Oral voriconazole for empiric antifungal treatment in patients with uncomplicated febrile neutropenia

STUDY OBJECTIVE: To determine the success rate and toxicity profile of oral voriconazole when used as empiric antifungal therapy in patients with uncomplicated persistent neutropenic fever. DESIGN: Retrospective medical record review. SETTING: University hospital. PATIENTS: Twenty-seven patients who received oral voriconazole as empiric antifungal treatment during 31 episodes of persistent neutropenic fever between August 1, 2003, and April 1, 2006. MEASUREMENTS AND MAIN RESULTS: Data were collected on patient demographics, diagnosis, cancer treatment plan, voriconazole regimen, dates of voriconazole treatment, other antibiotics administered during the episode of fever, and adverse events. Patient survival data from at least 3 months of follow-up were also collected. Treatment success, which was defined as survival to the resolution of fever without a need to change antibiotics and without new fungal infections, was also determined. Median duration of therapy was 11 days (range 2-54 days). No patient discontinued the drug because of toxicity. The success rate was 55% (95% confidence interval [CI] 36-73%). For all patients, 90-day survival from the start of voriconazole treatment was 81% (95% CI 63-93%). Neither treatment success nor 90-day survival rates differed significantly when they were compared by the route used for loading doses or by the presence of a possible invasive fungal infection at the start of voriconazole therapy. CONCLUSION: Oral voriconazole appears to be a safe empiric antifungal treatment with an encouraging rate of activity for patients with neutropenia and uncomplicated persistent fever. Further research, including randomized controlled trials comparing the efficacy of intravenous versus oral voriconazole, is needed.     

Safe and effective outpatient treatment of adults with chemotherapy-induced neutropenic fever.

PURPOSE: The safe and effective outpatient treatment of adults with chemotherapy- induced neutropenic fever is reviewed. SUMMARY: Chemotherapy-induced neutropenic fever is a potentially life-threatening circumstance in high-risk patients. The standard of care for neutropenic fever is inpatient treatment with i.v. broad-spectrum antibiotics. Within the past 5-10 years, there has been growing interest in oral therapy and outpatient treatment for carefully selected low-risk patients. Outpatient treatment has the potential to avoid patient exposure to multidrug-resistant organisms found in the hospital, provide a more comfortable environment for the patient and his or her family, and achieve significant cost savings. Two risk-assessment tools have been developed to identify patients with a low risk of developing complications from neutropenic fever. A limited number of clinical trials have been conducted to evaluate outpatient treatment of low-risk patients. The evidence from well-designed randomized controlled trials comparing the safety and efficacy of outpatient therapy with standard therapy is not extensive. However, some centers have reported successful outpatient therapy in low-risk patients with febrile neutropenia. The greatest amount of evidence for outpatient treatment of neutropenic fever is available for the combination regimen of ciprofloxacin plus amoxicillin-clavulanate. Clinical practice guidelines are available to guide patient evaluation, antibiotic selection, monitoring, and follow-up. CONCLUSION: The accepted standard for treatment of neutropenic fever remains inpatient therapy with i.v. broad-spectrum antibiotics. However, some centers have had success treating selected low-risk patients with neutropenic fever as outpatients.     

Current guidelines on the use of antibacterial drugs in patients with malignancies

Patients with malignant disease may be predisposed to bacterial infections because of neoplastic disruption of normal tissue barriers, exogenous immunosuppressive therapy (drugs with or without radiation), and intrinsic host immune deficits secondary to these diseases. Diminished polymorphonuclear leucocyte numbers or function and impaired humoral immunity are highly correlated with the development of serious bacterial infections. The usual signs and symptoms of infection may be absent or altered in a compromised host. Therapy must be instituted promptly upon clinical suspicion of bacterial infection, and empirical choices should usually include combinations that are synergistic for likely pathogens based on knowledge of the local predominant flora and susceptibility data. Synergism has most often been demonstrated in combinations that utilise a beta-lactam (semisynthetic penicillin or cephalosporin) and an aminoglycoside. Triple drug therapy has not been shown to be advantageous. Monotherapy with third generation cephalosporins, carbapenems, monobactams, or ureidopenicillins has not been proven to offer advantages over 2-drug regimens for these patients. Granulocytopenic patients who respond to 2-drug therapy but remain neutropenic may need continued treatment until the neutropenia subsides. Those who do not respond and remain febrile with an unclear focus may need to be started on antifungal therapy in addition to the antibacterial agent. The use of oral agents for the prophylaxis of neutropenic patients against bacteraemia remains controversial. If drugs are used, co-trimoxazole and nystatin suspension may be preferable.     

