Hickman catheter-related infections in neutropenic patients: insertion in the operating theater versus insertion in the radiology suite.

PURPOSE: To determine the influence of microbial air quality during Hickman catheter insertion in the operating theater versus insertion in the radiology suite on the incidence of catheter-related infections (CRIs). PATIENTS AND METHODS: Hemato-oncologic patients with prolonged neutropenia on antimicrobial prophylaxis were entered onto the study. Catheters were inserted by experienced radiologists under sonographic and fluoroscopic guidance. RESULTS: Forty-eight Hickman catheters in 39 patients were inserted (23 in the operating theater, 25 in the radiology suite). CRIs were seen in 16 catheters (33%; six per 1,000 catheter days; eight in each group). Local infections were found in nine catheters (22%; six in the operating theater v three in the radiology suite; not significant [NS]), catheter-related bacteremia was found in 10 (29%; three in the operating theater v seven in the radiology suite; NS). Coagulase-negative staphylococci (CoNS) caused all CRIs. Despite early vancomycin therapy, 11 (69%; four in the operating room group v seven in the radiology suite group; NS) of the catheters with CRIs had to be removed prematurely. At 90 days after insertion, catheter survival was 78% and 60% (NS) for the operating room and radiology suite, respectively. Multivariate analysis showed that neutropenia increased the CRI risk 20-fold (P =.004) and was strongly related to premature catheter removal owing to infection (relative risk = 11.9; P =.009). Neutropenia on the day of insertion was also significantly correlated with CRI (P =.04) and premature catheter removal owing to infection (P =.03). Serial cultures of blood, exit site, and catheter hub did not predict the development of CRI. CONCLUSION: The high incidence of Hickman CRI caused by CoNS was not associated with insertion location (operating theater v radiology suite). Neutropenia, including neutropenia on the day of insertion, was a significant risk factor for CRI and infection-related catheter removal.

Liposomal and lipid-based formulations of amphotericin B.

Encapsulating amphotericin B (AmB) into liposomes or binding of AmB to other lipid carriers results in a significant reduction of toxicity of AmB and possibly an increased therapeutic index. Following promising clinical results with investigational formulations, three industrial compounds have been developed: AmBisome, Amphocil (Amphotericin B Colloidal Dispersion) and Amphotericin B Lipid Complex (ABLC, Abelcet). These three formulations differ significantly in composition and pharmacokinetics. AmB serum levels after ABLC and Amphocil administration are low, but after AmBisome much higher. However, the interpretation of the pharmacokinetic data is hampered by the inability to separate free AmB fractions from tissue-, protein- and lipid carrier bound fractions. All three compounds share a considerable reduction of nephrotoxicity. However, the acute reaction rates differ among these compounds. Amphocil showing the highest and AmBisome the lowest rate. Unfortunately, efficacy data of ongoing trials comparing these formulations with conventional AmB are scarce. Therefore, for the moment we can recommend these compounds only in cases of intolerance to or failure on AmB therapy. The optimal therapeutic dosages have not been established, but dosages as low as 1 mg/kg should be avoided in the initial treatment of fulminant fungal infections, since efficacy may be inferior to equal doses of conventional AmB.

The use of lipid formulations of amphotericin B for systemic fungal infections.

Despite its considerable toxicity, amphotericin B (AmB) remains the 'golden standard' in the treatment of many systemic fungal infections. To reduce this toxicity, with the aim of increasing its therapeutic index, AmB can be encapsulated into liposomes or bound to lipid carriers. Following promising clinical results with investigational formulations, three industrial compounds are available at this moment: Abelcet (Amphotericin B Lipid Complex, ABLC), Amphocil (Amphotericin B Colloidal Dispersion) and AmBisome. These three formulations differ significantly in composition and pharmacokinetics. All three compounds share a considerable reduction of nephrotoxicity, but the number of acute reactions differ among these compounds, Amphocil showing the highest and AmBisome the lowest rate. Increased therapeutic indexes for all three formulations were shown only in some of the animal models for several fungal infections. Four recent clinical trials comparing these formulations with AmB demonstrated their clinical efficacy but failed to clearly show an increased therapeutic index. Therefore these compounds can be recommended in cases of intolerance to or failure on AmB therapy. The optimal therapeutic dosages have not been established, but dosages as low as 1 mg/kg should probably be avoided in the initial treatment of fulminant fungal infections, since efficacy may be inferior to equal dosages of conventional AmB.

Psoas abscess: report of a series and review of the literature.

