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We evaluated the predictive value of chills, bacteraemia and endotoxaemia for in-hospital mortality and survival at 5-10 years long-term follow-up in a prospective cohort of 'early sepsis' patients presenting with fever resulting from community-acquired pneumonia or pyelonephritis. Febrile patients with chills had bacteraemia more often (RR 3.1, 95% CI 1.8-5.4) than those without chills. Neither chills nor bacteraemia were significantly related to in-hospital mortality, but patients with endotoxaemia had a higher in-hospital mortality rate than those without endotoxaemia. Patients with chills had a significantly higher survival rate at long-term follow-up than those without chills on admission: the estimated risk of dying was 0.644 (95% CI 0.43-0.95, P = 0.029) for an individual with chills, compared to a person without chills, adjusting for the other factors [age cohort, underlying disease and the pro-inflammatory response in the blood, i.e. tumour necrosis factor-alpha (TNF-alpha) and blood leucocyte number, as scored on hospital admission] in the Cox proportional hazards model. Chills may characterize a patient subpopulation that upon pulmonary and urinary tract infection is able to raise a more rapid and/or efficient host response. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pneumocystis carinii pneumonia (PCP) occurs in immunocompromised patients without the acquired immunodeficiency syndrome (AIDS). There has been an increasing yearly number of cases of PCP in our patients without AIDS. OBJECTIVE: To determine the nature of the underlying disorder and previous immunosuppressive treatment in patients with PCP without AIDS. METHOD: A study of the charts of 78 such patients admitted to our hospital from 1980 through 1993. RESULTS: The number of PCP cases per year increased during the period studied. All patients had an underlying disorder, either hematologic malignancy (49%), solid organ tumor (4%), vasculitis or other immunologic disorder (22%), or they had undergone renal transplantation (17%) or bone marrow transplantation (9%). Previous immunosuppressive medication consisted of prednisone or other corticosteroids in 72 (92%) of 78 patients, cytotoxic drugs in 55 (71%) of 78 patients, both in 50 (64%) of 78 patients, and none in one patient. Quantification of previous corticosteroid treatment showed a large variability among patients. The overall mortality rate for patients was 35% (27/78). Mortality was significantly higher in patients with a concomitant pulmonary infection (P = .01), an underlying disorder other than that which resulted in renal transplantation (P = .03), mechanical ventilation (P < .001), previous chemotherapy (P = .04), as well as previous cyclophosphamide treatment (P = .01). A trend toward a higher mortality in patients with previous corticosteroid use was detected (P = .06). CONCLUSION: Pneumocystis carinii pneumonia may complicate a variety of immunocompromised states, with considerable mortality. Pneumocystis carinii pneumonia occurred at all levels of immunosuppression; no threshold level could be defined. [ABSTRACT FROM AUTHOR]

Triazole resistant A. fumigatus has been documented in many parts of the world. In the Netherlands, incidence is now above 10% and results in the need for long-term parenteral therapy with liposomal amphotericin B (LAmB). The long terminal half-life of LAmB suggests that intermittent dosing could be effective, making the application of outpatient antifungal therapy (OPAT) possible. Here, we report our experience with the use of OPAT for Invasive Fungal Infections (IFI). All adult patients treated with LAmB with a 2 or 3 times weekly administration via the outpatient departments in four academic tertiary care centers in the Netherlands and Belgium since January 2010 were included in our analysis. Patient characteristics were collected, as well as information about diagnostics, therapy dose and duration, toxicity, treatment history and outcome of the IFI. In total, 18 patients were included. The most frequently used regimen (67%) was 5 mg/kg 3 times weekly. A partial response to the daily treatment prior to discharge was confirmed by CT-scan in 17 (94%) of patients. A favorable outcome was achieved in 13 (72%) patients. Decrease in renal function occurred in 10 (56%) cases but was reversible in all and was treatment limiting in one patient only. The 100-day mortality and 1-year mortality after initiation of OPAT were 0% and 6%, respectively. In a selected population, and after confirmation of initial response to treatment, our data support the use of OPAT with LAmB for treatment of IFI in an intermittent dosing regimen., (© The Author(s) 2020. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: There is a lack of severity assessment tools to identify adults presenting with febrile urinary tract infection (FUTI) at risk for complicated outcome and guide admission policy. We aimed to validate the Prediction Rule for Admission policy in Complicated urinary Tract InfeCtion LEiden (PRACTICE), a modified form of the pneumonia severity index, and to subsequentially assess its use in clinical practice., Methods: A prospective observational multicenter study for model validation (2004-2009), followed by a multicenter controlled clinical trial with stepped wedge cluster-randomization for impact assessment (2010-2014), with a follow up of 3 months. Paricipants were 1157 consecutive patients with a presumptive diagnosis of acute febrile UTI (787 in validation cohort and 370 in the randomized trial), enrolled at emergency departments of 7 hospitals and 35 primary care centers in the Netherlands. The clinical prediction rule contained 12 predictors of complicated course. In the randomized trial the PRACTICE included guidance on hospitalization for high risk (>100 points) and home discharge for low risk patients (<75 points), in the control period the standard policy regarding hospital admission was applied. Main outcomes were effectiveness of the clinical prediction rule, as measured by primary hospital admission rate, and its safety, as measured by the rate of low-risk patients who needed to be hospitalized for FUTI after initial home-based treatment, and 30-day mortality., Results: A total of 370 patients were included in the randomized trial, 237 in the control period and 133 in the intervention period. Use of PRACTICE significantly reduced the primary hospitalization rate (from 219/237, 92%, in the control group to 96/133, 72%, in the intervention group, p < 0.01). The secondary hospital admission rate after initial outpatient treatment was 6% in control patients and 27% in intervention patients (1/17 and 10/37; p < 0.001)., Conclusions: Although the proposed PRACTICE prediction rule is associated with a lower number of hospital admissions of patients presenting to the ED with presumptive febrile urinary tract infection, futher improvement is necessary to reduce the occurrence of secondary hospital admissions., Trial Registration: NTR4480 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4480 , registered retrospectively 25 mrt 2014 (during enrollment of subjects).

