Search

Background: Diagnosing pneumonia can be challenging in general practice but is essential to distinguish from other respiratory tract infections because of treatment choice and outcome prediction. We determined predictive signs, symptoms and biomarkers for the presence of pneumonia in patients with acute respiratory tract infection in primary care., Methods: From March 2012 until May 2016 we did a prospective observational cohort study in three radiology departments in the Leiden-The Hague area, The Netherlands. From adult patients we collected clinical characteristics and biomarkers, chest X ray results and outcome. To assess the predictive value of C-reactive protein (CRP), procalcitonin and midregional pro-adrenomedullin for pneumonia, univariate and multivariate binary logistic regression were used to determine risk factors and to develop a prediction model., Results: Two hundred forty-nine patients were included of whom 30 (12%) displayed a consolidation on chest X ray. Absence of runny nose and whether or not a patient felt ill were independent predictors for pneumonia. CRP predicts pneumonia better than the other biomarkers but adding CRP to the clinical model did not improve classification (- 4%); however, CRP helped guidance of the decision which patients should be given antibiotics., Conclusions: Adding CRP measurements to a clinical model in selected patients with an acute respiratory infection does not improve prediction of pneumonia, but does help in giving guidance on which patients to treat with antibiotics. Our findings put the use of biomarkers and chest X ray in diagnosing pneumonia and for treatment decisions into some perspective for general practitioners.

Chronic diarrhoea occurs in patients of all ages and is a very common reason for patient visits to a general practitioner or medical specialist. The differential diagnosis of chronic diarrhoea is extensive and identification of the underlying cause can be challenging. In this article we answer 12 topical questions concerning the management of chronic diarrhoea in practice.

Background: In adults with febrile urinary tract infection (fUTI), data on optimal treatment duration in patients other than non-pregnant women without comorbidities are lacking., Methods: A randomized placebo-controlled, double-blind, non-inferiority trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥ 18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days (the second week being ciprofloxacin 500 mg or placebo orally twice daily). Patients indicated to receive antimicrobial treatment for at least 14 days were excluded from randomization. The primary endpoint was the clinical cure rate through the 10- to 18-day post-treatment visit with preset subgroup analysis including sex. Secondary endpoints were bacteriologic cure rate at 10-18 days post-treatment and clinical cure at 70-84 days post-treatment., Results: Of 357 patients included, 200 were eligible for randomization; 97 patients were randomly assigned to 7 days and 103 patients to 14 days of treatment. Overall, short-term clinical cure occurred in 85 (90%) patients treated for 7 days and in 94 (95%) of those treated for 14 days (difference -4.5%; 90% CI, -10.7 to 1.7; P non-inferiority  = 0.072, non-inferiority not confirmed). In women, clinical cure was 94% and 93% in those treated for 7 and 14 days, respectively (difference 0.9; 90% CI, -6.9 to 8.7, P non-inferiority  = 0.011, non-inferiority confirmed) and, in men, this was 86% versus 98% (difference -11.2; 90% CI -20.6 to -1.8, P superiority  = 0.025, inferiority confirmed). The bacteriologic cure rate was 93% versus 97% (difference -4.3%; 90% CI, -9.7 to 1.2, P non-inferiority  = 0.041) and the long-term clinical cure rate was 92% versus 91% (difference 1.6%; 90% CI, -5.3 to 8.4; P non-inferiority  = 0.005) for 7 days versus 14 days of treatment, respectively. In the subgroups of men and women, long-term clinical cure rates met the criteria for non-inferiority, indicating there was no difference in the need for antibiotic retreatment for UTI during 70-84 days follow-up post-treatment., Conclusions: Women with fUTI can be treated successfully with antibiotics for 7 days. In men, 7 days of antibiotic treatment for fUTI is inferior to 14 days during short-term follow-up but it is non-inferior when looking at longer follow-up., Trial Registration: The study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].