We describe a series of twelve patients with a psoas abscess seen in a three-year period in a university hospital and a large teaching hospital in the Netherlands. In our series, five of the 12 patients had a primary psoas abscess. The predisposing conditions were intravenous drug use, diabetes mellitus, prostate carcinoma and haematoma in the psoas muscle in a patient with haemophilia A. Seven of the 12 patients had a secondary psoas abscess. Five cases were due to vertebral osteomyelitis including two cases of tuberculosis. In the other two cases it was due to colitis and urinary tract infection. It is remarkable that in our series there was only one patient with a psoas abscess secondary to a disease of the digestive tract, while this is the most common cause of a secondary psoas abscess in the literature. There were two cases of tuberculosis which is an emerging disease again.

Urological complaints in relation to indinavir plasma concentrations in HIV-infected patients.

OBJECTIVE: To assess the relationship between indinavir-associated urological complaints and indinavir plasma concentrations. DESIGN: Case series, comparing indinavir plasma concentrations in cases with average concentrations in a control group. METHODS: Patients taking 800 mg indinavir three times a day (tid), who presented with overt urological complaints (renal colic, flank pain or haematuria) were selected for the study. Plasma indinavir concentrations were measured by means of a standardized high performance liquid chromatography (HPLC) method. Plasma samples taken at 1.5-8 h after the last indinavir ingestion were included for evaluation. Results were compared with the full pharmacokinetic curves of indinavir plasma concentrations from a control group of 14 patients taking 800 mg indinavir tid without urological complaints, and were expressed as concentration ratios. A ratio of 1 indicated a plasma concentration equalling the average concentration in the control population at the same point in time after the ingestion of indinavir. RESULTS: Seventeen patients (five women) were enrolled and the indinavir concentrations of 15 patients could be evaluated. Fourteen (93%) patients had a concentration above the mean of the controls, 12 (80%) patients had a concentration above the upper 95% confidence limit, and one (7%) patient had a concentration below the lower 95% confidence limit. The mean indinavir concentration in patients with urological complaints (ratio range 0.55-11.49) was significantly higher than the average concentration and the upper 95% confidence limit of the control group (P < 0.05). The results could not be explained by differences in weight, sex or drug interactions. Two patients had chronic active hepatitis B infection. In six patients with indinavir concentrations above the upper 95% limit, indinavir was reduced to 600 mg tid. Upon repeat measurement after the dose adjustment, their indinavir plasma concentrations fell within the 95% confidence interval around the mean of the control population. All six patients remained asymptomatic and had viral loads of less than 500 copies per ml after a follow-up of 5-16 months. CONCLUSIONS: Urological complications occurring during indinavir treatment were associated with elevated indinavir plasma concentrations in 80% of patients in this study. Indinavir plasma concentrations should be monitored upon presentation of urological complaints, on the basis of which dose reductions may be applied if brief interruption and increased hydration are ineffective.

Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis.

OBJECTIVE: Amphotericin B deoxycholate initial therapy and fluconazole maintenance therapy is the treatment of choice for AIDS-associated cryptococcal meningitis. However, the administration of amphotericin B is associated with considerable toxicity. A potential strategy for reducing the toxicity and increasing the therapeutic index of amphotericin B is the use of lipid formulations of this drug. DESIGN AND METHODS: HIV-infected patients with cryptococcal meningitis were randomized to treatment with either liposomal amphotericin B (AmBisome) 4 mg/kg daily or standard amphotericin B 0.7 mg/kg daily for 3 weeks, each followed by fluconazole 400 mg daily for 7 weeks. During the first 3 weeks, clinical efficacy was assessed daily. Mycological response was primarily evaluated by cerebrospinal fluid (CSF) cultures at days 7, 14, 21 and 70. RESULTS: Of the 28 evaluable patients, 15 were assigned to receive AmBisome and 13 to receive amphotericin B. Baseline characteristics were comparable. The time to and the rate of clinical response were the same in both arms. AmBisome therapy resulted in a CSF culture conversion within 7 days in six out of 15 patients versus one out of 12 amphotericin B-treated patients (P = 0.09), within 14 days in 10 out of 15 AmBisome patients versus one out of nine amphotericin B patients (P = 0.01), and within 21 days in 11 out of 15 AmBisome patients versus three out of eight amphotericin B patients (P = 0.19). When Kaplan-Meier estimates were used to compare time to CSF culture conversion, AmBisome was more effective (P < 0.05; median time between 7 and 14 days for AmBisome versus > 21 days for amphotericin B). AmBisome was significantly less nephrotoxic. CONCLUSIONS: A 3-week course of 4 mg/kg AmBisome resulted in a significantly earlier CSF culture conversion than 0.7 mg/kg amphotericin B, had equal clinical efficacy and was significantly less nephrotoxic when used for the treatment of primary episodes of AIDS-associated cryptococcal meningitis.

