HPV typing in the group with borderline cytological abnormalities is more than 99%. CONCLUSIONS: In cervical screening with an interval of 5 years, HPV can be reliably used as triage point in cases of borderline cytological abnormalities.

Empirical treatment followed by a test-and-treat strategy is more cost-effective in comparison with prompt endoscopy or radiography in patients with dyspeptic symptoms: a randomized trial in a primary care setting.

OBJECTIVE: Management of patients with dyspepsia remains controversial. No consensus has yet been reached concerning diagnostic and medical strategies. We conducted a randomized trial to assess the effectiveness of three management strategies for patients with uninvestigated persistent dyspeptic symptoms. METHODS: A total of 199 patients presenting in primary care with dyspeptic symptoms (age 18-65 years, no alarming symptoms) were randomized to either empirical treatment with omeprazole and, in the case of symptomatic relapse, serological Helicobacter pylori infection testing plus eradication therapy (treat-and-test group), prompt upper gastrointestinal endoscopy (endoscopy group) or prompt upper gastrointestinal radiography (radiography group) followed by directed medical treatment. Symptoms, patients' satisfaction and use of resources were recorded during 6 months of follow-up. RESULTS: Sixty-nine patients were assigned to the treat-and-test group, 64 to the radiography group and 66 to the endoscopy group. The median age was 44 years; 104 patients were male and 37% were H.pylori infected. A total of 170 patients (85%) returned the 6 months questionnaire. The numbers of patients with complete symptom relief in the treat-and-test group, endoscopy group and radiography group were 21, 16 and 15, respectively, at 3 months (P = 0.59), and 23, 13 and 12, respectively, at 6 months (P = 0.05). Twenty-two patients in the treat-and-test group underwent endoscopy or radiography. Two patients in the endoscopy group and four patients in the radiography group underwent more than one diagnostic test. The average medical cost per patient for the treat-and-test group was euro 276, for the endoscopy group euro 426 and for the radiography group euro 321, respectively. CONCLUSION: Empirical treatment followed by a test-and-eradicate strategy resulted in fewer diagnostic tests, more symptom relief and lower medical costs compared with prompt upper gastrointestinal radiography or endoscopy in the management of uninvestigated patients with persistent dyspeptic symptoms.

Antibiotic use and resistance of Streptococcus pneumoniae in The Netherlands during the period 1994-1999.

Antibiotic use in The Netherlands during the period 1994-1999 is described in relation to the resistance of routine isolates of Streptococcus pneumoniae. The average antibiotic use in the study period was 3.4 defined daily doses per 1000 persons per day (DDD/1000/day) penicillins, 0.066 DDD/1000/day beta-lactams other than penicillins, 2.3 DDD/1000/day tetracyclines and 0.71 DDD/1000/day trimethoprim and sulphonamides, without apparent rise or decline. In contrast, the use of macrolides doubled from 0.51 DDD/1000/day in 1994 to 1.0 DDD/1000/day in 1997 and stayed at 1.07 DDD/1000/day in 1998 and 1999. In 1994 the first pneumococci isolated from patients showed 0.7% resistance to penicillin (intermediate plus full resistance), 2.5% to erythromycin, 4.2% to co-trimoxazole and 4.7% to tetracycline. In 1999 first isolates showed 1.5% resistance to penicillin, 3.8% to erythromycin, 4.4% to co-trimoxazole and 6.6% to tetracycline. The modest but significant rise in the resistance to erythromycin may have been caused by the increased use of macrolides in the years 1994-1997. The rise in resistance to penicillin seemed not to be related to increased beta-lactam use.

Comparative pharmacokinetics of the carbapenems: clinical implications.

During the last few decades, several carbapenems have been developed. The major characteristic of the newer drugs, such as MK-826, is a prolonged half-life. Alternatively, some carbapenems have been developed that can be given orally, such as CS-834 and L-084. Although imipenem and panipenem have to be administered with a co-drug to prevent degradation by the enzyme dehydropeptidase-1 and reduce nephrotoxicity, the newer drugs such as meropenem, biapenem and lenapenem are relatively stable towards that enzyme. Structural modifications have, besides changes in pharmacology, also led to varying antimicrobial properties. For instance, meropenem is relatively more active against Gram-negative organisms than most other carbapenems, but is slightly less active against Gram-positive organisms. Except for half-life and bioavailability, the pharmacokinetic properties of the carbapenems are relatively similar. Distribution is mainly in extracellular body-water, as observed both from the volumes of distribution and from blister studies. Some carbapenems have a better penetration in cerebrospinal fluid than others. In patients with renal dysfunction, doses have to be adjusted, and special care must be taken with imipenem/cilastatin and panipenem/betamipron to prevent accumulation of the co-drugs, as the pharmacokinetic properties of the co-drugs differ from those of the drugs themselves. However, toxicity of the co-drugs has not been shown. The carbapenems differ in proconvulsive activity. Imipenem shows relatively the highest proconvulsive activity, especially at higher concentrations. Pharmacodynamic studies have shown that the major surrogate parameter for antimicrobial efficacy is the percentage of time of the dosage interval above the minimum inhibitory concentration (MIC). The minimum percentage percentage of time above the MIC (TaM) needed for optimal effect is known in animals (30 to 50%), but not in humans. It is probably less than 100%, but may be higher than 50%. Dosage regimens currently in use result in a TaM of about 50% at 4 mg/L, which is the current 'susceptible' breakpoint determined by the National Committee for Clinical Laboratory Standards (NCCLS) for most micro-organisms. Dosage regimens in patients with reduced renal clearance should be based on the TaM. The increased half-life of the newer carbapenems will probably lead to less frequent administration, although continuous infusion may still be the optimal mode of administration for these drugs. The availability of oral carbapenems will have a profound effect on the use of carbapenems in the community.

