Optimizing antimicrobial therapy. A method for antimicrobial drug use evaluation.
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Anti-Bacterial Agents↗
Biomedical subjects
B J Kullberg
Publications and source records attributed to B J Kullberg.
Combined effect of fluconazole and recombinant human interleukin-1 on systemic candidiasis in neutropenic mice.
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.
Animals↗
No effect of recombinant human interleukin-1 on numbers of peripheral blood and peritoneal leukocytes during acute inflammation.
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.
Acute Disease↗
Purpura fulminans and symmetrical peripheral gangrene caused by Capnocytophaga canimorsus (formerly DF-2) septicemia--a complication of dog bite.
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.
Adult↗
Evaluation of cloxacillin concentrations in plasma and muscle tissue during cardiopulmonary bypass.
Concentrations of cloxacillin in plasma and deep thoracic muscle tissue were measured in 10 patients who underwent elective coronary bypass surgery or valve replacement. One g of cloxacillin was administered after the induction of anaesthesia and 1 g cloxacillin was added to the oxygenator pump priming fluid before the start of the procedure. Blood and tissue samples were obtained before, during and after cardiopulmonary bypass. The relation between unbound plasma concentrations and total tissue contents of the drug was calculated. It was shown that measurement of the free plasma concentration may provide fairly reliable information on the free concentrations of cloxacillin in the tissues, and that determination of tissue contents may therefore not be necessary. Due to the administration of the second dose of cloxacillin at the start of cardiopulmonary bypass free tissue contents were just adequate in most patients. However, to obtain adequate tissue concentrations after bypass it is recommended that a third dose of the antibiotic be administered before the end of the operation.
Adult↗
[Tropical malaria; does prophylaxis become simpler?].
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Animals↗
Role of granulocytes in increased host resistance to Candida albicans induced by recombinant interleukin-1.
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.
Analysis of Variance↗
Legionella infection with acute renal failure and thrombocytopenia mimicking allograft rejection. A pitfall in post-transplantation diagnosis.
A patient is described who developed cavitary Legionella pneumonia 2 weeks after kidney transplantation. The initial pulmonary symptoms were followed by severe thrombocytopenia and acute renal failure. Although acute irreversible graft rejection was suspected, this was not supported by the pathology findings in the resected kidney, which were compatible with tubular damage. We presume that the extrapulmonary symptoms were caused by Legionellosis.
Acute Kidney Injury↗
Multiple endocrine neoplasia type 2b with a good prognosis.
Three patients with the multiple endocrine neoplasia syndrome type 2b (MEN 2b) and a good prognosis are described. During a follow-up period of 41 to 84 months, only little progression of metastases of medullary carcinoma of the thyroid was observed. In one of the patients, liver metastases of medullary carcinoma of the thyroid were already present in biopsy specimens taken 22 years earlier. In two patients bilateral pheochromocytomas were completely removed. These observations show that, in contrast to the general view, the clinical course of MEN 2b can be as indolent as that of MEN 2a or sporadic forms of the tumors involved, despite the presence of metastases. This may indicate that factors other than the type of inheritance contribute to the outcome of the disease.
Adult↗
Amphotericin B versus amphotericin B plus 5-flucytosine: poor results in the treatment of proven systemic mycoses in neutropenic patients.
Twenty-eight neutropenic (< 500 granulocytes/microliters) adults with microbiologically or histologically proven systemic mycosis were randomly assigned to receive either amphotericin B alone (0.5 mg/kg/day; n = 14) or amphotericin B (0.5 mg/kg/day) plus 5-flucytosine (150 mg/kg/day; n = 14) intravenously. Therapy was given for an average duration of 10 days in both groups, amounting to a total dose of amphotericin B of 338 mg and 308 mg, respectively. The mean duration of granulocytopenia was 18 days in the amphotericin B group and 20 days in the combination group. Only two patients treated with amphotericin B alone and three given the combination survived. Adverse events were similar in both groups with an elevation of the serum creatinine in six cases during the administration of amphotericin B alone and in seven cases treated with the combination. No other serious adverse events were encountered. Treatment with both regimens was disappointing partly because mycosis was too far advanced by the time therapy was begun and neutrophils were recovered in only half the patients.
Adult↗
The impact of nontuberculous mycobacteria on management of presumed pulmonary tuberculosis.