Empiric antimicrobial therapy of febrile neutropenic patients undergoing haematopoietic stem cell transplantation

This study was conducted to assess the efficacy and toxicity of intravenous (i.v.) ceftazidime and ciprofloxacin in neutropenic febrile patients undergoing high dose myeloablative therapy and hematopoietic stem cell transplantation (HSCT). All patients undergoing HSCT for leukaemia, lymphoma, multiple myeloma and solid tumours received open-label ceftazidime 2 g i.v. every 8 h and ciprofloxacin 400 mg i.v. every 12 h if they developed fever while they were neutropenic. Success with or without modification of this regimen was defined as survival through the neutropenic period; failure was defined as death secondary to infection. Of 106 patients treated with this regimen, the success rate was 99%. Sixty-one of the patients (57.5%) defervesced within 48-72 h and remained afebrile without regimen modification. In 41.5% of the cases (44/106), the regimen was modified because of persistent fever. One patient died secondary to sepsis. The combination of ceftazidime and ciprofloxacin as initial empiric antibacterial therapy in febrile neutropenic patients undergoing myeloablative therapy and HSCT is highly effective and is associated with minimal toxicity.     

Safety and efficacy of low-dose amphotericin B lipid complex for empirical antifungal therapy of neutropenic fever in patients with hematologic malignancies

Amphotericin B lipid complex (ABLC) has been investigated as an empirical antifungal treatment for neutropenic patients with persistent fever of unknown origin (FUO). We studied the safety and efficacy of low dose ABLC (1 mg/kg/day) for empirical treatment of neutropenic FUO. Sixty-one patients with hematologic malignancies developing 69 episodes of neutropenic FUO after chemotherapy or hematopoietic stem cell transplantation were included in the study. The median patient age was 47 years (18-68). The median duration of neutropenia (< 0.5 x 10(9)/l) was 17 days (7-45) and the median duration of ABLC therapy was 8 days (2-19). Thirteen patients (19%) suffered from mild to moderate infusion-related adverse events. Creatinine levels were stable in 42 cases (61%), improved in 9 (13%) and deteriorated in 18 (26%), with no other significant toxicities. Among 67 evaluable episodes, the response rate (resolution of fever during the period of neutropenia without developing a fungal infection) was 67%, while 33% were treatment failures. Low-dose ABLC is safe, well tolerated and seems to be at least as effective as c-AmB for empirical antifungal therapy of FUO. Randomized trials at this dose level comparing ABLC with c-AmB or other lipid formulations are warranted.     

Unusual presentations of infection in neutropenic patients

Neutropenic patients may have unusual presentations of infection because of their inability to mount an adequate inflammatory response and their susceptibility to infection caused by less virulent organisms. About 60% of febrile episodes are associated with no other signs and symptoms and no infecting organism can be identified, yet most respond to antibacterial therapy. If not treated promptly, infection in neutropenic patients can progress rapidly. Unusual sites of infection include typhlitis, perirectal infections and atypical forms of cellulitis.     

