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.

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.

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.

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.

Ceftazidime monotherapy for pulmonary melioidosis in a traveler returning from Thailand.

A patient with deteriorating pulmonary melioidosis rapidly recovered after treatment with ceftazidime. To prevent possible relapses, an oral maintenance regimen of amoxicillin and clavulanic acid was prescribed for a period of three months. Melioidosis is caused by Pseudomonas pseudomallei. It is an insidious disease because of its variable clinical presentation, possible long-term asymptomatic carriage, broad-spectrum resistance to first-line antibiotics, and high mortality rate. As in our patient, the diagnosis should be particularly considered when there is reduced immunologic resistance and previous exposure in endemic areas, such as Southeast Asia.

Pharmacokinetics of antimicrobial drugs in cystic fibrosis. Aminoglycoside antibiotics.

Patients with cystic fibrosis (CF) show abnormal aminoglycoside pharmacokinetics. After a conventional dose, the serum concentrations in CF patients are lower than those in nonCF patients. The lower serum concentrations in CF might be explained by increased total body clearance and/or a larger volume of distribution. The therapeutic range of aminoglycosides is narrow due to oto- and nephrotoxicity. The changed pharmacokinetics and the narrow therapeutic range make it difficult to ensure that patients with CF are adequately and safely treated with aminoglycosides. The mode of administration of aminoglycosides influences the antibacterial effect of these agents on Pseudomonas aeruginosa and the development of possible side effects. The therapeutic implications of these facts are discussed.

Tobramycin in patients with cystic fibrosis. Adjustment in dosing interval for effective treatment.

The efficacy of the dosing regimen of tobramycin was investigated in 28 patients with cystic fibrosis who had an acute exacerbation of chronic pulmonary infection with Pseudomonas aeruginosa. The initial dose of tobramycin was 3.3 mg/kg of body weight three times daily (ie, 10 mg/kg/day). A highly significant relationship was found between the serum concentration of tobramycin before the dose and the change in the forced expiratory volume in one second (FEV1), both measured on the tenth day of treatment (rs = 0.75; p less than 0.001). In nine of the 16 patients who had a six-hour serum concentration of 1 mg/L or less on the tenth day of treatment, the eight-hour dosing interval of tobramycin was shortened to achieve a serum concentration of tobramycin of about 1 mg/L before the dose. In the other seven patients, the dosage of tobramycin was not changed. On the 20th day, seven of the nine patients in whom the dosing interval was shortened exhibited an increase in FEV1 of 20 percent or more. Such an increase was observed only in one of the seven patients in whom the dosing interval was not reduced (p less than 0.05). We conclude that individualizing the dosage of tobramycin in patients with cystic fibrosis results in a better clinical outcome.

Pharmacokinetics of tobramycin in patients with cystic fibrosis. Implications for the dosing interval.

The pharmacokinetics of tobramycin were evaluated in 15 patients (8 to 22 years of age) with cystic fibrosis (CF). A dose of 3.0 to 3.3 mg/kg of body weight was given intravenously over 20 minutes, and concentrations in serum were followed up to eight hours after initiation of the infusion. In the calculation of pharmacokinetic parameters, a two-compartment open model was used. The elimination half-life of the drug was highly inversely correlated with age (p less than 0.0004), and body weight (p less than 0.00002). Total body clearance (TBC), and volume of distribution at steady state (VDSS) were directly correlated with age and body weight. However, when TBC and VDSS were corrected for BSA, no correlation could be demonstrated. The mean one-hour and eight-hour serum concentrations of tobramycin were 5.40 and 0.45 microgram X ml-1, respectively. Between patients, considerable differences were found in the time after administration at which the serum concentration decreased below 1 microgram X ml-1. This interpatient variation has clinical implications for tobramycin therapy in CF, in particular for the dosing interval.

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.

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.

Endemic acinetobacter in intensive care units: epidemiology and clinical impact.