Bacterial infections such as febrile urinary tract infection (fUTI) may run a complicated course that is difficult to foretell on clinical evaluation only. Because the conventional biomarkers erythrocyte sedimentation rate (ESR), leucocyte count, C-reactive protein (CRP) and procalcitonin (PCT) have a limited role in the prediction of a complicated course of disease, a new biomarker-plasma midregional pro-adrenomedullin (MR-proADM)-was evaluated in patients with f UTI. We conducted a prospective multicentre cohort study including consecutive patients with f UTI at 35 primary-care centres and eight emergency departments. Clinical and microbiological data were collected and plasma biomarker levels were measured at presentation to the physician. Survival was assessed after 30 days. Of 494 fUTI patients, median age was 67 (interquartile range 49-78) years, 40% were male; two-thirds of them had significant co-existing medical conditions. Median MR-proADM level was 1.42 (interquartile range 0.67-1.57) nM; significantly elevated MR-proADM levels were measured in patients with bacteraemia, those admitted to the intensive care unit, and in 30-day and 90-day non-survivors, compared with patients without these characteristics. The diagnostic accuracy for predicting 30-day mortality in fUTI, reflected by the area-under-the-curve of receiver operating characteristics were: MR-proADM 0.83 (95% CI 0.71-0.94), PCT 0.71 (95% CI 0.56-0.85); whereas CRP, ESR and leucocyte count lacked diagnostic value in this respect. This study shows that MR-proADM assessed on first contact predicts a complicated course of disease and 30-day mortality in patients with fUTI and in this respect has a higher discriminating accuracy than the currently available biomarkers ESR, CRP, PCT and leucocyte count., (© 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.)

We report the first case of rickettsialpox caused by Rickettsia akari in the Netherlands. The diagnosis was suspected based on clinical grounds and was confirmed by Western blot analysis with cross-adsorption. Because the arthropod vector (Liponyssoides sanguineus) is ubiquitous, we suspect that the disease is under-diagnosed in non-endemic areas., (Copyright © 2011 International Society for Infectious Diseases. All rights reserved.)

Objectives: To assess risk factors for fluoroquinolone resistance in community-onset febrile Escherichia coli urinary tract infection (UTI)., Methods: A nested case-control study within a cohort of consecutive adults with febrile UTI presenting at primary healthcare centres or emergency departments during January 2004 through December 2009. Resistance was defined using EUCAST criteria (ciprofloxacin MIC >1.0 mg/L). Cases were subjects with fluoroquinolone-resistant E. coli, and controls those with fluoroquinolone-susceptible isolates. Multivariable logistic regression analysis was used to identify potential risk factors for fluoroquinolone resistance., Results: Of 787 consecutive patients, 420 had E. coli-positive urine cultures. Of these, 51 (12%) were fluoroquinolone resistant. Independent risk factors for fluoroquinolone resistance were urinary catheter [odds ratio (OR) 3.1; 95% confidence interval (CI) 0.9-11.6], recent hospitalization (OR 2.0; 95% CI 1.0-4.3) and fluoroquinolone use in the past 6 months (OR 17.5; 95% CI 6.0-50.7). Environmental factors (e.g. contact with animals or hospitalized household members) were not associated with fluoroquinolone resistance. Of fluoroquinolone-resistant strains, 33% were resistant to amoxicillin/clavulanate and 65% to trimethoprim/sulfamethoxazole; 14% were extended-spectrum β-lactamase (ESBL) positive compared with <1% of fluoroquinolone-susceptible isolates., Conclusions: Recent hospitalization, urinary catheter and fluoroquinolone use in the past 6 months were independent risk factors for fluoroquinolone resistance in community-onset febrile E. coli UTI. Contact with animals or hospitalized household members was not associated with fluoroquinolone resistance. Fluoroquinolone resistance may be a marker of broader resistance, including ESBL positivity.

