Shahe Vartivarian

The Epidemiology of Hematogenous Candidiasis Caused by Different Candida Species

The medical records of patients with hematogenous candidiasis at M. D. Anderson Cancer Center (Houston) between 1988 and 1992 were retrospectively reviewed. There were 491 episodes of infection (6 per 1,000 admissions), 79% of which occurred outside the intensive care unit setting. A significant decrease in incidence was observed among patients with leukemia over the study period, together with a relative decrease in Candida albicans and Candida tropicalis infections and an increase in Candida krusei and possibly Candida glabrata infections. In the multivariate analysis, fluconazole prophylaxis provided strong protection against the development of C. tropicalis infection (odds ratio [OR] = 0.08) and C. albicans infection (OR = 0.15), in comparison with protection against infections due to other species, but it was the single most important determinant for the relative increase in C. krusei (OR = 27.07) and C. glabrata (OR = 5.08) infections. In conclusion, there has been a substantial shift in the epidemiology of hematogenous candidiasis caused by different Candida species in recent years. Fluconazole appears to be playing a major role in this observed shift.

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.

A changing pattern of susceptibility of Xanthomonas maltophilia to antimicrobial agents: implications for therapy.

The in vitro susceptibilities of 130 Xanthomonas maltophilia isolates to 12 antibiotics--trimethoprim-sulfamethoxazole, minocycline, ticarcillin-clavulanate, ceftazidime, cefoperazone, cefoperazone-sulbactam, imipenem, ciprofloxacin, and the investigational quinolones PD 117558, PD 117596, PD 127391, and sparfloxacin--were determined by a microtiter broth dilution technique. Other than the investigational quinolones, the most active antibiotics were minocycline, trimethoprim-sulfamethoxazole, and ticarcillin-clavulanate, in order. However, the first two were not bactericidal, while about half of the isolates exhibited intermediate susceptibility to ticarcillin-clavulanate. Patterns of susceptibility to trimethoprim-sulfamethoxazole and ciprofloxacin relative to the years of isolation of these strains reflected the development of resistance to the antibiotic prophylaxis practices in the hospital. We recommend that a combination of antibiotics, such as trimethoprim-sulfamethoxazole, minocycline, and ticarcillin-clavulanate, at or close to the maximum tolerated doses be in the treatment of serious X. maltophilia 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.

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.

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.

Serious complications of vascular catheter-related Staphylococcus aureus bacteremia in cancer patients

Over the period 1986 to 1989, 53 cancer patients were identified with catheter-relatedStaphylococcus aureus bacteremia at the University of Texas M.D. Anderson Cancer Center. Septic thrombosis was diagnosed in 12 (23 %) patients and was suspected in another 3 (6 %). Of the 12 patients, five developed deep-seated infections (septic emboli, endocarditis, meningitis, abscess), compared with 2 of the 38 other patients with no septic thrombosis (p<0.01). Fever persisted for more than three days after antibiotic initiation in 52 % of the patients with complications (septic thrombosis and/or deep-seated infections), compared with 19 % of those without complications (p<0.02). Of the three patients with complications who were treated for 14 days with intravenous antistaphylococcal antibiotics, two relapsed; in contrast, all of the nine patients with complications who were treated for more than 14 days (mean 4 weeks) were cured, and none relapsed (p<0.05). Of the nine patients with complications who were treated with a long course of therapy, only one required surgery. The possibility of septic thrombosis and/or deep-seated infections should be considered in all cancer patients with catheter-relatedStaphylococcus aureus bacteremia, and if present, the condition should be treated with appropriate intravenous antibiotics for at least four weeks.

Mucocutaneous and Soft Tissue Infections Caused by Xanthomonas maltophilia: A New Spectrum

