Treatment of neutropenia-related fungal infections with granulocyte colony-stimulating factor-elicited white blood cell transfusions: a pilot study.

Neutropenia-related fungal infections can be life-threatening despite antifungal therapy. We evaluated the role of recombinant granulocyte colony-stimulating factor (rG-CSF)-elicited white blood cell (WBC) transfusions in patients with neutropenia-related fungal infections. Adult patients with hematologic malignancies, absolute neutrophil counts (ANC) <500/microl and fungal infections refractory to amphotericin B, received daily transfusions of rG-CSF-elicited and irradiated WBC transfusions from related donors. Donors received 5 microg/kg/day of rG-CSF subcutaneously. Donors achieved a mean ANC of 29.4 x 10(3) per microliter. The mean yield of neutrophils per transfusion was 41 x 10(9) (range, 10-116). Fifteen patients received a median of eight transfusions (range, 3-16). Fourteen patients had received rG-CSF for a median of 12 days. The median ANC baseline was 20/microl. Eleven patients had favorable responses and eight of them remained free of infection 3 weeks after therapy. Favorable responses occurred among patients with better Zubrod performance status (median, 3 vs 4) and shorter duration of both profound neutropenia (median, 15 vs 25 days) and active infection (median, 8 vs 17 days). The mean 1- and 24-h post-transfusion ANCs were 594/microl (range, 98-1472/microl) and 396/microl (range, 50-1475/microl), respectively. Adverse reactions were observed in nine of 35 donors and in the recipients of six of 130 transfusions. rG-CSF-elicited WBC transfusions may be a safe and promising approach for treating neutropenia-related fungal infections.

Stenotrophomonas (Xanthomonas) maltophilia urinary tract infection. A disease that is usually severe and complicated.

BACKGROUND: Stenotrophomonas (Xanthomonas) maltophilia has emerged as a causative agent of serious nosocomial infections. However, well-documented cases of urinary tract infection with this organism have rarely been reported. METHODS: review of the medical records of patients admitted to a large cancer center with cultures yielding S maltophilia from urinary sources during a 15-month period. RESULTS: All urinary tract infections were serious: 13 were complicated and two were acute uncomplicated pyelonephritis. The urinary tracts of 13 other patients were colonized with S maltophilia. Most of the colonized and infected patients were hospitalized with genitourinary malignancy, underwent urinary catheterization, and were receiving antibiotics inactive against S maltophilia. Neutropenia and urinary structural abnormalities were significantly associated with infection. The clinical course of infection was usually severe: fever (100%), sepsis disorder (47%), neutrophilia (70% of patients without neutropenia), bacteremia (13%) and death (7%). Still, response to treatment was prompt. CONCLUSIONS: Stenotrophomonas maltophilia urinary tract infection is usually associated with a severe clinical course. Risk factors for urinary colonization by this organism include hospitalization, urinary catheterization, and administration of inactive antibiotics. Risk factors for urinary tract infection include neutropenia and urinary structural abnormalities. In the presence of these risk factors, treatment of S maltophilia should be considered in patients with urinary colonization by the organism or in those with nosocomial urinary tract infection caused by an unknown pathogen and that is unresponsive to therapy with the antibiotics that are used to treat the common uropathogens.

Primary Candida pneumonia. Experience at a large cancer center and review of the literature.