Background: Radiologic evaluation of adults with febrile urinary tract infection (UTI) is frequently performed to exclude urological disorders. This study aims to develop a clinical rule predicting need for radiologic imaging., Methods: We conducted a prospective, observational study including consecutive adults with febrile UTI at 8 emergency departments (EDs) in the Netherlands. Outcomes of ultrasounds and computed tomographs of the urinary tract were classified as "urgent urological disorder" (pyonephrosis or abscess), "nonurgent urologic disorder," "normal," and "incidental nonurological findings." Urgent and nonurgent urologic disorders were classified as "clinically relevant radiologic findings." The data of 5 EDs were used as the derivation cohort, and 3 EDs served as the validation cohort., Results: Three hundred forty-six patients were included in the derivation cohort. Radiologic imaging was performed for 245 patients (71%). A prediction rule was derived, being the presence of a history of urolithiasis, a urine pH ≥7.0, and/or renal insufficiency (estimated glomerular filtration rate, ≤40 mL/min/1.73 m(3)). This rule predicts clinically relevant radiologic findings with a negative predictive value (NPV) of 93% and positive predictive value (PPV) of 24% and urgent urological disorders with an NPV of 99% and a PPV of 10%. In the validation cohort (n = 131), the NPV and PPV for clinically relevant radiologic findings were 89% and 20%, respectively; for urgent urological disorders, the values were 100% and 11%, respectively. Potential reduction of radiologic imaging by implementing the prediction rule was 40%., Conclusions: Radiologic imaging can selectively be applied in adults with febrile UTI without loss of clinically relevant information by using a simple clinical prediction rule.

Objective: Home-based treatment of acute pyelonephritis (AP) is generally reserved for young non-pregnant women who lack co-morbidity. This study, focusing on the elderly and patients with co-morbidity, evaluates the Dutch primary care guideline that recommends referral to hospital only in case of suspected deterioration to severe sepsis or failure of antibiotic treatment, irrespective of patient's age, sex or co-morbidity., Methods: A prospective observational cohort study including consecutive non-pregnant adults with AP. Clinical and microbiological outcome measures of non-referred patients from 35 primary health care centres (PHC) were compared to patients referred to two affiliating emergency departments (EDs)., Results: Of 395 evaluable patients, 153 were treated by PHCs and 242 referred to EDs. The median age was 63years [IQR 43-77], 34% were male, 58% had co-morbidity; all comparable between the PHC and ED group. Referred ED patients were more likely to have signs of sepsis and to have been pre-treated with antibiotics. Bacteraemia was present in 10% of patients in the PHC group and 27% in the ED group (RR 2.83; 95% CI: 1.64-4.86, p<0.001). Eight (5%) PHC patients were admitted during outpatient treatment but otherwise no major complications occurred. Clinical failure rates at 30days were similar between PHC patients and ED patients; 9% and 10% respectively. Mortality rates of PHC patients versus ED patients were 1% versus 5% at 30days (p=0.058) and 1% versus 7% at 90days (p=0.007). Complicated outcome occurred in 6% of the PHC patients versus 12% in the patients referred to ED (p=0.067)., Conclusion: In a health care system with a well-organized primary care system and clear guideline, the outcome of adults with acute pyelonephritis, including men, the elderly and patients with co-morbidity, selected for oral antibiotic treatment at home did not lead to major complications., (Copyright 2009 The British Infection Society. Published by Elsevier Ltd. All rights reserved.)

Introduction: Guidelines recommend that two blood cultures be performed in patients with febrile urinary tract infection (UTI), to detect bacteremia and help diagnose urosepsis. The usefulness and cost-effectiveness of this practice have been criticized. This study aimed to evaluate clinical characteristics and the biomarker procalcitonin (PCT) as an aid in predicting bacteremia., Methods: A prospective observational multicenter cohort study included consecutive adults with febrile UTI in 35 primary care units and 8 emergency departments of 7 regional hospitals. Clinical and microbiological data were collected and PCT and time to positivity (TTP) of blood culture were measured., Results: Of 581 evaluable patients, 136 (23%) had bacteremia. The median age was 66 years (interquartile range 46 to 78 years) and 219 (38%) were male. We evaluated three different models: a clinical model including seven bed-side characteristics, the clinical model plus PCT, and a PCT only model. The diagnostic abilities of these models as reflected by area under the curve of the receiver operating characteristic were 0.71 (95% confidence interval (CI): 0.66 to 0.76), 0.79 (95% CI: 0.75 to 0.83) and 0.73 (95% CI: 0.68 to 0.77) respectively. Calculating corresponding sensitivity and specificity for the presence of bacteremia after each step of adding a significant predictor in the model yielded that the PCT > 0.25 μg/l only model had the best diagnostic performance (sensitivity 0.95; 95% CI: 0.89 to 0.98, specificity 0.50; 95% CI: 0.46 to 0.55). Using PCT as a single decision tool, this would result in 40% fewer blood cultures being taken, while still identifying 94 to 99% of patients with bacteremia.The TTP of E. coli positive blood cultures was linearly correlated with the PCT log value; the higher the PCT the shorter the TTP (R(2) = 0.278, P = 0.007)., Conclusions: PCT accurately predicts the presence of bacteremia and bacterial load in patients with febrile UTI. This may be a helpful biomarker to limit use of blood culture resources.