Clinical guidelines for the management of neutropenic patients with unexplained fever in Japan: validation by the Japan Febrile Neutropenia Study Group

The Japan Febrile Neutropenia Study Group (JFNSG) Trial was a multicenter, open, randomized study designed to validate the first Japanese guidelines for the management of neutropenic cancer patients with unexplained fever issued in 1998. The trial compared cefepime monotherapy with cefepime plus amikacin combination therapy in febrile neutropenic patients with hematological disorders. The JFNSG found that monotherapy with cefepime was, in general, as effective as combination therapy. In terms of subset analyses, defervescence appeared to occur more frequently in leukemic patients and in those with profound neutropenia treated with the dual combination. The conclusion of the trial was that the 1998 guidelines were applicable to the Japanese febrile neutropenic patient population. The JFNSG met again in 2003 to revise these guidelines. An important addition to the guidelines was a distinction between low- and high-risk patients. Low-risk febrile neutropenic patients can receive oral ciprofloxacin or levofloxacin, with or without amoxicillin/clavulanic acid, on an outpatient basis, or intravenous (i.v.) monotherapy with cefepime, ceftazidime or a carbapenem. High-risk patients can receive i.v. cefepime, ceftazidime or a carbapenem, or an i.v. dual combination with cefepime, ceftazidime or a carbapenem plus an aminoglycoside. Those patients with a documented infection with methicillin-resistant Staphylococcus aureus should also receive a glycopeptide. It remains to be determined whether existing assessment scoring systems apply to Japanese patients; whether a broad-spectrum cephalosporin plus an aminoglycoside combination is required as the initial management of patients with acute leukemia and/or profound neutropenia; which antibacterial drugs should be used when first- and second-line agents fail; what are the appropriate oral agents and dosing regimens for low-risk patients; whether serology or the polymerase chain reaction should be the preferred marker for initiating preemptive antifungal therapy; and whether the azoles or the candins should be the preferred antifungal agents.     

Grand rounds. Immune globulin in the treatment of autoimmune thrombocytopenic purpura

Two patients with autoimmune thrombocytopenic purpura (ATP) who received high-dose intravenous immune globulin before undergoing splenectomy are described, and the pathogenesis, clinical presentation, diagnosis, and treatment of chronic ATP are reviewed. One patient was a 62-year-old white man who was admitted to the hospital with a history of thrombocytopenia and probable steroid-induced diabetes mellitus. The second patient was a 24-year-old black woman who was admitted for recurrent bleeding episodes and splenectomy. In both patients, immune globulin 1.5 g/kg administered over four to six days resulted in marked elevations of platelet counts. ATP is a platelet disorder of unknown etiology. Platelets with surface-bound antiplatelet antibody are destroyed by the reticuloendothelial system. As the platelet count falls below 30,000-50,000/cu mm, the patient may manifest signs of bleeding such as petechiae, purpura, ecchymosis, menorrhagia, epistaxis, and bleeding from other mucosal surfaces. Corticosteroids are the initial treatment of choice. Splenectomy is considered for children with the life-threatening hemorrhage and for patients who do not respond to corticosteroids. Patients who are refractory to steroid therapy and splenectomy may respond to immunosuppressant agents. Approximately, 80% of patients treated with immune globulin have responded with an increase in platelet count, although this increase is sometimes transient. Immune globulin therapy is recommended for emergency treatment of ATP, as preoperative medication before splenectomy, and for young children in order to postpone splenectomy. Despite a good response to treatment, immune globulin therapy should not be considered a cure for ATP.     

Hepatosplenic candidiasis in non-neutropenic patients: a case report and literature survey

Hepatosplenic candidiasis is an increasingly recognized infectious complication in patients who have an underlying malignancy and/or have chemotherapy-induced neutropenia. Only six cases of hepatosplenic candidiasis in non-neutropenic patients have been described to date, to which we add a seventh. Our patient had many of the classically described manifestations of hepatosplenic candidiasis, and responded well to therapy with amphotericin B. Retrospective comparative analysis of cases of hepatosplenic candidiasis reveals that non-neutropenic patients seem to respond well to medical therapy that is less intensive than that given to neutropenic subjects (total dosage of amphotericin B 0.84 g vs. 2.70 g, respectively) and tend to have a better prognosis (mortality rate 33% vs. 44%, respectively).     