AIMS: To assess whether Acinetobacter isolates obtained over 20 months in a tertiary care hospital were epidemiologically related; to establish the clinical importance of the organisms; and to identify the isolates according to the recent taxonomy. METHODS: Fifty eight Acinetobacter isolates from 49 patients collected during 1984 and 1985 were investigated. Most isolates were from respiratory tract specimens from intensive care patients. The organisms were typed by cell envelope protein electrophoresis and by a quantitative carbon source growth assay; patients' charts were reviewed to differentiate between colonisation and infection; representative isolates were identified to species level by DNA-DNA hybridisation. RESULTS: Twelve protein profiles were distinguished in the isolates. Forty two isolates were of the same protein profile (profile I); other profiles were observed in a few or single isolates. Cluster analysis of carbon source growth divided profile I isolates into two groups--one of isolates from 1984 and one from 1985. They were identified as A baumannii and associated with infections in eight patients. Four other infections were caused by acinetobacters with other protein profiles (three of A baumannii; one of the unnamed DNA group 3). CONCLUSIONS: Apart from sporadic strains, two strains of the same protein profile, but distinguishable by carbon source growth, were successively endemic. Cluster analysis was a valuable tool in the interpretation of typing and epidemiological data. The 12 (28%) infections of Acinetobacter in 43 patients in intensive care suggest that the presence of these organisms in wards of severely ill patients should be a cause of concern.

Ecology of Pseudomonas aeruginosa in patients with cystic fibrosis.

The occurrence of various Pseudomonas aeruginosa strains in the sputum of 15 patients with cystic fibrosis (CF) was monitored over periods ranging from 2 to 60 months. Isolates of P. aeruginosa were typed by four different techniques, namely serotyping, active and passive pyocin typing, and phage typing. The maximum number of different serotypes found in the patients was three (one serotype in nine patients; two serotypes in five patients; three serotypes in one patient). Pyocin and phage typing showed no marked differences between strains of the same serotype in individual patients. Exacerbations of chronic respiratory infection were not associated with changes in the sputum flora, the composition of P. aeruginosa strains in which remains constant over long periods in patients with CF.

Rapid diagnosis of acute meningococcal infections by needle aspiration or biopsy of skin lesions.

OBJECTIVES: To evaluate the usefulness of Gram staining and culture of skin lesions in patients with acute meningococcal infections. DESIGN: Retrospective study. SETTING: Community hospital and intensive care unit of a teaching hospital. SUBJECTS: 51 patients admitted from 1989 to 1993 with proved meningococcal infections and microbiological examination of specimens from skin lesions. INTERVENTIONS: Needle aspiration of a skin lesion before start of antibiotic treatment in 26 patients in the community hospital; punch biopsy of skin lesion after start of antibiotic treatment in 25 patients in the teaching hospital. MAIN OUTCOME MEASURES: Detection of meningococci by Gram staining of specimens from skin lesions according to category of infection (meningococcaemia, meningitis, meningitis with shock, or septic shock without meningitis). RESULTS: Bacteria were detected in the specimen from haemorrhagic skin lesions by culture or Gram staining, or both in 32 (63%) patients. The sensitivity of the Gram stain was 51% and did not differ significantly from its sensitivity in detecting bacteria in cerebrospinal fluid. In meningococcal sepsis, however, a Gram stained skin lesion was significantly more sensitive (72%) than Gram stained cerebrospinal fluid (22%). In patients with meningitis skin lesions gave positive results on staining more often if shock was present. The results for punch biopsy specimens were not affected by antibiotics as Gram staining gave positive results up to 45 hours after the start of treatment and culture gave positive results up to 13 hours. CONCLUSION: Microbiological examination of skin lesions is informative, especially in patients with sepsis and inconclusive results from cerebrospinal fluid, and may provide a diagnosis in such patients within 45 minutes. It differentiates well between meningitis with and without haemodynamic complications, and the result is not affected by previous antibiotic treatment.

[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.

[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.

[Postanginal sepsis caused by Fusobacterium necrophorum: Lemierre syndrome]. / Postangineuze sepsis door Fusobacterium necrophorum: het syndroom van Lemierre.

Postanginal sepsis or Lemierre's syndrome is characterised by septic thrombophlebitis of the jugular vein, metastatic abscesses in the lungs, soft tissues, joints or elsewhere, occurring several days to two weeks after tonsillitis or pharyngitis. The primary pathogen is a Gram-negative anaerobic rod, mostly Fusobacterium necrophorum. Previously healthy, young adults are affected mainly and the syndrome was seen more frequently in the pre-antibiotic era than it is nowadays. In the three young patients described here, a girl aged 15 and two boys aged 18 and 16, F. necrophorum was isolated from blood or pus. Histories and examinations were suggestive of Lemierre's syndrome. Ultrasound and CT scanning of the neck and other localisations proved to be important diagnostic tools in assessing the diagnosis. Response to therapy was slow and depended in at least one case on adequate drainage of abscesses. If the syndrome is suspected, initial antibiotic treatment should provide adequate coverage of anaerobic bacteria. In previously healthy patients with chills and fever occurring several days after a sore throat, Lemierre's syndrome should be considered.