Background: Current guidelines on the management of urinary tract infection recommend treating febrile urinary tract infection or acute pyelonephritis with antimicrobials for at least 14 days. Few randomized trials showed the effectiveness of treatment durations of 5 to 7 days but this has only been studied in young previously healthy women., Methods/design: A randomized placebo-controlled double-blind multicenter non-inferiority trial in which 400 patients with community acquired febrile urinary tract infection will be randomly allocated to a short treatment arm (7 days of ciprofloxacin or 7 days of empirical beta-lactams +/- gentamicin intravenously with early switch to oral ciprofloxacin followed by 7 days of blinded placebo) or standard treatment arm (7 days of ciprofloxacin or 7 days of empirical beta-lactams +/- gentamicin intravenously with early switch to oral ciprofloxacin followed by 7 days of blinded ciprofloxacin). The study is performed in the Leiden region in which one university hospital, 6 general hospitals and 32 primary health care centers are clustered. Patients eligible for randomization are competent patients aged 18 years or above with a presumptive diagnosis of acute pyelonephritis as defined by the combination of fever, one or more symptoms of urinary tract infection and a positive urine nitrate test and/or the presence of leucocyturia. Exclusion criteria are known allergy to fluoroquinolones, female patients who are pregnant or lactating, polycystic kidney disease, permanent renal replacement therapy, kidney transplantation, isolation of ciprofloxacin-resistant causal uropathogen, renal abscess, underlying chronic bacterial prostatitis, metastatic infectious foci and inability to obtain follow-up. The primary endpoint is the clinical cure rate through the 10- to 18-day post-treatment visit. Secondary endpoints are the microbiological cure rate 10- to 18-day post-treatment, the 30- and 90-day overall mortality rate, the clinical cure rate 70- to 84-day post-treatment, relapse rate of UTI and adverse events or complications during 90 days of follow-up., Discussion: This study aims to demonstrate that 7 days of antimicrobial treatment is non-inferior as compared with 14 days of treatment in patients with febrile urinary tract infection. In addition, it will generate insights into the side-effects of antimicrobial treatment in relation to its duration. The study population will also include men, the elderly and patients with significant co-morbidity. Reflecting daily practice of primary health care and emergency departments, the results of this study can be generalized to other locations.

A 75-year-old woman with a history of asthma, rhinitis and nasal polyps was admitted due to petechial lesions on the lower left leg and weakness of the right foot. Six weeks prior to admission, she had started treatment with montelukast 10 mg daily. Based on the asthma, eosinophilia, mononeuritis of the right leg and a skin biopsy showing small vessel vasculitis with eosinophilic granulocytes, the patient was diagnosed with Churg-Strauss syndrome (CSS). After consulting with the pulmonologist, montelukast therapy was discontinued and replaced with a combined preparation of a parasympatholytic and a P2-sympathomimetic. The patient was also given prednisone 60 mg daily, which resulted in prompt clinical improvement and resolution of the eosinophilia. Development of CSS has been associated with the use of montelukast and should be considered in patients with asthma who develop new symptoms, such as neuritis, vasculitis of the skin or pulmonary infiltrates with an increase in eosinophilia during montelukast therapy. In these patients, treatment with montelukast should be discontinued, although whether a causal relationship exists between montelukast and CSS continues to be debated in the literature.

Reported here is the case of a 72-year-old renal transplant recipient with stenosis of the neo-ureter requiring stents, who was admitted to hospital with pyonephrosis caused by fungus balls. Fluconazole-resistant Candida sake was grown. Treatment with external drainage of the renal pelvis and intravenous and local administration of caspofungin resulted in relief of the obstruction. Eradication of the infection was achieved by surgical removal of the ureter with all stents and construction of a cysto-pyelostomy.

Objective: To asses the cost-effectiveness of voriconazole in comparison to conventional amphotericin B and itraconazole for the treatment of invasive aspergillosis in the Netherlands., Methods: The cost-effectiveness of voriconazole in comparison to conventional amphotericin B or itraconazole was evaluated with a decision tree model followed by a life-time Markov model, focusing on long-term survival of patients treated for invasive aspergillosis. Efficacy after 12 weeks of treatment from clinical trials was used to estimate long-term effectiveness by extrapolating these short-term results over time. Information on medical resource consumption, treatment pathways and switch proportions were obtained from both the literature and Experts. Probabilistic analysis was used to compare the cost-effectiveness among the regimens., Results: With voriconazole, the mean cost for treating invasive aspergillosis per patient was E32 651 (2.5th percentile and 97.5th of uncertainty distribution: E30 037; E36 859), compared to E33 616 (E30 920; E39 633) for conventional amphotericin B and E29 115 (E23 537; E61 414) for itraconazole. The mean survival of patients treated with voriconazole was 174.0 life weeks (160.1; 188.8), compared to 116.1 life weeks (104.8; 128.0) for conventional amphotericin B and 150.4 life weeks (109.1; 194.4) for itraconazole. The beneficial effects of voriconazole on both cost and effectiveness compared with conventional amphotericin B resulted in a probability of 69.8% that voriconazole was a dominant treatment (i.e. less costs and longer survival). The incremental cost-effectiveness ratio of voriconazole versus itraconazole was E150 per life week (i.e. 7800 euros per life-year gained). Depending on the willingness to pay (WTP) the probability of being cost-effective vs. itraconazole increased to a maximum probability of 70%., Conclusion: In the treatment of invasive aspergillosis, voriconazole is dominant over amphotericin B and cost-effective in comparison to itraconazole.