Olanzapine-associated neuroleptic malignant syndrome in a patient receiving concomitant rivastigmine therapy

Neuroleptic malignant syndrome (NMS) is an idiosyncratic and uncommon but serious adverse effect that has been reported with both typical and atypical antipsychotic agents. We describe a 58-year-old man with Down syndrome and dementia who was receiving low-dose olanzapine and rivastigmine therapy; he developed NMS 4 months after starting olanzapine. The patient presented with altered mental status, rigidity, fever, diaphoresis, and tremor, and his creatine kinase level was elevated. Olanzapine was discontinued, and the patient fully recovered; antipsychotic therapy was not restarted. Based on the Naranjo adverse drug reaction probability scale, olanzapine was the probable cause of the patient's NMS. In addition, use of rivastigmine in combination with olanzapine may have placed the patient at greater risk for NMS, possibly due to an acetylcholine-dopamine imbalance. Clinicians should be aware of the potential for NMS even with low doses of antipsychotics, particularly in patients who have a limited ability to communicate. Concomitant administration of cholinesterase inhibitors such as rivastigmine may represent an unrecognized risk factor for NMS development.     

Pattern analysis shows beneficial effect of fluoxetine treatment in mild depression

In a multicentered study, 372 patients with mild major depressive disorder with a Hamilton Rating Scale for Depression (HAM-D) score of 15 to 19 were randomly assigned to 6 weeks of treatment with placebo or 20 mg, 40 mg, or 60 mg/day of fluoxetine. Patients were rated weekly for improvement and the appearance of side effects. Pattern analysis of treatment response showed more patients in the active drug treatment groups having a persistent or a delayed persistent response, the types of response specifically associated with active treatment. Analyses of mean changes in treatment measures showed little difference among treatment groups. This may be explained in part by different distributions in outcome, placebo patients having had a higher frequency of mild improvement with fewer negative and very positive outcomes. Response rate analyses favor the active treatments numerically, but only one of the comparisons is statistically significant. These findings suggest a specific role for fluoxetine treatment in mildly depressed patients who do not respond promptly or who respond inconsistently to nonspecific treatment.     

Use of the critical path with the electronic chart system using meropenem, vancomycin, liposome amphotericin B for the febrile neutropenia

Febrile neutropenia (FN) is a serious complication associated with morbidity and mortality. To manage infections in neutropenic patients, it is necessary to administer empirical antibiotic therapy in a timely and efficient manner. We developed an electronic critical pathway system for a computer-stored medical record system (EGMAIN-GX, Fujitsu), which matches FN patients to either: i) the first-line therapy with meropenem (3 g/day) alone, or ii) the second-line therapy with meropenem plus vancomycin (2 g/day). If patients do not respond to the first-line therapy within 72 hours, then they are provided with the second-line therapy. A total of 28 FN events were treated in 14 patients presenting with hematological malignancies. The mean and median neutrophil counts were 42 (0-300)/microl and 0/microl, respectively. The response rates with the first-line and second-line therapies were 57% and 93%, respectively. There were no serious adverse events. Meropenem is a highly effective treatment for FN. Use of an electronic critical pathway system could ensure that neutropenic patients receive this necessary empiric therapy in a timely manner so as to prevent the serious complications associated with FN.     

Augmentation of milnacipran by risperidone in treatment for major depression

Milnacipran, one of the serotonin noradrenaline reuptake inhibitors (SNRIs) to which venlafaxine and duloxetine belong, is a new antidepressant that has recently become available in many countries. Despite the advances in pharmacotherapy, almost one third of patients with depressive illness respond inadequately to monotherapy with such an antidepressant. We herein describe five patients with major depression who responded partially, but not fully, to milnacipran alone and remarkably improved with an adjunct of risperidone. In addition, milnacipran plus risperidone was found to be a useful augmentation for treatment-refractory depression in 3 of the 5 patients. The minimum dose of risperidone, 0.5 or 1 mg/d, was efficacious. The time of response after addition of risperidone was within 4 d. Our experience suggests that an augmentation therapy of milnacipran plus risperidone is useful for treating patients with depression who only partially respond to various types of antidepressants and for treatment-refractory depression.     