A new species, Phialophora europaea, causing superficial infections in humans.

A new species, Phialophora europaea, member of the P. verrucosa complex, is introduced. It is distinguished from existing species by reduced, flaring phialidic collarettes and inability to assimilate melibiose as sole source of carbon. Analysis of ITS1 and 2 rDNA of six strains attributed to the species show it to be clearly individualized. All strains originated from cutaneous and nail infections of humans in North-western Europe. A key to morphologically similar taxa is provided.

Identification of multiresistant Staphylococcus epidermidis in neonates of a secondary care hospital using pulsed field gel electrophoresis and quantitative antibiogram typing.

AIMS: To determine the diversity of types of Staphylococcus epidermidis in a neonatal care unit of a secondary care hospital in the Netherlands. METHODS: In a prospective study, specimens from nose, ear, axilla, umbilicus, and groin were taken from patients twice a week during a period of up to two weeks. All isolates were typed by both pulsed field gel electrophoresis (PFGE) and antibiogram analysis. RESULTS: Fifty three S epidermidis isolates from 15 of 24 patients were obtained in one to four surveys. Fourteen isolates from six patients had a common PFGE pattern and were of one multiresistant antibiogram type. The remaining 39 isolates were allocated to 24 sporadic PFGE types and were more susceptible to antibiotics. Colonisation with the multiresistant strain correlated with a long period of stay and with the use of specific antibiotics. The multiresistant isolates were related closely to isolates of S epidermidis found in a recent study in a teaching hospital in the vicinity of the secondary care hospital. CONCLUSION: Repeated sampling and the use of two typing methods allowed the identification of two closely related multiresistant S epidermidis strains in two hospitals in the same area.

Pharmacokinetic optimisation of antibacterial treatment in patients with cystic fibrosis. Current practice and suggestions for future directions.

Antibacterials play a central role in the medical management of patients with cystic fibrosis (CF). Administration of adequate dosages of antibacterials results in pronounced beneficial effects on the morbidity and mortality of this patient group. The dosage of the antibacterial that is needed for optimal treatment depends on the individual patient's pharmacokinetics and the pharmacokinetic-pharmacodynamic effect on the micro-organism of relevance in the host. In general, the disposition of antibacterial drugs in patients with CF is not as 'atypical' as once thought. Recent research with adequately matched controls demonstrated that, for a few beta-lactam antibacterials only, a CF-specific increase of the total body clearance seems to exist and that the large volumes of distribution observed are the result of malnutrition and the relative lack of adipose tissue. Pharmacokinetic-pharmacodynamic relationships in patients with CF are less well studied. Apart from the pharmacokinetics, there is a need for optimisation of antibacterial therapy. For the aminoglycosides, pharmacokinetic optimisation based on measured serum drug concentrations is common practice. The Sawchuk-Zaske method based on peak and trough drug concentrations is widely used. A more sophisticated approach is the 'goal-oriented model-based Bayesian adaptive control' method, where integration of mathematically determined optimally (D-optimally) sampled serum drug concentrations and a population model results in the most likely set of individual pharmacokinetic parameter values suitable for further pharmacokinetic optimisation of the therapy. A future development is the integration of changing serum drug concentrations and killing rates of the target micro-organism to a pharmacokinetic-pharmacodynamic surrogate relationship to optimise drug therapy. The latter approach may be extremely useful in deciding on the frequency of aminoglycoside administration as well as the optimal use of the beta-lactam antibacterials and fluoroquinolones.

Synergism between tobramycin and ceftazidime against a resistant Pseudomonas aeruginosa strain, tested in an in vitro pharmacokinetic model.