Objectives: Secretory leukocyte protease inhibitor (SLPI) forms an integral part of the lung's defence, by its antimicrobial activity and by its ability to neutralize serine proteases that are released by granulocytes into the inflammatory exudate. Here, we investigate in febrile patients admitted to hospital whether plasma SLPI can serve as a marker of lung infection., Methods: We prospectively determined the SLPI concentration in 152 febrile patients (median 73 [inter-quantile range (IQR): 58-82] year; 50% male) admitted to hospital because of infection of the airways (n = 44) or pneumonia (n = 108; i.e. consolidation on chest X-ray), and in 48 febrile patients (78 [IQR: 71-85] year; 52% male) admitted because of pyelonephritis, as well as afebrile age-matched controls (n = 38). In addition, erythrocyte sedimentation rate (ESR), peripheral blood leukocytes, plasma TNFalpha and IL-10, and parameters of the APACHE-II score were determined on admission., Results: In febrile patients, SLPI was significantly increased (P < 0.001) compared with afebrile controls (63 [IQR: 50-76] ng/mL): plasma SLPI (113 [IQR: 83-176] ng/mL) was highest (P < 0.005) in patients with pneumonia compared with other groups (88 [IQR: 70-118] ng/mL). Only in patients with pneumonia, bacteremia significantly increased (P < 0.01) SLPI concentrations. Using a radiological classification of pulmonary infiltrates based on their size, it was found that plasma SLPI was proportional to the extent of lung tissue involved: the median concentration increased from 95 [IQR: 74-139] ng/mL in unilateral segmental consolidation up to 271 [IQR: 180-460] ng/mL in bilateral lobar consolidations. In a multivariate analysis, the association between SLPI and extent of consolidation was about two-fold stronger than, and independent of, the association between SLPI and erythrocyte sedimentation rate, TNFalpha, and parameters of the composite APACHE-II score, such as heart rate and blood pressure, that reflect severity of illness., Conclusion: SLPI is an indicator of the presence and extent of pneumonia in febrile patients admitted to hospital. In patients with an infection with its primary source located outside the lung, plasma SLPI likely reflects the mucosal response to circulating inflammatory mediators reflecting severity of illness.

We describe a HBsAg-positive patient with non-Hodgkin's lymphoma who underwent aggressive chemotherapy. After discontinuation of chemotherapy, he developed jaundice due to a reactivation of the hepatitis B. Serum HBeAg and HBV DNA turned positive, indicating active virus replication. Abdominal CT-scan showed a large solitary tumour mass in the liver and the serum alpha-fetoprotein level was extremely high, suggesting HBV-related hepatoma. After discontinuation of chemotherapy, the patient died of non-Hodgkin's lymphoma and hepatocellular carcinoma. Throughout treatment of HBsAg-positive patients with cytotoxic or immunosuppressive therapy, careful monitoring of serum aminotransferase levels and HBV DNA is essential. Aggressive chemotherapy may have to be discontinued or changed to a milder regimen if hepatitis occurs.

Pneumocystis carinii pneumonia (PCP) is an infection of immunocompromised patients. The purpose of our study was to estimate the risk of PCP in renal transplant recipients in relation to number, timing, and type of rejection treatments and to cytomegalovirus (CMV) infection. In a case-control study, 15 renal transplant recipients with proven PCP were compared with 95 controls. The relative risks of PCP for 1, 2, and > or = 3 rejection treatments vs. no such treatment were 1.7 (95% CI, 0.2-12.5), 4.8 (95% CI, 0.9-25.5), and 9.5 (95% CI, 1.6-56.4). The relative risk of PCP for renal transplant recipients with negative pretransplantation CMV serology was 3.2 (95% CI, 1.0-10.2), and for the combination of recipient-negative and donor-positive pretransplantation CMV serology it was 5.7 (95% CI, 1.4-22.3). The relative risk of PCP for patients with CMV infection was 5.0 (95% CI, 1.6-15.8). The risk of PCP in renal transplant recipients was positively related to the number but not the timing or type of rejection treatments. The risk of PCP was also increased in cases of CMV infection, irrespective of the number of rejection treatments.

Azithromycin, a recently introduced antibiotic, offers the potential advantages of short-course administration and lower toxicity compared to other macrolides. Approved for the treatment of mild pneumonia, this drug was investigated in a study of patients hospitalized for community-acquired pneumonia. In an open-labelled randomized study, oral azithromycin was compared with intravenous benzylpenicillin in patients suspected to have pneumococcal pneumonia. Azithromycin was also compared with erythromycin, both administered orally, in all other patients. Three hundred thirty-four patients with community-acquired pneumonia were hospitalized, 108 of whom were randomized; 104 could be evaluated. A need for intravenous therapy was the most common reason for exclusion. In the pneumococcal group, 35 patients received azithromycin and 29 benzylpenicillin. The clinical and radiological success rate achieved with azithromycin (83%) was considerably higher than that achieved with benzylpenicillin (66%), though the difference was not significant. In the non-pneumococcal group, 19 patients received azithromycin and 21 erythromycin; no differences in the success rate were found (79% and 76%, respectively). Eight patients on azithromycin had a blood culture positive for Streptococcus pneumoniae; in three of these patients therapy was changed. None of the five patients with pneumococcal bacteraemia who received benzylpenicillin required a change in therapy. It is concluded that oral azithromycin, administered as short-course therapy, is an appropriate antibiotic for treating patients with community-acquired pneumonia. However, it is not yet certain that azithromycin is a good choice for patients with pneumococcal bacteraemia.