We reviewed the experience over 20 years with primary Candida pneumonia among fatal cancer cases at our hospital. Unequivocal evidence of primary Candida pneumonia has been reported in only 55 cases. We report here 31 such cases. Unlike patients with disseminated candidiasis, and contrary to previous studies concentrating on cancer patients, only 9 of our 31 patients had severe neutropenia. In this report, the lack of organ involvement other than the lungs at complete autopsy examination, the exclusion of patients with candidemia, the very high percentage of intrabronchial and intra-alveolar fungal involvement without vascular invasion, and the concomitant presence of candidal esophagitis in some patients suggest that the mechanism of entry of the infectious particles may have been aspiration of oropharyngeal contents. The major clinical manifestations of primary Candida pneumonia are fever and tachypnea. Radiologically, nonspecific patchy infiltrates can be seen. Histopathologically, there is prevalence of bronchopneumonia, hemorrhage, and necrosis. The only accepted criterion for the definitive diagnosis of Candida pneumonia is histologic demonstration of the fungus in lung tissue. In contrast to previous reports, we demonstrated that primary Candida pneumonia can be life-threatening in patients with cancer since it directly contributed to the death of 84% of the patients in the present series. Very little data are available on the therapy and outcome of patients with Candida pneumonia. However, primary Candida pneumonia in the compromised host should be treated as a life-threatening infection with systemic antifungal therapy.

Disseminated coccidioidomycosis. Unusual manifestations in a cardiac transplantation patient.

Because of the immunosuppressive therapy received by patients undergoing cardiac transplantation, disseminated infections, including disseminated fungal infections, often develop. Disseminated coccidioidomycosis developed in a 23-year-old man soon after undergoing orthotopic cardiac transplantation. Clinical manifestations included an unusual rash, severe myositis and arthropathy, a rapid downhill course, and pathologic evidence of widespread fungal invasion, including invasion of the cardiac graft. Detailed travel and geographic histories, and perhaps skin testing and antibody determinations for geographic-specific pathogens, should be part of the preoperative evaluation of all transplant candidates.

Predictors of adverse outcome in cancer patients with candidemia.

BACKGROUND: Many factors, including severity of illness, neutropenia, intravenous catheter management, and drug therapy may affect the outcome of candidemia in cancer patients. METHODS: The records of all patients at M. D. Anderson Cancer Center who developed one or more positive blood cultures for Candida spp between January 1, 1988, and December 31, 1992, were retrospectively reviewed. Four hundred ninety-one episodes of candidemia were identified, for which 476 had complete medical records, which were reviewed in detail. RESULTS: By 3-month follow-up, 52% of the patients had died. Neutropenia, higher APACHE III score, and visceral dissemination were associated with poor prognosis. Cure rates, adjusted for severity of illness, were similar for fluconazole and amphotericin B treatment. Exchange of central venous catheters was associated with a modest improvement in prognosis. CONCLUSION: Several factors that influence the outcome of candidemia in cancer patients have been identified. These factors may be relevant for the clinical management of cancer patients with candidemia, and for the design of therapeutic trials.

Norfloxacin in the treatment of uncomplicated gonococcal infections.

Norfloxacin, an oral fluoroquinolone antibacterial, is active in vitro against a variety of gram-positive and gram-negative pathogens, including both penicillinase-producing and non-penicillinase-producing strains of Neisseria gonorrhoeae. An earlier study demonstrated that a two-dose regimen of norfloxacin was as effective as standard therapy with spectinomycin for treating gonococcal urethritis, including infections caused by penicillinase-producing organisms. In this randomized study of treatment for uncomplicated gonococcal infection in men and women, three oral treatment regimens were compared: patients received either two doses of norfloxacin (600 mg twice daily), a single dose of norfloxacin (800 mg), or a single-dose ampicillin (3.5 g)/probenecid (1.0 g) regimen (as recommended by the Centers for Disease Control). All three treatment regimens achieved similar cure rates. Although the number of patients treated was too small to yield statistically significant conclusions, it appears that norfloxacin may be slightly better treatment for rectal and pharyngeal gonococcal infections than ampicillin and probenecid. Additionally, norfloxacin was well tolerated in this study. Thus, based on a review of these data, norfloxacin appears to be an alternative, single-dose, oral treatment regimen for uncomplicated gonococcal infection.

Randomized comparison between antibiotics alone and antibiotics plus granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived in cancer patients with fever and neutropenia.