The incidence of invasive zygomycosis, a severe and often life-threatening infection, is increasing. The most common manifestations are pulmonary infection (following anti-cancer chemotherapy or haematopoietic stem-cell transplant) and invasive rhinocerebral infection (in patients with diabetes mellitus or iron overload). Iron metabolism plays an important role in the pathogenesis of infection in these high-risk populations. Rapid diagnosis, reversal of the underlying predisposition and timely surgical debridement are the underlying principles of therapy for this disease.

In this article we review the available data concerning meningitis caused by Capnocytophaga canimorsus. The clinical presentation of this rare condition is described with the emphasis on associated conditions and management issues. Two additional cases, illustrating the difficulties in recognizing this rare disease, are presented. Reviewing a total of 28 reported cases, a preceding bite-incident by a cat or dog, or close contact with these animals, was described in the majority of cases (89%). Patients had a median age of 58 years; splenectomy and alcohol abuse were noted in, respectively, 18% and 25% of patients. Only in one case immune suppressive drug use was reported. The diagnosis C. canimorsus meningitis should be considered in healthy and immunocompromised adults, especially after splenectomy, who present with symptoms attributable to meningitis and a history of recent exposure to dogs or cats. The possibility of this condition has implications for both the diagnostic work-up and the treatment of the patient.

Development of communication skills is an important aspect of the training of young physicians. In our hospital, we have developed a programme consisting of monthly 1-hour meetings in which the residents in internal medicine discuss incidents and communication problems with patients or their relatives. During these meetings, residents give feedback to each other under the supervision of the consultation-liaison psychiatrist. Important issues that have been discussed include refusal of treatment by patients, how to handle aggression, how to respond to complaints, relating bad news to patients, euthanasia, and dealing with personal problems or work-related stress. The meeting is well attended and appreciated by the residents. We believe that this approach of improving communication skills based on actual problems encountered in daily practice makes a valuable contribution to the training of young doctors.

The azole antifungal voriconazole and the echinocandin caspofungin have recently become available for the treatment of invasive mycoses. Fluconazole remains the drug of choice for candidemia, except for infections with one of the resistent species such as Candida krusei and some strains of Candida glabrata. In these cases, as well as in patients who cannot tolerate azoles in connection with side effects or drug interactions, caspofungin is an attractive alternative. Voriconazole has become the drug of choice for severe invasive aspergillosis. Itraconazole is a good alternative for milder and chronic forms of aspergillosis. The use of conventional amphotericin B will be limited by the availability of the new drugs. In view of their high costs, the lipid-bound forms of amphotericin B will usually be given only as salvage therapy in case of failure, in patients who are unable to tolerate either conventional amphotericin or one of the newer agents, and for the treatment of zygomycosis.

Patients with systemic mastocytosis (SM) can suffer from disabling symptoms related to mast cell mediator release or mast cell infiltration, requiring mast cell eradication. In the present absence of any curative therapy, a recent case report describing the efficacy of cladribine showed promising results. In a pilot study, the efficacy of cladribine (0.10-0.13 mg/kg in a 2-hour infusion, days 1-5; repeated at 4-8 weeks until 6 cycles) was studied. Ten patients with SM with severe symptoms were treated. Four patients were classified as having indolent or smoldering mastocytosis, 3 as having aggressive systemic mastocytosis, and 3 as having SM with an accompanying hematologic malignancy. Nine patients received 6 courses, 1 patient stopped because of toxicodermia. All responded concerning signs, symptoms, and mast cell parameters (serum tryptase and urinary histamine metabolite excretion), although none achieved a complete remission. Prolonged follow-up is required, as response is ongoing in most cases. One patient relapsed within 11 months and showed a second response. Side effects were mainly related to bone marrow suppression. Single-agent cladribine is an effective and relatively safe treatment for severe systemic mastocytosis. The optimal dose and schedule need to be explored.