In the present study, the role of virulence factors in and the effect of opsonization on the interactions between Bordetella pertussis and human monocytes were investigated. The methods used facilitated the distinction between attachment and ingestion of bacteria by monocytes. Nonopsonized virulent B. pertussis cells attached to monocytes. Nonopsonized B. pertussis mutant strains deficient in filamentous hemagglutinin, fimbriae, or pertactin exhibited a reduced adherence to monocytes compared with that of their respective parental strains. Nonopsonized avirulent B. pertussis cells did not attach to monocytes. These results led to the conclusion that fimbriae and pertactin are involved in the adherence of nonopsonized virulent B. pertussis cells to monocytes and confirm the role of filamentous hemagglutinin in this process. In the absence of opsonins, about 40% of the monocyte-associated virulent B. pertussis cells were ingested. When B. pertussis cells were preopsonized with inactivated normal serum, about 50% of the monocyte-associated virulent B. pertussis cells were phagocytosed and about 80% of the monocyte-associated avirulent B. pertussis cells were ingested. These results indicate that virulence factors inhibit opsonin-mediated ingestion of B. pertussis by monocytes.

Toxic shock syndrome (TSS) is a well-defined clinical syndrome attributed to certain exotoxins produced by Staphylococcus aureus. The acute episode is often characterized by a toxic encephalopathy, possibly caused by direct neurotoxicity of these exotoxins, although this mechanism has never been proven. We describe a patient who developed TSS, meningitis and cauda equina syndrome simultaneously several days after lumbar laminectomy. A space-occupying lesion was excluded. Enterotoxin C-producing S. aureus was cultured from the surgical wound and the cerebrospinal fluid (CSF). The patient recovered from TSS but remained partially paralyzed. Presumably the cauda equina syndrome was caused by neurotoxic effects of the intrathecally produced S. aureus exotoxins. This case provides evidence for the neurotoxic effects of TSS-associated S. aureus exotoxins.

Rhinocerebral mucormycosis was diagnosed in a 75-year-old woman with a history of type II diabetes mellitus. This rare opportunistic infection is caused by fungi belonging to the order of Mucorales. The patient had a severe osteomyelitis of the base of the skull, resulting in complaints of headache and diplopia. She was treated with intravenous colloidal amphotericin B, surgical excision, and later with liposomal amphotericin B. She died of respiratory failure. Mucormycosis is usually a rapidly fulminant infection. This patient showed a remarkably chronic course.

The tumour-like lesions of the rare disease malakoplakia, which consist of macrophages containing undigested coliform bacteria, are often misdiagnosed as a carcinoma. Although an infectious aetiology is likely, no antimicrobial therapy has been successful in the long-term. Since ciprofloxacin penetrates well into macrophages, this drug was given to two patients with advanced malakoplakia (500 mg twice daily). After long-term treatment all granulomatous lesions disappeared. Thus, malakoplakia can be cured by antibiotic treatment.

Neutropenia induced by intensive chemotherapy and allogeneic bone marrow transplantation are increasingly commonly complicated by fungal infections; thus prophylaxis may be justified. The authors surveyed the literature and culled their experience - few randomized trials have been done and definitions have often been poor. In prophylaxis of mucosal candidosis, miconazole and clotrimazole may both be more effective than placebo. Nystatin is ineffective and ketoconazole of medicine efficacy. Fluconazole is effective at 50 mg/day and 400 mg/day. Itraconazole and amphotericin B both need further evaluation. In prevention of systemic candidosis, oral nystatin prophylaxis, up to 4 X 10(6) U/day, is usually unsuccessful, though compliance is variable. Oral amphotericin B in low doses is ineffective, but 50 mg or more 4 times daily may prevent systemic candidosis, though compliance is variable. Oral ketoconazole, 400-600 mg/day, is possibly effective prophylaxis in neutropenia but not after bone marrow transplantation; liver function (often abnormal in these patients) is a problem, as is tolerability. Oral fluconazole is well tolerated, has reliable serum concentrations and is effective following bone marrow transplantation, but the optimum dose is uncertain. In bone marrow transplantation, intravenous amphotericin B, 0.1 mg/kg/day, appears to be effective; there are no data in neutropenia. Oral itraconazole (capsules, 200 mg/day) may be active; data are scanty. In prevention of invasive aspergillosis, itraconazole, 200 mg/day, is probably active, but only if adequate serum concentrations are achieved. New oral and intravenous itraconazole formulations in cyclodextrin may achieve more reliable serum concentrations. No oral drug provides effective prophylaxis against Torulopsis, Fusarium, Trichosporon, or Pseudallescheria.