Cefoperazone/sulbactam versus cefoperazone plus mezlocillin: empiric therapy for febrile, neutropenic bone marrow transplant patients

We conducted a prospective, randomized trial in 132 patients undergoing bone marrow transplantation comparing cefoperazone in combination with sulbactam (S), N = 66, vs. cefoperazone plus mezlocillin (CM), N = 66, as empiric antibiotic therapy for fever and neutropenia. Overall duration of neutropenia was 3-55 (median, 13) days. Forty-one patients had positive initial cultures (S = 22 and CM = 19). Twelve of these 41 patients responded to initial study antibacterial agent treatment (S = 6 and CM = 6). Twenty-nine of 41 patients were withdrawn from study because of clinical deterioration, continued fever, or persistently positive cultures (S = 16 and CM = 13). Of the 90 patients who had culture-negative fever (S = 44 and CM = 46), 44 subjects responded with or without the addition of amphotericin B (S = 21 and CM = 23). Thirty-seven of 90 patients were withdrawn from study due to continued fever or clinical deterioration (S = 17 and CM = 20). Nine patients were withdrawn as a result of rash or diarrhea (S = 6 and CM = 3). We conclude that in patients undergoing bone marrow transplantation, there was no difference in efficacy between cefoperazone/sulbactam and the combination of cefoperazone plus mezlocillin in the empiric treatment of the febrile neutropenic patient. Since the majority of initial infections were due to gram positive bacteria, consideration should be given to broadening initial empiric antibacterial agent therapy with drugs that possess potent activity against these organisms.     

Abatacept.

PURPOSE: The pharmacology, pharmacokinetics, indications, clinical efficacy, adverse effects, drug interactions, dosing, and administration of abatacept are discussed. SUMMARY: Abatacept is the first drug in a new class of agents known as selective costimulator modulators. Abatacept has been shown to decrease tumor necrosis factor (TNF)-alpha, which is important to the inflammatory response. Abatacept inhibits T-cell function but does not deplete T cells. Activated T cells are important in the inflammatory cascade, ultimately leading to joint inflammation and irreversible structural damage. In patients with rheumatoid arthritis, there is chronic inflammation of the synovial tissue lining the joint capsule. Abatacept is indicated for reducing the signs and symptoms of moderate to severe rheumatoid arthritis in adult patients who have had an inadequate response to at least one disease-modifying antirheumatic drug. Studies in adult patients with rheumatoid arthritis have evaluated abatacept in patients with an inadequate response to either methotrexate or TNF-alpha blocking agents. One trial showed that abatacept produced a favorable six-month clinical response in patients who had previously failed to respond to anti-TNF-alpha therapy. In a study of concurrent abatacept and methotrexate therapy, the addition of abatacept produced favorable outcomes in patients who were not adequately responding to methotrexate alone. CONCLUSION: Abatacept, a newly approved agent for the treatment of rheumatoid arthritis, has shown promising results in patients who have had an inadequate response to other treatment modalities. Abatacept therapy should be reserved for patients who have failed other time-tested treatment modalities, including TNF-alpha antagonists. Results from ongoing postmarketing studies will help determine abatacept's place in therapy.     

Potential of clindamycin in addition to vancomycin for the treatment of oxacillin-resistant Staphylococcus aureus septicemia persisting under vancomycin therapy

We observed seven patients with persistent fever and staphylococcemia under vancomycin-containing antimicrobial regimens who promptly improved as clindamycin was added to the initial antibiotics. Moreover, in all these patients a striking increase in peak and trough serum inhibitory activity (SIR) and serum bactericidal activity (SBA) levels was observed after addition of clindamycin. SIA and SBA levels after administration of a single dose of vancomycin (500 mg), clindamycin (600 mg) or vancomycin + clindamycin were also measured in three healthy volunteers against six ORSA isolates. Unsatisfactory peak SBA levels (0% of cases 1:8) were obtained after vancomycin administration. Vice versa, peak SBA levels 1:8 were obtained in 94% of the cases after clindamycin and in 100% of cases after vancomycin + clindamycin. Time-kill studies showed a borderline or incomplete bactericidal activity of vancomycin against three ORSA isolates from infections that manifested poor or slow response to vancomycin therapy. The combination with clindamycin did not result in a synergistic interaction between the two drugs. It is concluded that addition of clindamycin may be useful in some cases of ORSA septicemia that show poor or slow response to vancomycin therapy. The recommendation for a wider use of this combination of antibiotics requires further documentation of efficacy.     