Two male patients aged 55 and 77 years, respectively, presented to the casualty department with fever, chills and right abdominal upper quadrant tenderness. They also had hyperbilirubinaemia. Based on CT scan findings and blood cultures yielding Bacteroides fragilis, a diagnosis of pylephlebitis (septic thrombophlebitis of the mesenteric veins and/or the portal vein) was made. This is a condition with a mortality rate of 10-70%. Primary sources such as diverticulitis are often seen in patients with pylephlebitis, in which bacteria are drained by the mesenteric veins and cause a thrombus in the portal system. In the two patients no primary focus was detected. They were treated with intravenous antibiotic therapy followed by oral antibiotics, and were discharged in good health. Pylephlebitis can be complicated by liver abscesses. Treatment consists of broad-spectrum antibiotics which are adjusted based on the blood cultures results. The duration of treatment is between two and six weeks, depending on the presence of liver abscesses. In patients with abscesses that cannot be drained, longer treatment may be indicated.

The increasing frequency of fungal infections in immunocompromised patients together with the emergence of strains resistant to currently used antifungal drugs point to an increased need for a new class of antimycotics. Antimicrobial peptides are promising candidates for the treatment of fungal infections since they have both mechanisms of action distinct from available antifungal agents and the ability to regulate the host immune defence systems as well. This review focuses on Candida albicans as a large amount of work on the mechanisms of action of classical antifungals as well as antimicrobial peptides, such as defensins, protegrins, histatins and lactoferrin (LF)-derived peptides, has been performed in this yeast. Analogues of these antimicrobial peptides and combinations of antimicrobial peptides with classical antimycotics are under investigation for treatment of candidiasis.

Objective: To ascertain the correlation between chills, bacteraemia, infection type and clinical progress in patients presenting with fever to the casualty department., Design: Prospective, descriptive., Method: Anamnestic, clinical and microbiological data were registered from patients with fever (> 38.2 degrees C rectal) presenting to the Casualty Department of the Leiden University Hospital and the Bronovo Hospital, in the period 1 February 1994-31 July 1995 respectively 1 February 1996-31 July 1997., Results: A total of 764 patients (424 men and 340 women; median age: 66 years) were included in the study. A chill was reported by 270 patients (35%). Bacteria were isolated from the blood culture in the case of 141 patients (18%). The relative risk (RR) for bacteraemia in the case of a chill was 2.8 (95% CI: 2.1-3.8); the positive predictive value of a chill for bacteraemia was 31% and the negative predictive value 89%. For 683 (89%) of the 764 patients the cause of the fever was probably or certainly an infection, which was mostly pulmonary (319 patients; 42%) or urogenital (112 patients; 15%) in origin. The positive predictive value was 24% for patients with respiratory tract infections and 48% for patients with urinary tract infections. Mortality occurred in the case of 62 patients (8%) after a median admission period of 11 days. The patients who died were older than the patients discharged (p < 0.01) and there was a statistically significant correlation between mortality with bacteraemia (RR: 1.1) and serious comorbidity (RR: 6.1)., Conclusion: There was a strong correlation between the chill indicated in the anamnesis and bacteraemia, especially in patients with a urinary tract infection. Bacteraemia, advanced age and serious comorbidity were unfavourable prognostic factors.

Tuberculous aortitis with a tuberculous mycotic aneurysm and an aortoduodenal fistula was diagnosed in a 38-year-old man with tuberculous cervical lymphadentitis and a 3-month history of recurrent gastrointestinal bleeding, in whom extensive investigation of the digestive tract had not revealed a bleeding lesion. Either by septic embolism or by direct extension from a neighboring focus, tuberculous infection can cause a mycotic aortic aneurysm with subsequent fistulation to the duodenum.

Two previously healthy adults, a man aged 69 and a woman aged 51 years, presented with spondylitis caused by Streptococcus agalactiae. One patient had fever and acute pain in the neck, the other progressive pain in the lower back. From cultures of blood and bone respectively. S. agalactiae was isolated. Both patients recovered after treatment with benzylpenicillin. S. agalactiae (group B streptococcus) is a wellknown cause of invasive infections in neonates and pregnant adults. Infections in nonpregnant adults are increasingly reported. Chronic conditions such as diabetes mellitus are strongly associated with disease caused by S. agalactiae.