Scintigraphic imaging of bacterial and fungal infection in granulocytopenic rats.

UNLABELLED: Scintigraphic imaging in granulocytopenic patients can be very useful to detect and localize infections, which often do not show localizing signs and symptoms. We studied the potential of 99mTc-labeled polyethylene glycol (PEG)-coated liposomes and 99mTc-labeled IgG to image bacterial and fungal infection in a granulocytopenic rat model. 67Ga-citrate was used as a reference agent. METHODS: 99mTc-PEG-liposomes, 99mTc-hydrazinonicotinate (HYNIC)-IgG or 67Ga-citrate was administered to granulocytopenic rats with a Staphylococcus aureus abscess or with unilateral invasive pulmonary aspergillosis. Imaging and biodistribution studies were performed. RESULTS: All agents visualized the S. aureus infection from 1 h after injection onward. However, only with 99mTc-PEG-liposomes and with 99mTc-HYNIC-IgG did activity in the infectious foci increase with time up to 24 h. 99mTc-PEG-liposomes and 99mTc-HYNIC-IgG showed significantly higher accumulation in the infectious focus compared with 67Ga-citrate (1.33+/-0.31 and 1.40+/-0.16 percentage injected dose per gram [%ID/g], respectively, versus 0.31+/-0.04 %ID/g 24 h after injection; P<0.05). At 24 h after injection, abscess-to-muscle ratios were highest for 99mTc-liposomes (72.1+/-19.1), followed by 99mTc-HYNIC-IgG (18.3+/-3.3) and 67Ga-citrate (4.4+/-0.7). In pulmonary aspergillosis, both 99mTc-PEG-liposomes and 99mTC-HYNIC-IgG showed significantly higher uptake in the infected lung than did 67Ga-citrate (3.6+/-0.4 and 8.3+/-0.8 %ID/g, respectively, versus 1.3 %ID/g at 24 h after injection; P<0.05). CONCLUSION: 99mTc-PEG-liposomes and 99mTc-HYNIC-IgG performed better than did 67Ga-citrate in the localization of peripheral bacterial infection and fungal infection in the lung in granulocytopenic rats. The high focal uptake and high target-to-nontarget ratios of 99mTc-PEG-liposomes and 99mTc-HYNIC-IgG indicate that both radiopharmaceuticals may become valuable agents to image infection in granulocytopenic patients.

Liposomal and lipid formulations of amphotericin B. Clinical pharmacokinetics.

Amphotericin B remains a very important drug for the treatment of fungal infections despite its toxicity. Encapsulation of amphotericin B into liposomes appears to reduce the toxic effects and to improve the clinical efficacy, allowing higher dosages to be given. The exact mechanism behind the reduced toxicity is not yet known. Amphotericin B is widely distributed after intravenous administration as the deoxycholate solubilisate. The highest concentrations are found in the liver, spleen and kidney. Protein binding and binding to the tissues is very high. The fate of the drug in the body is not known in detail. Renal and biliary excretion are both low and no metabolites have been identified. The drug is still detectable in the liver, spleen and kidney for as long as 1 year after stopping therapy. The pharmacokinetics of the different liposomal amphotericin B or lipid complexes of amphotericin B, which were recently developed, are quite diverse. A number of these preparations, such as amphotericin B lipid complex (ABLC), 'AmBisome' and amphotericin B colloidal dispersion (ABCD) are in clinical development. Their pharmacokinetics depend to a large extent on the composition and particle size of the liposomes or lipid complexes. Relatively large structures such as ABLC are rapidly taken up by the mononuclear phagocyte system, whereas smaller liposomes remain in the circulation for prolonged periods. In all studies only the total amphotericin B (both free and liposome- or lipid-associated) concentrations were determined. There is a need for studies correlating clinical efficacy and tolerability of liposomal amphotericin B with the pharmacokinetic properties of these formulations.

Difficult-to-treat infections.

The most common problems in the management of serious bacterial infections were reviewed. As illustrations, the diagnostic and therapeutic strategies in two types of deep-seated infections--both associated with a poor penetration of antibiotics--were discussed: (1) In suppurative central venous thrombophlebitis, conservative therapy frequently fails; if so, one should promptly switch to a surgical approach; (2) in most patients with a parapharyngeal space infection, a non-surgical approach can be recommended including early diagnosis by computed tomography (CT), CT-guided needle aspiration, prompt administration of benzylpenicillin in high and frequent dosages or continuously, and follow-up by CT. This regimen may prevent radical surgery even in the presence of deep neck or mediastinal abscesses.