PURPOSE: A prospective, randomized study was conducted to determine if recombinant human granulocyte-macrophage colony-stimulating factor (rh-GMCSF) (Escherichia coli-derived) could improve response rates to antibiotic therapy and shorten the duration of neutropenia in cancer patients. PATIENTS AND METHODS: A total of 107 febrile neutropenic cancer patients were randomly assigned to empiric therapy with ticarcillin-clavulanate (4 g ticarcillin + 0.1 g clavulanate i.v. every 4 hours) plus netilmicin (2 mg/kg i.v. every 8 hours) with or without rh-GMCSF (3 micrograms/kg per day i.v.). Clinical improvement, duration of neutropenia, and toxicity were monitored. RESULTS: Addition of rh-GMCSF to the antibiotics significantly improved the response rate (96% versus 82%, P = 0.03), but not the survival rate (93% versus 93%), in the evaluable patients. This difference in response rate was not significant when considering all patients in an intent-to-treat analysis. The number of patients who recovered from severe neutropenia ( < 100 cells/microliter) during the period of observation in the study was significantly greater among patients receiving the colony-stimulating factor, although the median duration of neutropenia was not affected. Superinfections and subsequent infections were not significantly different among the two treatment regimens. Side effects were more common among patients treated with the colony-stimulating factor. CONCLUSIONS: Our data do not support the routine administration of rh-GMCSF with antibiotics for patients with fever and neutropenia. Further studies should be conducted to identify those patients most likely to benefit from rh-GMCSF therapy, such as patients with persistent profound neutropenia and refractory infections.

Fluconazole versus amphotericin B in the treatment of hematogenous candidiasis: a matched cohort study.

PURPOSE: To compare the efficacy and toxicity of fluconazole and amphotericin B in the treatment of hematogenous candidiasis in cancer patients. PATIENTS AND METHODS: A matched cohort study of cancer patients with hematogenous candidiasis was conducted. Forty-five patients with hematogenous candidiasis who received fluconazole (200 to 600 mg/day) in an open-label trial at the University of Texas M. D. Anderson Cancer Center, Houston, Texas, between February 1990 and June 1992 were matched to 45 patients treated with amphotericin B (0.3 to 1.2 mg/kg/day) for the same diagnosis. Criteria for matching included the following prognostic variables at the initiation of therapy: pneumonia, neutropenia (< 1,000 cells/mm3), number of positive blood cultures before therapy, infecting Candida species, underlying disease, and the simplified acute physiology score. Response and survival at 48 hours, after 5 days of therapy, and at the end of therapy, as well as toxicity rates were obtained. Other post hoc analyses were performed. Differences in outcomes were assessed by the McNemar, the sign, and the log rank tests. RESULTS: Patients were similar with respect to the matching criteria, age, sex, status of underlying disease, use of antibiotics and growth factors, duration of treatment, presence and removal of central venous catheters, disseminated disease, and concomitant infections. Response rates at 48 hours and 5 days were similar between the two study groups. Overall response rates at the end of therapy were 73% for patients treated with fluconazole and 71% for patients treated with amphotericin B (P = 0.78). There were no differences in survival rates or causes of death. Toxicity was observed in 9% of patients treated with fluconazole and in 67% of patients treated with amphotericin B (P < 0.0001). Toxic effects of amphotericin B included nephrotoxicity, hypokaliemia, and fever and chills. CONCLUSION: Fluconazole is effective and better tolerated than amphotericin B for the treatment of hematogenous candidiasis in cancer patients.

Potential role of temocillin in the treatment of biliary sepsis.