Three patients with a cellular immunodeficiency were treated with rifabutin, clarithromycin and ethambutol for a disseminated infection with Mycobacterium avium-intracellulare complex (MAC). The patients developed uveitis, sometimes in combination with a transient rash, arthralgia, arthritis, jaundice and pseudojaundice. It seems likely that these reactions were caused by rifabutin, alone or together with other drugs such as clarithromycin. These adverse reactions probably depend on the dose, metabolism and excretion of the drug. Inhibition of cytochrome P450 seems to be an important mechanism.

Fluconazole is an effective alternative to amphotericin B for the treatment of serious infections caused by Candida albicans. Through a literature survey of candidal infections caused by non-albicans Candida spp., 43 cases treated with fluconazole were found. The most common causative organisms were Candida parapsilosis (14 patients), Candida glabrata (12 patients), and Candida tropicalis (11 patients). The dose of fluconazole varied from 50 to 400 mg daily. The median duration of treatment was 21 days. Overall efficacy was 77%. The efficacy against the various species was 93% for Candida parapsilosis, 50% for Candida glabrata, and 82% for Candida tropicalis. In conclusion, fluconazole is effective against the most common non-albicans Candida spp., although higher doses may be required for infections caused by Candida glabrata. Infections caused by Candida krusei should not be treated with fluconazole.

Aspergillus peritonitis is a rare complication of continuous ambulatory peritoneal dialysis. The case is described of a 68-year-old man in whom Aspergillus fumigatus was isolated from the peritoneal dialysate after recurrent peritonitis with Gram-negative rods in association with diverticulosis. Treatment consisting of removal of the catheter and intravenous administration of amphotericin B followed by oral itraconazole was successful. A review of the sparse literature (12 cases) displays uncertainties regarding diagnostic awareness, culture diagnosis, and therapeutic management. Next to institution of appropriate antifungal therapy, early removal of the peritoneal dialysis catheter is recommended, as delayed removal of the catheter appears to be associated with increased mortality and morbidity.

In three patients, women aged 27, 26, and 36 years respectively, boutonneuse fever was suspected, although they had not recently visited an endemic area. Serological investigation confirmed the diagnosis. Treatment with doxycycline was effective. Circumstantial evidence strongly suggested that the infection with Rickettsia conorii had been transmitted through dogs that had stayed in Mediterranean countries and had carried ticks to the Netherlands.

We describe two cases of terbinafine-associated hepatic injury, in which a mixed cholestatic-hepatocellular type of hepatitis was present. In both cases extrahepatic cholestasis and viral hepatitis were excluded and involvement of other drugs was unlikely. In the first patient all abnormalities have disappeared, but in the second patient alkaline phosphatase, aminotransferase and gamma-glutamyl transferase levels have remained elevated (follow up 3 months after cessation of treatment with terbinafine). Most likely, the terbinafine-associated hepatic injury in these patients was caused by an idiosyncratic rather than a direct hepatotoxic reaction.

To determine which patients are at high risk for disseminated fungal infection and should be given systemic prophylaxis, we studied the charts of 341 patients with malignant hematologic disorders who were admitted to our institution during 10 consecutive years. These patients represented 636 admissions; during these admissions, 60 invasive fungal infections occurred, with deaths in 44 cases. All patients who died of these infections either had persisting granulocytopenia and a poor prognosis for the underlying disease or suffered from chronic graft-vs.-host disease. Two of 58 patients who had no or low-level candidal colonization developed this infection (P < .001). Nine of the 10 patients with candidal infection had microbiologically proven bacteremia within the week preceding the candidal infection. After bone marrow transplantation, 8 of 10 patients with chronic graft-vs.-host disease vs. 2 of 36 without this disease (P < .001) developed fatal infection with Aspergillus species. The results of our study reveal that patients with high-level candidal colonization who were treated for microbiologically proven bacteremia and patients with chronic graft-vs.-host disease might benefit from systemic antifungal prophylaxis.