Treatment of fungal infections in neutropenic patients continues to be a major problem for the clinician. Treatment of such infections with amphotericin B is difficult, because of its many side-effects. In a neutropenic mouse model, itraconazole appeared to be as effective as amphotericin B against Candida albicans, and was more effective than amphotericin B in treating an Aspergillus infection in a patient with chronic granulomatous disease. In a randomized, comparative trial of itraconazole and amphotericin B as treatment for Candida and Aspergillus infections, 32 neutropenic patients were evaluated. Patients received either oral itraconazole, 200 mg twice daily, intravenous amphotericin B, 0.6 mg/kg/day, or in some cases of Candida infection intravenous amphotericin B, 0.3 mg/kg/day, plus flucytosine, 150 mg/kg/day. The causative organism of fungal infection was Candida spp. in 16 patients and Aspergillus spp. in 13 patients; 27 patients had pneumonia. The median duration of treatment was 13 days with amphotericin B and 20 days with itraconazole. Nine of 16 patients responded to amphotericin B, and 10 of 16 patients responded to itraconazole. Of the patients with Aspergillus infection, 6/8 treated with itraconazole and 2/5 treated with amphotericin B responded. Three patients with Aspergillus infection died in the amphotericin B arm and none in the itraconazole arm; 2 patients treated with itraconazole died from candidal infections. Absorption of itraconazole was unreliable in these seriously ill patients with disturbed gastrointestinal function. These results suggest that itraconazole could be an effective drug against systemic fungal infections in neutropenic patients. One retrospective study also suggest that itraconazole is superior to ketoconazole in prophylaxis for Aspergillus infections. Further studies are needed.

Recombinant human interleukin-1 (IL-1) can prolong the survival of mice with severe systemic bacterial or fungal infections. In order to assess whether this is due to an effect of IL-1 on the production of leukocytes or their migration to the site of infection, the influence of IL-1 on the influx of leukocytes to the site of an acute inflammation was studied in normal and in granulocytopenic mice. The numbers of granulocytes, lymphocytes, and monocytes or macrophages in both the circulation and the peritoneal cavity were determined during an acute sterile inflammation elicited by intraperitoneal injection of either newborn calf serum (NBCS) or heat-killed Candida albicans, and during a peritoneal infection with viable C. albicans. After normal mice were injected intraperitoneally with NBCS or 10(7) CFU heat-killed or viable C. albicans, the number of peritoneal granulocytes rose sharply within 6 h. Pretreatment of mice with a single intraperitoneal dose of 80 ng IL-1 24 h before injection of an inflammatory stimulus did not influence the course of the numbers of leukocytes in the circulation or in the peritoneal cavity. When mice were rendered granulocytopenic by cyclophosphamide, both the influx of granulocytes into the peritoneal cavity and the concomitant rise in the number of peripheral blood granulocytes after injection of NBCS, killed or viable C. albicans was virtually absent. Pretreatment of granulocytopenic mice with IL-1 did not influence the course of the numbers of leukocytes in either the circulation or the peritoneal cavity. These findings show that the beneficial effect of a single dose of IL-1 on the course of candidal infections in normal or granulocytopenic mice is not attributable to the influx of granulocytes or monocytes.

Systemic mycosis constitute a serious threat for the patient with granulocytopenia. The most important causative agents are Candida spp., Aspergillus spp. and, to a lesser extent, Cryptococcus neoformans, Mucoraceae and Pseudoallescheria boydii. Treatment of such infections with amphotericin B is difficult, because of the many side-effects of this medicine, such as hypotension, fever, shivering, thrombophlebitis, nephrotoxicity, renal tubular acidosis, hypokalaemia, anaemia and thrombocytopenia. In addition, the efficacy of amphotericin B in the treatment of proven mycotic infections in granulocytopenic patients is not very great. Itraconazole is a new, oral antifungal agent which is active in vitro and in animal experiments against both Candida and Aspergillus. In patients without granulocytopenia, itraconazole appeared to be effective in the treatment of deep Candida and Aspergillus infections. On the basis of the above data, a randomized comparative investigation was carried out unto the efficacy of amphotericin B and itraconazole in the treatment of systemic mycoses in neutropenic patients.

In a randomised clinical trial, we compared the efficacy of the new triazole drug itraconazole (200 mg orally twice daily) with that of amphotericin B (0.6 mg/kg daily or 0.3 mg/kg in combination with flucytosine) in neutropenic (less than 500 x 10(6)/l neutrophils) patients with proven or highly suspected systemic fungal infections. Patients with unexplained fever alone were not included in the study. Of the 40 patients enrolled, 32 patients (16 males, 16 females) were evaluable. Sixteen patients (median age 49 years) were treated with itraconazole for a median period of 20 days and 16 patients (median age 32 years) received amphotericin B for a median period of 13 days. The overall clinical response was 10/16 (63%) for patients treated with itraconazole and 9/16 (56%) for patients treated with amphotericin B (P greater than 0.90). Itraconazole seemed to be more effective against Aspergillus infections, whereas amphotericin B seemed to be more effective against candidal infections, although the differences were not statistically significant.

