This multinational, double-blind trial compared caspofungin, an echinocandin, with liposomal amphotericin B as empirical antifungal therapy in 1095 patients with persistent fever and neutropenia. ...Caspofungin was as efficacious as the standard therapy and was better tolerated, with less nephrotoxicity and fewer drug-related adverse events.
This multinational trial compared caspofungin with liposomal amphotericin B. The results support an effective new option for empirical antifungal therapy in high-risk patients.
Invasive fungal infections are important causes of illness and death in patients with neutropenia who receive chemotherapy for cancer or who undergo hematopoietic stem-cell transplantation.
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Persistent fever in patients with neutropenia who are receiving broad-spectrum antibiotics may be the only clinical indication of an invasive fungal infection.
Amphotericin B and its lipid formulations, as well as triazoles (fluconazole, itraconazole, and voriconazole), have been studied as empirical antifungal agents in patients with persistent fever and neutropenia.
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However, these agents may be associated with toxicity and adverse drug interactions and have a limited spectrum of activity, erratic bioavailability, unpredictable pharmacokinetics, . . .
Background. Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum ...triazole with in vitro and in vivo activity against Aspergillus species. Methods. We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. Results. Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee—assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50–11.04; P = .006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. Conclusions. Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.
Infection in the neutropenic patient has remained a major clinical challenge for over three decades. While diagnostic and therapeutic interventions have improved greatly during this period, increases ...in the number of patients with neutropenia, changes in the etiologic agents involved, and growing antibiotic resistance have continued to be problematic. The evolving etiology of infections in this patient population is reviewed by Dr. Donowitz. Presently accepted antibiotic regimens and practices are discussed, along with ongoing controversies. In Section II, Drs. Maki and Crnich discuss line-related infection, which is a major infectious source in the neutropenic. Defining true line-related bloodstream infection remains a challenge despite the fact that various methods to do so exist. Means of prevention of line related infection, diagnosis, and therapy are reviewed. Fungal infection continues to perplex the infectious disease clinician and hematologist/oncologist. Diagnosis is difficult, and many fungal infections will lead to increased mortality even with rapid diagnosis and therapy. In Section III, Dr. Pappas reviews the major fungal etiologies of infection in the neutropenic patient and the new anti-fungals that are available to treat them. Finally, Dr. Rolston reviews the possibility of outpatient management of neutropenic fever. Recognizing that neutropenics represent a heterogeneous group of patients, identification of who can be treated as an outpatient and with what antibiotics are discussed.
In 1993, similar to 15,000 allogeneic and autologous bone marrow transplantations were carried out worldwide (M. Bortim, International Bone Marrow Transplant Registry, Milwaukee; personal ...communication). Transplantation has been utilized with increasing frequency for treatment of malignant and nonmalignant hematologic diseases, solid tumors, and metabolic and genetic disorders. Infection and graft-vs.-host disease (GVHD) remain the major sources of morbidity and mortality in recipients of bone marrow transplants. Infections occur as a direct result of the predictable, sequential suppression of host defenses that is caused by marrow transplantation. The severity and type of infection also depend on a number of other factors including the type of transplant, the presence and degree of histocompatibility mismatch, T lymphocyte manipulation (depletion), type of graft-vs.-host prophylaxis employed, severity of GVHD, and viral and fungal infections occurring before transplantation. Previous antibiotic exposures, including antibiotic prophylaxis, may also help to define the infections that develop. While it would be overly simplistic to suggest that specific infections occur only at specific times in the transplantation process, it is nevertheless helpful to divide the transplantation process into specific phases, each of which is characterized by specific host defense defects and is associated with a specific group of infections. (DBO)
Background. Long‐dwelling tunnelled central venous catheters provide reliable access for infusion therapy of patients with cancer, but can result in serious bloodstream infections. The incidence of ...such infections has been documented, but few studies have assessed potential risk factors, and to the authors' knowledge, none have measured the effect of neutropenia upon the incidence of these infections.
Methods. A cohort of 71 adult patients with cancer with long‐dwelling tunnelled central venous catheters was followed for a total of 12,410 catheter days until catheter removal, death, or end of study for the occurrence of catheter‐related infection or sepsis of unknown origin. Fifteen factors were assessed for association with these infections.
Results. Thirteen patients (18%) experienced a catheter‐related infection (1.0/1000 catheter days), and 23 (32%) experienced sepsis of unknown origin. Neutropenia was associated significantly with risk for catheter‐related infection (relative risk RR = 15.1, 95% confidence interval CI 2.7‐86.9) and sepsis of unknown origin (RR = 10.3, 95% CI 4.0‐26.8). Inpatient status, acute leukemia, and cytosine arabinoside therapy also were associated with sepsis of unknown origin, but not when adjusted for neutropenia.
Conclusion. Of the 15 potential risk factors studied, neutropenia was the only independent risk factor for infection related to long‐dwelling tunnelled central venous catheters and for sepsis of unknown origin. Cancer 1995;75:1367‐75.