Rational diagnostic steps in acute pyelonephritis with special reference to ultrasonography and computed tomography scan

Depending on the severity of the clinical syndrome, acute pyelonephritis may require more extensive imaging diagnostics. In the uncomplicated form of the disease, ultrasonography does not appear to be absolutely necessary. In clinically severe cases, however, which fail to respond to antibiotic therapy, ultrasound is the optimal procedure for ruling out urinary tract obstruction. Where there is clinical suspicion of complications—proven risk factors, persistent fever and/or continuing pathological inflammation parameters (elevated C-reactive protein levels in serum)—ultrasonography is the primary imaging technique for the exclusion of pyonephrosis, as well as for other complicating factors such as calculi, etc. In cases of insufficient response to antibiotic therapy, we recommend performing a renal computed tomography scan with contrast medium, in order to rule out hypoenhancing zones as hints for severe tissue alterations. This procedure is in accordance with the suggestions of the Society for Uroradiology. In the future, DMSA scintigraphy might constitute an equivalent diagnostic method for the exclusion of these focal inflammatory changes. Above all, DMSA scintigraphy makes it possible to anticipate the development of scars following acute pyelonephritis.     

Caspofungin: a review of its use in the treatment of fungal infections

Caspofungin (Cancidas) is the first of a new class of antifungal agents, the echinocandins, that inhibit the synthesis of the fungal cell wall component beta-(1,3)-D-glucan. Caspofungin is administered once daily by slow intravenous infusion and is used to treat infections caused by Candida spp. and Aspergillus spp.Caspofungin is a valuable new antifungal agent with a novel mechanism of action. In comparative clinical trials, caspofungin was no less effective than liposomal amphotericin B in the empirical treatment of neutropenic patients with persistent fever, amphotericin B deoxycholate in the treatment of invasive candidiasis or fluconazole in the treatment of oesophageal candidiasis. Caspofungin also displayed broadly similar efficacy to amphotericin B deoxycholate in oesophageal or oropharyngeal candidiasis and was effective as salvage therapy in patients with invasive aspergillosis who were refractory to or intolerant of standard therapy. The tolerability profile of caspofungin was similar to that of fluconazole and superior to that of amphotericin B deoxycholate and liposomal amphotericin B. Therefore, in the appropriate indications, caspofungin is a viable alternative to amphotericin B deoxycholate, liposomal amphotericin B or fluconazole.     

Pharmacoeconomic analysis of caspofungin versus liposomal amphotericin B as empirical antifungal therapy for neutropenic fever.

PURPOSE: An analysis was conducted that evaluated and compared the cost differences between caspofungin and liposomal amphotericin B when the medications were used as empirical antifungal therapy for persistent fever during neutropenia. METHODS: Rates of drug use and impaired renal function (IRF) were based on data from published studies. IRF was defined as a doubling of the serum creatinine level or, if the creatinine level was elevated at enrollment, an increase of at least 1 mg/dL. The estimates of the costs for drug acquisition and treating IRF were derived using published data and applied to compare caspofungin with liposomal amphotericin B. Sensitivity analyses were performed by varying the IRF and relative acquisition costs to assess the effect of these factors on the cost differences. RESULTS: The acquisition costs per patient were 6942 dollars for liposomal amphotericin B and 3996 dollars for caspofungin. The estimated cost per patient from IRF was 3173 dollars for liposomal amphotericin B and 793 dollars for caspofungin. Combining drug acquisition and IRF costs, the overall treatment cost per patient for caspofungin was 5326 dollars less than for liposomal amphotericin B. In sensitivity analyses of drug costs, the price of liposomal amphotericin B would have to be 23.95 dollars per vial for the overall treatment costs to be equal. CONCLUSION: Comparison of cost estimates derived from published data revealed that a combined estimate of acquisition costs and costs related to the treatment of IRF was lower for caspofungin than for liposomal amphotericin B for empirically treating patients with neutropenic fever.