Synergism between two antibiotics is usually tested by a checkerboard titration technique, or by time-kill methods. Both methods have the disadvantage that synergism is determined at constant concentrations of the antibiotics, which do not reflect reality in vivo. In the present study we determined whether synergism between tobramycin and ceftazidime can be found at declining concentrations below the MIC, and whether change in dosing sequence of the antibiotics would result in differences in killing. Three monotherapy and six combination therapy schedules were tested in an in vitro pharmacokinetic model, using a Pseudomonas aeruginosa resistant to both antibiotics. During all q8h dosing schedules the peak concentration (Cmax) was adjusted to the MIC for the strain of both antibiotics. During all monotherapy regimens bacterial growth was present, while all six combination therapy schedules showed significant killing. At t = 24 h there were no differences between all combination therapy schedules, but at t = 8 h the two combination therapy schedules with administration of tobramycin once daily showed a significantly faster killing. By using the area under the killing curve (AUKC) as a parameter for synergistic killing, simultaneous combination therapy starting with tobramycin once daily was significantly better than all other regimens. We conclude that there is synergism between tobramycin and ceftazidime at declining antibiotic concentrations below the MIC, resulting in a pronounced killing of a resistant Pseudomonas strain. Infections due to resistant Pseudomonas strains could possibly be treated by a synergistic combination of these drugs.

[Campylobacter infections in pregnancy]. / Campylobacter-infecties in de zwangerschap.

In two pregnant women aged 39 and 35, who presented with fever and diarrhoea, Campylobacter was cultured from a blood sample. They were treated with antibiotics. One had a healthy neonate, in the other intrauterine foetal death had occurred. Campylobacter species have increasingly been recognized as possible causes of septic abortion, premature labour and neonatal sepsis. Early recognition and treatment of maternal Campylobacter infection may reduce the risk of serious foetal or neonatal complications.

[Myiasis caused by Dermatobia hominis]. / Myiasis door Dermatobia hominis.

In two patients, a woman of 35 and a man of 62 years old, myiasis caused by the larvae of the fly Dermatobia hominis was diagnosed. Both patients had recently returned from a visit to Central America. This ectoparasitosis is found in Central and South America. Patients present themselves with an insect bite which fails to heal. If the clinical presentation is unknown, the disease may well be mistaken for furunculosis. The condition may be easily treated by applying vaseline to the insect bite, which causes extrusion of the larva.

Clinical evaluation and reproducibility of the Pastorex Aspergillus antigen latex agglutination test for diagnosing invasive aspergillosis.

AIMS: The performance of the Pastorex Aspergillus antigen latex agglutination test for the detection of galactomannan in sera of patients at risk for invasive aspergillosis was evaluated, and the impact of storage on the reproducibility of the antigen titre was tested. METHODS: During a one year period, 392 serum samples were obtained from 46 patients at risk for invasive aspergillosis and tested for the presence of galactomannan using an Aspergillus latex agglutination test (Pastorex). Twenty three positive serum samples which had been stored at -20 degrees C for 2-16 months were retrospectively retested. Furthermore, two positive serum samples were stored at -20 degrees C and -70 degrees C and prospectively tested at three month intervals for a period of 15 months. RESULTS: The Pastorex Aspergillus test was positive in eight patients with microbiological, radiological, or histological evidence for invasive aspergillosis, but was negative in the initial serum sample from five of these patients. In two patients with histological evidence for invasive aspergillosis no positive reaction was found in six samples. Six of 13 (45%) serum samples which had been stored at -20 degrees C for longer than six months had lost reactivity, while one of 10 (10%) samples had lost reactivity when stored up to six months. Two serum samples which had been stored at -20 degrees C and -70 degrees C and prospectively retested at three month intervals for 15 months, maintained stable antigen titres. CONCLUSIONS: The Pastorex Aspergillus test is too insensitive to diagnose invasive aspergillosis in an early stage, but may contribute to the diagnosis when cultures remain negative and serial samples are obtained. To maintain a good reproducibility, serum samples should be stored at -70 degrees C when the period of storage exceeds six months.

Cellulitis as first clinical presentation of disseminated cryptococcosis in renal transplant recipients.

Two renal transplant recipients with cellulitis due to Cryptococcus neoformans are described. The patients were treated empirically for a presumed bacterial erysipelas, but without response. Examination of skin biopsies revealed C. neoformans as the causative organism. In both patients the cellulitis was the presenting clinical manifestation of disseminated cryptococcosis. Therapy with antifungal agents was successful. Disseminated cryptococcal disease occurs mainly in immunocompromised patients. When left untreated, it nearly always has a fatal course. Early diagnosis and appropriate therapy are therefore essential.

Chronic polyarthritis due to Pseudomonas aeruginosa.

We present a 45-year-old male patient with chronic obstructive lung disease treated with low-dose corticosteroids, who developed a chronic septic polyarthritis due to Pseudomonas aeruginosa following a surgical wound infection. Due to the mild synovitis and the absence of systemic signs of infection the diagnosis was delayed for nearly 2 years and resulted in severe joint destruction.