Temocillin concentrations were determined in the gallbladder bile and/or common bile duct bile obtained intraoperatively from 20 patients, and in the T-tube bile of 5 postoperative patients. Blood samples were also obtained for determining the concomitant serum antibiotic concentrations. In 6 patients with cholelithiasis, but without common bile duct obstruction or acute infection, the mean temocillin concentrations were 890 mg/L in gallbladder bile and 1030 mg/L in common bile duct bile. In the group of 6 patients with common bile duct obstruction, the antibiotic concentrations ranged between 5.6 and 88 mg/L (mean 38.8 mg/L) in gallbladder bile and between 'undetectable' and 700 mg/L in common bile duct bile. In patients with biliary sepsis, a further reduction in temocillin bile concentrations was observed, and postoperatively, the T-tube bile temocillin concentrations were in the range of 21 to 460 mg/L (mean 130 mg/L). The clinical efficacy of temocillin in the 7 patients with acute cholecystitis was judged to be satisfactory. Our results suggest that temocillin may be considered as a potentially useful antibiotic in the treatment of patients with biliary tract sepsis caused by susceptible organisms.

Stenotrophomonas maltophilia meningitis. Report of two cases and review of the literature.

The authors report two cases of meningitis caused by Stenotrophomonas maltophilia in cancer patients following placement of an Ommaya reservoir for treatment of meningeal carcinomatosis. In addition, they review eight other cases of S. maltophilia that have been reported to date. Stenotrophomonas maltophilia meningitis is often associated with neurosurgical procedures; however, spontaneous infection may also occur, mainly in neonates. The disease's clinical presentation is similar to that of other forms of meningitis caused by Gram-negative bacilli. The overall mortality rate of this disease is 20% and is limited to neonates with spontaneous meningitis in whom effective antibiotic therapy is delayed. Meningitis caused by S. maltophilia in the modern era should be considered in immunocompromised hosts with significant central nervous system disease who have undergone neurosurgical procedures and who do not readily respond to broad-spectrum antimicrobial coverage.

Virulence properties and nonimmune pathogenetic mechanisms of fungi.

This article summarizes some of the potential fungal virulence factors, their effect on the host's defense systems, and their regulation by host factors. Immunopathogenesis is not discussed, but the role of adherence by fungal organisms to human surfaces and foreign bodies in pathogenesis is described. Dimorphism and, less commonly, phenotypic switching may play important roles in initiating and establishing infections by several fungi. Toxins, especially exotoxins, do not seem to participate significantly in pathogenesis; however, various enzymes (proteases, phospholipases) may represent virulence properties of Candida, Aspergillus, and a number of other fungi. The interaction of the organisms with their hormonal milieu, the iron-scavenging capacities of various fungi, and their potential role in pathogenesis are delineated. The immunosuppressive effects of certain fungal antigens, such as yeast mannans, are discussed.

Aspergillosis.

Aspergillus spores are ubiquitous in the environment and may become concentrated in hospital ventilation systems. Colonization in normal hosts can lead to allergic diseases ranging from asthma to allergic bronchopulmonary aspergillosis. Normal hosts rarely develop invasive disease, which is primarily an infection of severely immunocompromised patients. The major predisposing factors for infection include prolonged neutropenia, chronic administration of adrenal corticosteroids, the insertion of prosthetic devices, and tissue damage due to prior infection or trauma. Since Aspergillus spp. are respiratory pathogens, the most common form of infection is pneumonia followed by sinusitis. Patients with preexistant cavitary disease may develop noninvasive aspergillomas. Most infections are caused by Aspergillus fumigatus. The organism is capable of invading across all natural barriers, including cartilage and bone. It has a propensity for invading blood vessels causing thrombosis and infarction. The diagnosis of pulmonary infection is usually difficult to establish because the organism is seldom cultured from sputum and can represent contamination in some cases. Therapy is immunocompromised hosts is less than satisfactory and amphotericin B is the only agent with significant activity. There is anecdotal evidence to suggest that the addition of 5-fluorocytosine to amphotericin B may be beneficial.

Iron assimilation in Cryptococcus neoformans.