BACKGROUND: The presence of nontuberculous mycobacteria (NTM) in sputum or bronchial washings may cause diagnostic problems which affect clinical management. PATIENTS AND METHODS: In a retrospective analysis of 135 patients in a Dutch tuberculosis center, patients with NTM isolates were thoroughly investigated. Colonization or contamination by NTM was differentiated from true lung disease. RESULTS: 25 HIV-seronegative and two HIV-seropositive patients with NTM were identified. NTM were a likely cause of disease in only 14 (52%) patients. In 15 (55%), their presence led to preliminary diagnosis and treatment of tuberculosis. Unnecessary or inappropriate treatment was instituted in 17 (63%) patients with NTM. In two patients, detection of NTM in sputum also led to delay in diagnosing malignant disease. CONCLUSION: In this series, NTM in sputum or bronchial washings poorly reflected disease and often led to diagnostic and therapeutic errors. Although it is common knowledge that the presence of NTM should be considered in smear-positive patients, this apparently is a diagnostic pitfall in clinical practice. Reliable DNA-based techniques and better communication between physicians and microbiologists may improve management of suspected mycobacterial infections.
Adult↗
Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial.
BACKGROUND: Voriconazole has proven efficacy against invasive aspergillosis and oesophageal candidiasis. This multicentre, randomised, non-inferiority study compared voriconazole with a regimen of amphotericin B followed by fluconazole for the treatment of candidaemia in non-neutropenic patients. METHODS: Non-neutropenic patients with a positive blood culture for a species of candida and clinical evidence of infection were enrolled. Patients were randomly assigned, in a 2:1 ratio, either voriconazole (n=283) or amphotericin B followed by fluconazole (n=139). The primary efficacy analysis was based on clinical and mycological response 12 weeks after the end of treatment, assessed by an independent data-review committee unaware of treatment assignment. FINDINGS: Of 422 patients randomised, 370 were included in the modified intention-to-treat population. Voriconazole was non-inferior to amphotericin B/fluconazole in the primary efficacy analysis, with successful outcomes in 41% of patients in both treatment groups (95% CI for difference -10.6% to 10.6%). At the last evaluable assessment, outcome was successful in 162 (65%) patients assigned voriconazole and 87 (71%) assigned amphotericin B/fluconazole (p=0.25). Voriconazole cleared blood cultures as quickly as amphotericin B/fluconazole (median time to negative blood culture, 2.0 days). Treatment discontinuations due to all-cause adverse events were more frequent in the voriconazole group, although most discontinuations were due to non-drug-related events and there were significantly fewer serious adverse events and cases of renal toxicity than in the amphotericin B/fluconazole group. INTERPRETATION: Voriconazole was as effective as the regimen of amphotericin B followed by fluconazole in the treatment of candidaemia in non-neutropenic patients, and with fewer toxic effects. RELEVANCE TO PRACTICE: There are several options for treatment of candidaemia in non-neutropenic patients, including amphotericin B, fluconazole, voriconazole, and echinocandins. Voriconazole can be given both as initial intravenous treatment and as an oral stepdown agent.
APACHE↗
Cytokines as therapy for opportunistic fungal infections.
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Animals↗
Reduced adrenal response and increased mortality after systemic Klebsiella pneumoniae infection in interleukin-6-deficient mice.
During bacterial infections, both the immune system and the hypothalamus-pituitary-adrenal (HPA) axis are activated. The role of IL-6 in the activation of the HPA axis during bacterial sepsis is not fully understood. The aim of the present study was to investigate the role of endogenous IL-6 in a potentially lethal infection with Klebsiella pneumoniae and the concomitant activation of the HPA axis. We examined the mortality of IL-6-/- and IL-6+/+ mice after intravenous (i.v.) infection with K. pneumoniae as well as the bacterial outgrowth in several organs. Subsequently, the influence of endogenous IL-6 on the effect of i.v. administration of K. pneumoniae on the plasma levels of corticosterone and the pro-inflammatory cytokines TNF-alpha and IL-1alpha was investigated in these mice. The present study demonstrates that IL-6-/- mice are more susceptible than IL-6+/+ mice to a systemic Gram-negative infection with K. pneumoniae, leading to increased outgrowth of microorganisms in the organs of the mice. Moreover, this infection is associated with a reduced adrenal response in IL-6-/- mice. We conclude that IL-6-/- mice are more susceptible to Gram-negative bacterial infections, which is mainly due to an impaired recruitment of granulocytes to the site of infection in the absence of IL-6. Furthermore, the reduced adrenal response may be an explanation for the strong inflammatory response with higher TNF-alpha plasma levels in IL-6-/- mice.
Adrenal Glands↗