A series of clinical isolates of herpes simplex virus type 2 were taken from a patient with chronic lymphocytic leukemia. Acyclovir (ACV) susceptibility assays revealed that some isolates were resistant to ACV and cross-resistant to ganciclovir but not to phosphonoacetic acid. The nature of the resistance was examined further. A number of cloned variants were generated, and thymidine kinase and DNA polymerase assays were carried out. Variants that were resistant to ACV were found to be thymidine kinase deficient. Evidence for alteration in the DNA polymerase was not found when ACV triphosphate or phosphonoacetic acid was used as the inhibitor. In vivo studies with the plaque-purified viruses showed that ACV resistance was associated with a reduced neurovirulence. In a zosteriform model, virus resistant to ACV was unable to induce secondary spread in the same dermatome, to invade the peripheral nervous system or the central nervous system, or to establish latent infections.

Fluconazole (UK-49,858) is a new bis-triazole antifungal drug that can be administered both orally and intravenously. We conducted an open clinical trial on the efficacy of fluconazole (50-100 mg) once daily in 20 non-neutropenic patients with deep-seated fungal infections. Seventeen patients (eight females, nine males, median age 56 years) could be evaluated clinically. All patients had an underlying disease, while eight also received immunosuppressive therapy. The median duration of treatment was 33 days (range 8-194 days). Clinical cure or improvement was achieved in 14 of 17 patients (82%). Nine patients were both clinically and microbiologically cured. Fluconazole was especially effective in patients with candidal infections. Two patients with cryptococcal meningitis were clinically cured; one of the two was also microbiologically cured. No serious side effects of fluconazole were encountered.

A case is presented of rupture of a mycotic thoracoabdominal aneurysm caused by Salmonella typhimurium in a patient on immunosuppressive therapy following kidney transplantation. After initial medical treatment, surgery consisted of local debridement and implantation of an aortic prosthesis. Lifelong antibiotic treatment was prescribed because of the combination of immunosuppressive therapy, the history of recurrent S. typhimurium bacteremia and the presence of an aortic prosthesis.

A case of Hodgkin's disease with eosinophilia in the cerebrospinal fluid without blood eosinophilia is presented. An additional remarkable feature was the finding of eosinophilia in Auerbach's myenteric plexus. Cerebrospinal fluid eosinophilia is usually associated with blood eosinophilia and this is often caused by helminthic infections of the CNS. The finding of cerebrospinal fluid eosinophilia without blood eosinophilia in any patient with Hodgkin's disease should point the physician to the possibility of a localization of tumour in the CNS.

In order to develop a suitable model for studying the role of granulocytes and monocytes in resistance against pathogenic microorganisms, we investigated the effect of irradiation and cytostatic treatment (cyclophosphamide and VP-16) on the number of both peripheral blood and peritoneal leukocytes in male Swiss mice. Irradiation and cyclophosphamide treatment severely decreased the number of both granulocytes and monocytes in peripheral blood, whereas VP-16 only lowered the number of blood monocytes to a significant degree and had little effect on the number of blood granulocytes or lymphocytes. When normal mice were injected intraperitoneally with newborn calf serum (NBCS) the number of peritoneal granulocytes rose about 100-fold within 6 h. In irradiated and cyclophosphamide-treated mice, this influx of granulocytes into the peritoneal cavity was virtually eliminated, as was the concomitant increase in the number of blood granulocytes; in VP-16-treated mice, on the other hand, the number of peripheral blood and peritoneal granulocytes increased to the same degree as in normal mice. An increase in the number of peripheral blood monocytes and peritoneal macrophages occurred 24-48 h after injection of NBCS in normal mice. This increase was significantly impaired by irradiation as well as by treatment with cyclophosphamide or VP-16.

Natural and synthetic immunomodulators that increase nonspecific resistance to infection are also known to induce interleukin 1 (IL 1) production. Previous studies have demonstrated a protective effect of recombinant human IL 1 beta against death from infection caused by Pseudomonas aeruginosa. In the present study we investigated the effect of IL 1 beta or IL 1 alpha on the survival of neutropenic mice with a lethal Candida albicans infection. Mice with cyclophosphamide-induced neutropenia were injected with 3 X 10(5) C. albicans i.v. When 80 ng IL 1 beta was given as a single i.p. injection 24 h before the infection, survival compared to that in control animals was as follows: 100% vs. 97% at 24 h, 83% vs. 70% at 48 h and 70% vs. 23% at 72 h after the infection (p less than 0.01). The effect of IL 1 was also apparent when it was given 1/2 h before or 6 h after the infection. The results obtained with 80 ng IL 1 alpha given at 24 h before infection were similar to that obtained with IL 1 beta. The numbers of Candida cultured from the blood, liver, spleen, and kidney were not significantly different in IL 1 beta-treated and control animals. Passive transfer of serum obtained from mice pretreated with IL 1 to recipient mice did not provide protection against a subsequent lethal candidal infection. In conclusion, the present study demonstrates that IL 1 beta and IL 1 alpha prolong survival in neutropenic mice with a lethal C. albicans infection.