We studied the effects of iron chelators and of a thallium salt on growth of Cryptococcus neoformans in defined medium. An oxidant-sensitive mutant strain was found to require exogenous ferric iron for growth. Using this strain, we found that the synthetic iron chelator, N-hydroxyethylenediamine triacetate (HEDTA), in several saturation states, stimulated growth as well as the comparably saturated siderophore deferoxamine. This non-specific result makes the existence of a cryptococcal ferrihydroxamate receptor doubtful. The catechols, caffeic acid, L-3, 4-dihydroxyphenylalanine, epinephrine, gallic acid, 3-hydroxytyramine (dopamine) and norepinephrine, were tested for growth stimulation in iron deprivation, under conditions in which deferoxamine was stimulatory. Catechols were found to be either neutral or inhibitory. The ferrous iron chelator, bathophenanthroline disulfonate (BPDS), inhibited growth strongly in the absence of exogenous iron, suggesting that ferric ion must be reduced before it can be internalized. Direct evidence of extracellular reduction was provided by accumulation of red-coloured ferrous-BPDS complex. The inhibition caused by BPDS was relieved by ferric HEDTA, even in the presence of 10-fold increased BPDS, suggesting a second, low-affinity, non-reductive iron uptake pathway. This inference was further supported by the observation that toxicity of the non-reducible ferric analogue, thallium (III), is relieved by iron repletion.

Extracellular iron reductases: identification of a new class of enzymes by siderophore-producing microorganisms.

This study identifies extracellular iron reductases in culture supernatant fluids of the siderophore-producing microorganisms Escherichia coli and Pseudomonas aeruginosa. These enzymes were constitutively produced and reduced and released iron from a variety of ferric chelators. Dialyzable cofactors, necessary for the transfer of electrons in the enzymatic reduction of iron, were identified. The reductases were sensitive to treatment with proteinase K and guanidine-HCl, were not associated with siderophore activity, and were apparently released from the cell as extracellular enzymes. The acquisition of 59Fe2+ by cell suspensions of E. coli and P. aeruginosa was saturable, suggesting that the ferrous iron generated by these reductases can be bound and transported. Salmonella typhimurium mutants feoB, tonB, entB, and entBfeoB, deficient in numerous known iron uptake pathways, were found to exhibit substantial extracellular iron-reducing activities over that of the parent. A hypothesis is proposed in which the extracellular iron reductases excreted by siderophore-producing microorganisms may be responsible for the mobilization of iron during conditions of iron repletion when siderophores are repressed and may also function in concert with siderophores during periods of iron starvation.

Emerging fungal pathogens in immunocompromised patients: classification, diagnosis, and management.

Fungi such as Fusarium species, Trichosporon species, Curvularia species, and Alternaria species previously were thought to represent contamination or harmless colonization when isolated from immunocompromised patients. More recently, the pathogenic role of these and other fungi has been clearly established. Three diverse groups of fungi are responsible for these emerging infections: the agents of phaeohyphomycosis and hyalohyphomycosis and certain yeasts. Reports of the emergence of these organisms as significant pathogens may be ascribed to increasing awareness by physicians and microbiologists, aggressive culture of patient specimens, increasingly cytotoxic chemotherapy, and selection of resistant organisms by the widespread empirical use of amphotericin B. Infections with these fungi tend to be disseminated and are frequently fatal in immunocompromised hosts. Treatment of these infections is not standardized. Experimental therapy in murine models of fungal infections suggests a role for newer agents, combination antifungal chemotherapy, and immunotherapy.

Iron acquisition systems of Listeria monocytogenes.

The uptake of iron by Listeria monocytogenes was studied. The microorganism was found to bind both 59Fe(II) and [59Fe3+]citrate. In contrast, L. monocytogenes was unable to acquire iron from [59Fe3+]ferroxamine or [59Fe3+]EDTA or as 59FeCl3. The data suggest that iron is acquired principally as iron(II) and that a citrate-inducible iron uptake system is also operative.

The clinical spectrum of stenotrophomonas (xanthomonas) maltophilia respiratory infection.