The incidence of invasive fungal infections in the immunocompromized host has increased during the past decade. Even the recently developed antifungal drugs are unable to cure these infections in patients with severely impaired host defense mechanisms. Cytokines have great potential to augment host resistance and as adjunctive therapy of invasive mycoses. We discuss the mechanisms of host defense against invasive candidiasis, aspergillosis, and cryptococcosis, and review the use of cytokines and growth factors in this setting. Interleukin-1 has been shown effective in an animal model of disseminated candidiasis, even during severe granulocytopenia. Interferon-gamma has been very effective as a modulator of resistance against a variety of fungal infections in vitro. The effect of interferon-gamma against disseminated candidiasis has been demonstrated in a mouse model. Activation of neutrophils is the main mechanism by which interferon-gamma enhances the elimination of Candida, and consequently the agent is not effective in severely granulocytopenic animals. Data on the role of colony-stimulating factors against fungal pathogens are accumulating, and trials with these agents for hematologic patients with invasive fungal infections are now being performed.

The effect of recombinant rat interferon-gamma (rIFN-gamma) on acute disseminated Candida albicans infection in mice was investigated. Outgrowth of C. albicans in kidneys, spleen, and liver of mice treated with one intravenous (iv) dose of rIFN-gamma before iv injection of 5 x 10(5) cfu of C. albicans was significantly lower than in controls over 7 days. rIFN-gamma was protective when given 1 day before, simultaneously with, or 1-3 days after infection but not when given 3 days before. In mice pretreated with hydrocortisone acetate, rIFN-gamma significantly reduced the outgrowth only when 10(3) cfu of C. albicans was injected. Injection of rIFN-gamma did not reduce the outgrowth of C. albicans in cyclophosphamide-pretreated mice and significantly increased the capacity of peripheral blood and exudate peritoneal granulocytes to kill C. albicans in vitro. Thus, rIFN-gamma enhances host resistance against acute disseminated C. albicans infection in mice through activation of polymorphonuclear leukocytes.

Two patients, a Surinamese man aged 50 and a Surinamese woman aged 56 exhibited a mycetoma of the foot, 30 and 28 years, respectively, after a local injury. Pathological examination revealed an aspecific chronic granulomatous inflammation. As causative agents a Fusarium species and a Cladosporium normodendrum, respectively, were cultured. The treatment consisted of curettage of fistulous ducts and administration of itraconazole.

Three case histories are described of patients, two women aged 62 and 57 and a man aged 75 years, who developed symptomatic hepatic injury five to six weeks after starting itraconazole treatment. In two of them the biochemical pattern of liver injury was cholestatic. Other causes of hepatic injury were excluded. Monitoring serum liver enzymes is advisable in patients treated with itraconazole for one month or longer.

The main conclusions of this study are that BCG/PPD-activated macrophages, in contrast to macrophages from control mice, exhibit an increased PMA-induced production of H2O2, kill about one-third of the phagocytosed Candida albicans, and cause more than 50% inhibition of the intracellular formation of germ tubes by C. albicans. Peritoneal macrophages from mice that were colonized post-natally with C. albicans do not show increased production of H2O2 upon stimulation with PMA and the intracellular outgrowth of germ tubes is inhibited to only a limited degree. These macrophages are capable of killing about 20% of the ingested C. albicans. In vivo, the number of Candida in the kidney, spleen and liver after intravenous injection of Candida albicans is significantly lower in BCG-treated mice than in control mice. Post-natal colonization with C. albicans has only a limited effect on the outgrowth of intravenously injected C. albicans in the spleen and liver but does not influence growth in the kidney. These results indicate that acquired immunity against a systemic Candida infection involves both oxidative and non-oxidative mechanisms of intracellular killing and that these mechanisms may have different effects on the yeast and hyphal forms of C. albicans.