Bioavailability of ciprofloxacin after multiple enteral and intravenous doses in ICU patients with severe gram-negative intra-abdominal infections.

BACKGROUND: Few data are available on the pharmacokinetics of multiple enteral dosing of ciprofloxacin in critically ill intensive care patients and none for those with severe gram-negative intra-abdominal infections (GNIAI). OBJECTIVE: To determine the bioavailability of enteral ciprofloxacin in tube-fed intensive care patients with severe GNIAI. DESIGN: A randomized crossover study. SETTING: University-based medical center. PATIENTS: 5 critically ill intensive care patients with GNIAI and an estimated creatinine clearance > 25 ml/ min who received continuous tube feeding. INTERVENTIONS: Multiple doses of enteral 750 mg b.i.d. versus 400 mg b.i.d.i.v. ciprofloxacin. MEASUREMENTS: The calculated 12-h area under the serum concentration versus time curve after 750 mg b.i.d. enteral dosing was equivalent to that after 400 mg b.i.d.i.v. The mean bioavailability of enteral dosing was 53.1% [95% confidence interval (CI) 43.5-62.8]. In seven additional patients, the mean serum steady-state concentration at 2 h after enteral administration was 3.9 microg/ml (95% CI 1.9-5.9), not significantly different from that found in the crossover study (p = 0.4). CONCLUSIONS: In tube-fed intensive care patients with severe GNIAI, the bioavailability of enteral ciprofloxacin is adequate.

Aspergillus osteomyelitis after liver transplantation: conservative or surgical treatment?

We report on a liver transplant recipient who developed coxarthritis and lumbar spondylodiscitis due to Aspergillus flavus. He was treated with high-dose liposomal amphotericin B for 2 months followed by itraconazole. Because of intractable pain and severe, irreversible damage of the left hip, a Girdlestone resection was performed. The spondylodiscitis was treated successfully with anti-fungal agents only, which indicates that, in the absence of neurological impairment, good clinical outcome can be achieved without surgery. This case demonstrates that surgical therapy, which is often proclaimed as unavoidable for the treatment of Aspergillus osteomyelitis, should be considered in particular in the case of intolerable pain due to irreversible joint damage or involvement of vital organs.

Meningococcal disease in The Netherlands, 1959-1981: the occurrence of serogroups and serotypes 2a and 2b of Neisseria meningitidis.

By means of a filter radioimmunoassay and the use of monoclonal anti-2a and anti-2b antibodies, we have serotyped 3164 of 3688 strains of Neisseria meningitidis isolated from patients in The Netherlands between 1959 and 1981. Serotypes 2a and 2b were distributed differently among the major serogroups A, B, C, and W-135. Neither of the types was found among group A strains. Type 2b strains of serogroup B emerged in 1965, causing a country-wide epidemic which reached a peak incidence in March and April of 1966 and continued to predominate within group B until 1979. Type 2a strains of serogroup C were responsible for a substantial number of sporadic cases over a long period without any association with outbreaks or with a shift in the pattern of the serogroup. After the appearance of group W-135 in 1971, W-135 strains caused a small non-focal epidemic wave. The upsurge of disease due to virulent sub-populations of strains B:2b and C:2a appeared to be closely related to a basic pattern of regular cyclical waves with peak intervals which differed for serogroups A, B, and C. In recent years both serotype 2a and 2b strains within the different serogroups fell to insignificant numbers. Our results show that retrospective large-scale serotyping of collected strains provides insight into the epidemiological patterns of endemic meningococcal disease.

Clinical features and risk factors of lactic acidosis following long-term antiretroviral therapy: 4 fatal cases.

Our objective was to describe clinical features and predisposing factors attributed to lactic acidosis in 4 HIV-infected patients on long-term nucleoside reverse transcriptase inhibitor (NRTI) therapy. All patients had received at least 6-20 months of NRTI-containing antiretroviral therapy: all used stavudine (d4T), in one combined with lamivudine (3TC), in the other 3 with didanosine (ddI); in one hydroxyurea was added. In all, the initial symptoms were gastrointestinal (nausea and vomiting), followed by tachypnoea preceding the lactic acidosis; death followed 6-22 days after admission (liver failure and uncontrollable arrhythmias). Treatment with riboflavin was unsuccessful in one patient. The only definite risk factor in all cases was NRTI-induced mitochondrial toxicity; one patient was concomitantly treated for Kaposi's sarcoma (with bleomycin and vinblastine) and one just recovered from pneumococcal sepsis. None of the patients had a history of chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. In all patients, some sort of toxicity to other previously used NRTIs had occurred earlier. Lactic acidosis occurred after months of NRTI therapy in patients who had already suffered other forms of NRTI toxicity. Concomitant diseases or comedication might have aggravated the mitochondrial toxicity of the NRTIs. Screening methods to detect mitochondrial toxicity are necessary, since lactic acidosis occurs rather unexpectedly, with a rapid, fatal course.