We investigated the clinical characteristics and treatment of patients with a distinctive triad of acute infusion-related reactions (AIRRs) to liposomal amphotericin B (L-AMB) via single-center and ...multicenter analyses. AIRRs occurred alone or in combination within 1 of 3 symptom complexes: (1) chest pain, dyspnea, and hypoxia; (2) severe abdomen, flank, or leg pain; and (3) flushing and urticaria. The frequency of AIRRs in the single-center analysis increased over time. Most AIRRs (86%) occurred within the first 5 min of infusion. All patients experienced rapid resolution of symptoms after intravenous diphenhydramine was administered. The multicenter analysis demonstrated a mean overall frequency of 20% (range, 0%-100%) of AIRRs among 64 centers. A triad of severe AIRRs to L-AMB may occur in some centers; most of these reactions may be effectively managed by diphenhydramine administration and interruption of L-AMB infusion.
Antibiotics with significant tissue penetration and intracellular accumulation may have an important role in the treatment of intracellular infections. However, clinically relevant evaluation of ...these antibiotics in vitro remains a challenge. Measurement of serum drug concentrations or serum bactericidal levels may not be relevant. Measurement of intracellular drug concentrations may be simplistic, given the complex interaction of drug, microbe, and phagocyte. The effect of an antibiotic on an intracellular organism depends on the drug's penetration into the cell, its intracellular location, its metabolism within the cell, and its antimicrobial activity within the organism's specific intracellular microenvironment. Legionella micdadei, an intracellular parasite that grows within monocytes, has been used for the evaluation of drugs like azithromycin that are concentrated intracellularly.
Hyperphosphatemia is common in patients with chronic kidney disease and is increasingly associated with poor clinical outcomes. Current management of hyperphosphatemia with dietary restriction and ...oral phosphate binders often proves inadequate. Tenapanor, a minimally absorbed, small-molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), acts locally in the gastrointestinal tract to inhibit sodium absorption. Because tenapanor also reduces intestinal phosphate absorption, it may have potential as a therapy for hyperphosphatemia. We investigated the mechanism by which tenapanor reduces gastrointestinal phosphate uptake, using in vivo studies in rodents and translational experiments on human small intestinal stem cell-derived enteroid monolayers to model ion transport physiology. We found that tenapanor produces its effect by modulating tight junctions, which increases transepithelial electrical resistance (TEER) and reduces permeability to phosphate, reducing paracellular phosphate absorption. NHE3-deficient monolayers mimicked the phosphate phenotype of tenapanor treatment, and tenapanor did not affect TEER or phosphate flux in the absence of NHE3. Tenapanor also prevents active transcellular phosphate absorption compensation by decreasing the expression of NaPi2b, the major active intestinal phosphate transporter. In healthy human volunteers, tenapanor (15 mg, given twice daily for 4 days) increased stool phosphorus and decreased urinary phosphorus excretion. We determined that tenapanor reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux, an effect mediated exclusively via on-target NHE3 inhibition.
Invasive fungal infections cause substantial morbidity and mortality in preterm infants. In this single-center, double-blind, placebo-controlled trial, extremely-low-birth-weight preterm infants who ...were given the antifungal agent fluconazole prophylactically for six weeks had significantly lower rates of fungal colonization and systemic fungal infection than control infants, without development of resistance to fluconazole or adverse effects on liver enzymes.
The use of fluconazole reduced the incidence of invasive fungal infection in extremely-low-birth-weight infants.
Despite aggressive antifungal treatment of invasive candida infection, systemic fungal disease is increasing in prevalence and leads to high rates of illness and death among preterm infants.
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Candida species rapidly colonize the skin and mucous membranes of about 60 percent of critically ill neonates and can progress to invasive infection.
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Fungal infection accounts for 9 percent of cases of late-onset sepsis in infants who weigh less than 1500 g and is associated with a mortality rate of 28 percent, as compared with 7 percent among infants in whom no infection develops.
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Critically ill neonates are at an increased . . .
The study presented here was performed in order to create a rule that identifies subjects at high risk for invasive candidiasis in the intensive care setting. Retrospective review and statistical ...modelling were carried out on 2,890 patients who stayed at least 4 days in nine hospitals in the USA and Brazil; the overall incidence of invasive candidiasis in this group was 3% (88 cases). The best performing rule was as follows: Any systemic antibiotic (days 1-3) OR presence of a central venous catheter (days 1-3) AND at least TWO of the following-total parenteral nutrition (days 1-3), any dialysis (days 1-3), any major surgery (days -7-0), pancreatitis (days -7-0), any use of steroids (days -7-3), or use of other immunosuppressive agents (days -7-0). The rate of invasive candidiasis among patients meeting the rule was 9.9%, capturing 34% of cases in the units, with the following performance: relative risk 4.36, sensitivity 0.34, specificity 0.90, positive predictive value 0.01, and negative predictive value 0.97. The rule may identify patients at high risk of invasive candidiasis.
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