The aim of the present study was to investigate the efficacy of treatment with a combination of fluconazole and human recombinant interleukin-1 alpha (IL-1 alpha) in normal or neutropenic mice with systemic Candida albicans infection. Six hours after intravenous injection of 5 x 10(4) CFU of C. albicans organisms, oral treatment twice daily with 2.5 or 10 mg of fluconazole per kg of body weight, a single intraperitoneal injection of 80 ng of IL-1, or a combination of the two was started. IL-1 had no influence on the antifungal activity of fluconazole in vitro or on the pharmacokinetics of fluconazole. For both normal and neutropenic mice, the number of C. albicans organisms cultured from the kidneys after 36 h of treatment was significantly lower in mice treated with IL-1 alone than in untreated animals. Treatment with fluconazole alone also significantly lowered the number of C. albicans organisms in the kidneys compared with that in untreated controls. In normal mice, the combination of fluconazole and IL-1 was not better than fluconazole alone. In neutropenic mice, combined treatment with IL-1 and 10 mg of fluconazole per kg led to significantly lower numbers of C. albicans organisms in the kidneys and the spleen than treatment with either agent alone. Although the precise mechanism by which IL-1 enhances resistance to infection is not clear, the additive effect of IL-1 and fluconazole in vivo indicates that combined therapy with immunomodulators and antifungal drugs is beneficial in immunocompromised mice with systemic fungal infections.

A 57-year-old female patient presented with a tenosynovitis due to Mycobacterium avium-intracellulare (MAI). A relapse occurred following surgical treatment, after which she was successfully treated with ansamycin and ethambutol. Previously reported cases of tenosynovitis due to MAI are reviewed and the treatment modalities are discussed.

In two general hospitals and one university hospital questionnaires were handed out to 646 outpatients who because of underlying diseases should be vaccinated annually against influenza. Questions concerned whether a patient was vaccinated, and if the vaccine had not been administrated, what the reason was. Answered questionnaires were received from 595 patients (92%). In the particular year 333 patients (56%) had received the vaccine. The majority of the immunized patients had received personal advice from their physician to have the vaccine. Lack of advice, the belief that vaccination is unnecessary, and fear of side effects were the most important reasons for not having the vaccine. We conclude that personal advice from the patients' physician, sending annual reminders to patients and offering the vaccine to patients in an easily accessible way, are the essential elements for a successful vaccination strategy.

About 50 percent of the patients who because of an underlying disease should be vaccinated annually against influenza, do not receive the vaccine. One of the major reasons is that they are not informed by their physicians about the need to be vaccinated. To understand the attitude of the physicians concerning influenza vaccination and the way the vaccination of these patients is organized, questionnaires were send to 250 general practitioners, 125 cardiologists and 125 pulmonologists in the Netherlands. Eighty-four percent of the questionnaires were returned. The results show that the physicians were well informed about the indications for vaccination. A minority of the physicians had doubts about the efficacy of the vaccine. Both specialists and general practitioners agreed that vaccination should be performed by the general practitioner. Instruction of the patients and application of the vaccine were generally rather well organized. It is to be expected, however, that improvement of the organization will enhance the rate of vaccination against influenza in the Netherlands.

Ganciclovir (DHPG) was used to treat eight patients with severe cytomegalovirus (CMV) disease after renal transplantation. Four had generalized disease, one had severe recurrent gastrointestinal bleeding and three had interstitial pneumonia. All patients responded to treatment, symptoms disappearing within 7 days (range: 3-22 days). Leukocytopenia and confusion were the main side-effects, both occurring in three patients. Encouraged by the effectiveness and the mild side-effects of ganciclovir we enlarged the indication for treatment. Five patients with CMV disease and concomitant rejection were treated with ganciclovir together with antirejection therapy. Four patients received methylprednisolone, one patient anti thymocyte globulin. CMV-related symptoms disappeared in all five patients. The only side-effect observed was a mild leukocytopenia in one patient. Renal function was preserved in three of the five patients. The virological response to the drug was also evaluated. Twelve patients had positive cultures in blood and/or urine before ganciclovir was started. In three patients the cultures became negative during follow-up. In eight patients cultures remained positive after ganciclovir treatment although in seven of these CMV had initially been absent from blood and/or urine. We conclude that ganciclovir treatment is clinically effective in severe CMV disease and that treatment with ganciclovir makes antirejection therapy during CMV disease possible.