During a 15-month retrospective clinical study in an academic referral-based cancer center, 26 patients with S. maltophilia respiratory tract infections were identified (which were associated with bacteremia in 13 patients). Five of these 26 patients had previously undescribed sinopulmonary involvement. The infections were typically nosocomial. Nine patients with solid tumors had malignant involvement of the respiratory tract (five with obstruction). In two patients, the infection co-existed with pulmonary aspergillosis. Fifteen patients (58%) died of the infection. The factors that correlated with a poor outcome included bacteremic pneumonia, persistent neutropenia, presence of obstruction, development of septic shock or multiple organ dysfunction, and delay in institution of appropriate antibiotic therapy. In multivariate analysis, only septic shock and delayed therapy remained significant. Trimethoprim-sulfamethoxazole and/or ticarcillin-clavulanate were most commonly associated with a favorable outcome.

Catheter-related infections caused by the Mycobacterium fortuitum complex: 15 cases and review.

Fifteen cancer patients have developed catheter-related infections caused by the Mycobacterium fortuitum complex (M. fortuitum and Mycobacterium chelonae) at M. D. Anderson Cancer Center since 1978. Eleven patients had bacteremia and four had catheter site infections. Nine infections were caused by M. fortuitum and six by M. chelonae. All four bacteremic patients whose catheters were initially removed and who were treated with antibiotics recovered, whereas for all of the seven bacteremic patients whose catheters remained in place, the infection relapsed or treatment failed. Six (86%) of the latter group ultimately responded to additional antibiotic therapy when the catheter was removed. Successful treatment of local catheter infections was accomplished by catheter removal alone or in combination with antibiotic therapy. Fourteen additional cases have been reported, and eight (57%) of these patients also had underlying cancer. Patients with septicemia or an infection at the catheter insertion site responded to catheter removal and appropriate antibiotics. Patients with infection in the catheter tunnel (tunnel infection) responded only after surgical excision of the tissue surrounding the infected tunnel. M. fortuitum complex is a cause of catheter-related bacteremia in patients with cancer. Appropriate treatment consists of antibiotic therapy and catheter removal. Tunnel infections usually also require surgical excision.

Moxalactam in the treatment of typhoid fever.

Moxalactam therapy was evaluated in 25 patients with typhoid fever. A satisfactory initial response was observed in all cases. Treatment for 3 days resulted in a much higher relapse rate (three of five patients) than did treatment for 5 days (one of nine patients). None of the 11 patients treated for 10 to 11 days relapsed. Moxalactam is effective in typhoid fever, but its use is better restricted to special indications.

Iron acquisition by Cryptococcus neoformans.

Iron is an essential element for the growth and metabolism of microbial cells. Most pathogenic microbes elaborate powerful iron chelating agents (siderophores) to mobilize iron from ferric ligands. The pathogenic yeast, Cryptococcus neoformans has not been found to produce siderophores and its mechanism of iron acquisition is unknown. This investigation explored an alternative pathway for iron acquisition by examining the interactions of iron with the cell surface. Iron uptake experiments were conducted utilizing radiolabelled ferrous iron and ferric iron chelates, with evidence for the presence of iron(II) receptors and the generation of ferrous iron by surface reduction. Hyperbolic kinetics were found when 59FeII was presented to the organism and uptake was blocked with bathophenanthroline sulphonate, an Fe2+ chelator. The yeast also acquired iron as [59Fe3+]-citrate and [59Fe3+]-pyrophosphate while bathophenanthroline sulphonate reduced the acquisition of these ferric ligands by 48% and 52% respectively. Pre-incubation with either ferric ligand also reduced iron acquisition by 50%. KCN inhibited uptake of iron(II) by 90% and uptake of [59Fe3+]-pyrophosphate and [59Fe3+]-citrate by 46% and 56% respectively; dinitrophenol had no effect on these processes. The data suggest that C. neoformans can (i) generate ferrous iron at the cell surface via a reduction of ferric chelates, with the subsequent acquisition of the ferrous iron, and (ii) acquire iron through the interaction of ferric chelates with a surface component.