Prevention of infections in hyposplenic and asplenic patients: an update.

Patients with functional or anatomic asplenia are at a significantly increased risk of overwhelming infection, particularly involving the encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenzae. The risk is highest in infants and young children, but adults also have an increased risk of infection. Preventive strategies are very important and fall into three major categories: immunoprophylaxis, antibiotic prophylaxis and education. Studies have shown that many asplenic patients are unaware of their increased risk for serious infection and the appropriate health precautions that should be undertaken. In this article we emphasise the need for preventive measures in hyposplenic and asplenic patients. We discuss the value of newly developed conjugate vaccines and the need for revaccination. Finally we draw up a recommendation for the preventive management in functional and anatomical asplenic patients.

[HIV infection in the Rijnmond area, 1985-1993: more transmission via heterosexual contact and drug use, and more female patients]. / HIV-infectie in de regio Rijnmond, 1985-1993: meer transmissie door heteroseksueel contact en drugsgebruik, en meer vrouwelijke patiënten.

OBJECTIVE: To evaluate the characteristics of HIV infected patients in the Rijnmond region during 1985-1993. DESIGN: Descriptive. SETTING: University Hospital Rotterdam-Dijkzigt (AZR). METHOD: Data of medical records of all HIV infected patients in AZR were prospectively collected from 1988 on and retrospectively for 1985-1987. RESULTS: During the period 1985-1993 510 HIV positive patients consulted an internist at AZR (eight were infected with HIV-2). During the study 255 patients developed AIDS. Since 1991 fewer than 50% of the new HIV infected individuals belonged to the risk group of homosexual and bisexual men. The majority was infected by intravenous drug abuse or by heterosexual intercourse. Half the population infected by heterosexual transmission came from HIV endemic areas. The increasing number of HIV infection among heterosexuals was associated with an increasing number of HIV infected women. CONCLUSION: The Rijnmond region showed a noticeable shift of risk groups with HIV infection: heterosexual transmission and intravenous drug abuse were the cause of HIV infection in more than half of the HIV infections at AZR in 1992 and 1993. Counselling, health care and treatment should take account of the diversity of cultural backgrounds of the patient groups.

[Treatment adherence amongst HIV-infected patients in Rotterdam: poorer prognosis independent of nationality in heterosexual infected patients, intravenous drug users, Negroid and Latin-American patients]. / Therapietrouw onder HIV-geïnfecteerden in Rotterdam: onafhankelijk van nationaliteit slechter bij heteroseksueel besmette patiënten, intraveneuzedruggebruikers, negroïde en Latijns-Amerikaanse patiënten.

OBJECTIVE: To assess adherence to antiretroviral therapy (ART) in Dutch and non-Dutch HIV-infected patients. DESIGN: Observational, cross-sectional study. METHODS: Consecutive HIV-infected patients taking ART and visiting the internal medicine outpatients' clinic at the Rotterdam Dijkzigt University Hospital between 1 February until 30 April 2001 were interviewed by a multilingual interviewer using a standard questionnaire. Classification of adherence was based on the interview data. Multivariate analysis was used to determine independent predictors of adherence. Nationality was defined as 'Dutch' if the person was born in the Netherlands, and otherwise as 'non-Dutch'. RESULTS: The 203 patients included in this study comprised 131 men and 69 women with an average age of 42 years. There were no data available on treatment adherence for 3 of the patients. Of the 81 Dutch patients, 60 (74%) adhered to the treatment compared with 68 (57%) of the 119 non-Dutch patients. However, after correction for sex, risk group, race and duration of treatment, there was no difference in treatment adherence between these two groups (OR: 0.6; 95% CI: 0.2-1.9). Failure to adhere to treatment was seen most frequently in the 109 heterosexually infected patients (OR: 2.6; 0.98-6.7), the 22 intravenous drug users (OR: 3.3; 1.04-10.1), as well as in the group of Negroid patients (OR: 3.5; 1.1-11.3) and Latin-American patients (OR: 8.5; 1.7-42.7).