We review the syndrome of Capnocytophaga canimorsus (DF-2) septicemia after exposure to dogs or cats. We describe a previously healthy patient who developed diffuse intravascular coagulation and symmetrical peripheral gangrene as a result of C. canimorsus septicemia after a dog bite. To our knowledge, this patient was the first to receive combined plasmapheresis and leukapheresis for C. canimorsus septicemia. Symmetrical peripheral gangrene is frequently associated with C. canimorsus septicemia and may lead to an early diagnosis in patients who become severely ill after a dog bite. Other complications include arthritis, meningitis, and endocarditis. These manifestations can also be found in previously healthy patients, although a prior splenectomy or other causes of impaired host defense clearly enhance the risk. Prompt treatment with penicillin G is required.

A 46-year-old man presented with Aspergillus fumigatus spondylodiscitis after lumbar surgery. He was successfully treated with the new antifungal drug itraconazole in combination with surgical débridement of the disc space. The patient has remained on itraconazole for more than a year and tolerated the drug well.

The effect of human recombinant interleukin-1 alpha (IL-1 alpha) on a systemic candidal infection in mice under various conditions of immunosuppression was investigated. In normal mice and in mice pretreated with cyclophosphamide, hydrocortisone acetate, or sublethal total body irradiation, the outgrowth of Candida albicans in the kidney was significantly reduced by the administration of a single intraperitoneal dose of 80 ng of IL-1 (P less than 0.05). In mice treated with either cyclophosphamide or irradiation, IL-1 also significantly reduced the outgrowth of C. albicans in the spleen. The protective effect of IL-1 was present when given 24 h before injection of C. albicans but also when IL-1 was given simultaneously with or 6 h after injection of C. albicans in cyclophosphamide-treated mice. The effect of IL-1 was independent of the presence or recruitment of granulocytes, since IL-1 inhibited the outgrowth of C. albicans in the kidneys and spleens of mice that were rendered severely granulocytopenic (less than 50 granulocytes per mm3) throughout the duration of the infection by either repeated injections of cyclophosphamide or sublethal total body irradiation. These results indicate that the enhancement of host resistance by IL-1 is not due solely to increased granulocytopoiesis or chemotaxis of granulocytes but strongly suggest that other mechanisms play a role in the protective effect of IL-1 against systemic infections.

Candida albicans may resist intracellular killing by macrophages through the formation of germ tubes. Antifungal drugs that inhibit intracellular germ tube formation could therefore facilitate host defence against C. albicans. We assessed the effects of amphotericin B and the new triazole drugs fluconazole and itraconazole on the multiplication and intracellular germ tube formation of C. albicans phagocytosed by murine peritoneal macrophages, and compared the findings with the effects of these drugs on C. albicans in the absence of macrophages. The fungicidal effect of amphotericin B against C. albicans in macrophages was less prominent than that found for extracellular candida. However, amphotericin B completely blocked germ tube formation of C. albicans both in macrophages and extracellularly. Fluconazole and itraconazole had little effect on the number of candida but significantly, although incompletely, inhibited germ tube formation both inside macrophages and extracellularly. The inhibition of intracellular germ tube formation by the triazoles may facilitate host defences against C. albicans and contribute to the efficacies of these drugs in vivo.

An 18-year-old boy with X-linked chronic granulomatous disease (CGD) developed Aspergillus fumigatus pneumonia and multifocal osteomyelitis. Treatment with amphotericin B resulted in only moderate improvement of the lesions and was accompanied by considerable toxicity. In contrast, administration of the new triazole drug itraconazole led to complete disappearance of all signs of infection. We conclude that itraconazole may be a valuable new drug for treating invasive aspergillosis in patients with CGD, although the duration of treatment remains to be established.