Xanthomonas maltophilia has emerged as a significant cause of morbidity and mortality in hospitalized patients, causing bacteremia and other serious infections, including pneumonia, endocarditis, mastoiditis, and meningitis [1-8]. Previous reports of infections involving the skin and soft tissues have mostly included wound infections [5, 9-18]. Reports of primary and metastatic X. maltophilia cellulitis in particular have been scarce [3, 4, 19-21]. We describe the diagnosis, course, and treatment of all cases of documented X. maltophilia infections of the mucocutaneous surfaces and soft tissues that occurred during a 15-month period at The University of Texas M.D. Anderson Cancer Center. Some of the infections had previously undescribed manifestations. Methods Patients We reviewed the records of the clinical microbiology laboratory of The University of Texas M.D. Anderson Cancer Center from October 1991 to December 1992 for all cultures positive for X. maltophilia. We also reviewed the medical records of all patients with positive cultures from mucocutaneous surfaces and soft tissues. Routine microbiological methods were used. Xanthomonas maltophilia was identified by the Vitek-AMS (BioMerieux; Hazelwood, Missouri) or the API-NFT (BioMerieux) recognition systems. Definitions We defined infection as positive cultures obtained from a site that manifested clinical signs of infection. No evidence could suggest other pathogens, including herpesvirus, isolated from the same site. We excluded patients who had phlebitis but had no signs of cellulitis. Patients who were infected with X. maltophilia that was isolated from the study sites but who did not meet the inclusion criteria were considered to be colonized and were thus excluded. We used definitions suggested by the Food and Drug Administration and Infectious Diseases Society of America for skin-skin structure infections [22]. Briefly, cellulitis was defined as warmth, erythema, and induration of skin or subcutaneous tissue or both, with or without pain. Mucocutaneous infection was defined as an ulcer associated with pain, swelling, and erythema. Response to therapy was defined as disappearance of all signs and symptoms of infection. Neutropenia was defined as a neutrophil count of less than 1000 cells/L. Results Xanthomonas maltophilia was isolated from various sites in 237 patients during the study period, and 114 patients were judged to have true X. maltophilia infections. Sixteen of the 237 patients fulfilled the inclusion criteria of our study. We included one additional patient who only had positive blood cultures for X. maltophilia and multiple nontraumatic subcutaneous nodules with no breakdown of overlying skin. There was no clustering of cases by either time or space. We divided the patients into two groups on the basis of the most likely route of acquisition of the infection: those with hematogenously spread metastatic lesions (6 patients) and those who probably acquired the infection by direct inoculation through the mucocutaneous surfaces (11 patients). This latter group had negative blood cultures and was further subdivided into patients with primary cellulitis (5 patients) and those with mucocutaneous infections (6 patients). The clinicopathologic characteristics of these patients are shown in Table 1. Table 1. Clinical Features of 17 Patients with Mucocutaneous and Soft Tissue Infections Caused by Xanthomonas maltophilia* Metastatic Cellulitis Five of six patients with metastatic cellulitis had leukemia refractory to treatment; in one patient, malignancy had been recently diagnosed, and the infection developed during the first course of chemotherapy. All patients had received broad-spectrum antibiotics within 10 days before the onset of their infections. In the patients receiving ciprofloxacin and ceftazidime, organisms causing the infections were susceptible to the antibiotics when infection occurred. All patients were hospitalized with severe neutropenia (<100 neutrophils/L) and fever. The lesions consisted of hard, nonfluctuant, tender skin or subcutaneous nodules in five patients (Figure 1). The nodules ranged in size from 0.5 1 cm to 5 6 cm and were characterized by warmth and a violaceous erythema of the overlying skin. In all five patients, tender areas of cellulitis surrounded the nodules or appeared in areas distant from the nodules. Culture of biopsy tissue from one of these distant cellulitic areas showed X. maltophilia. Black central necrosis (2 patients) or ulcerations (2 patients) developed in some of the nodules and cellulitic areas. The skin lesions involved the extremities, scalp, back, and abdomen in decreasing frequency. These lesions increased in size and number in four patients over a median of 2 days. One patient had a nodule (5 6 cm) of the right upper arm with surrounding cellulitis (3 cm in width); during the next 10 days, an area of cellulitis over the abdomen developed and increased in size. A second patient had a nodule (2 3 cm) of the right thigh with surrounding cellulitis (4 cm in width). Areas of cellulitis developed that increased in size over the next 3 days on the left thigh (as large as 2 2 cm), bilateral lower extremities (as large as 2 3 cm), back (as large as 3 4 cm), and scalp (as large as 2 3 cm). A third patient had a nodule of the left shin and cellulitis of the lateral aspect of the left lower extremity. The cellulitis increased in size over the next day to cover the area from the dorsum of the left foot to above the knee. A fourth patient had one nodule of the right lower leg (0.5 1 cm) and two nodules of the scalp (0.5 1 cm) with cellulitis involving the left lower leg and the left big toe. During the next day, one more nodule of the left lower extremity (1 1 cm) and two more nodules of the scalp (1 1 cm) developed with increasing cellulitis of both lower extremities. The fifth patient had a single nodule of the right elbow with surrounding cellulitis. Figure 1. Metastatic Xanthomonas maltophilia cellulitis. Top. Bottom. X. maltophilia Four of these patients developed septic shock, with confusion (3 patients), multiorgan failure (3 patients), and pneumonia (4 patients). Pathologic examination of biopsy tissue from three of the five patients with nodular lesions showed swelling of the endothelial cells and inflammatory infiltrates of the subcutaneous tissue and dermis (Figure 2). Two patients had necrotizing inflammation of the dermis. Figure 2. Histopathologic changes of metastatic Xanthomonas maltophilia skin lesions in two patients with acute leukemia. Top left. Top right. Bottom left. Bottom right. The sixth patient with metastatic cellulitis had multiple erythematous macular lesions involving the left lower extremity that were typical of ecthyma gangrenosum. During the next day, multiple new ecthymatous lesions of both lower extremities, the right upper extremity, and the scalp developed; they ranged in size from 1 1 cm to 5 6 cm. Septic shock with confusion, multiorgan failure, and pneumonia developed. Examination of biopsy tissue from this patient showed characteristic pathologic changes (consisting of infiltration of the dermal blood vessel walls, perivascular connective tissue, and papillary dermis with gram-negative rods) and fibrin thrombi within superficial and deep vessels with local necrosis of dermis, dermal blood vessels, and eccrine sweat coils (Figure 2). Two patients with metastatic cellulitis responded to trimethoprim-sulfamethoxazole when they recovered from myelosuppression. The remaining four patients died of active X. maltophilia infection and persistent neutropenia a median of 10 days after the onset of skin lesions. Mucocutaneous Infections The mucocutaneous lesions consisted of infected ulcers of the gingiva, lip, and buccal mucosa. Five of the six patients with mucocutaneous infections were febrile and neutropenic. All six were given chemotherapy for cancers that had recurred, and they received one or more broad-spectrum antibiotics within 10 days of the onset of their infections. In those patients receiving -lactam antibiotics, the X. maltophilia organisms were resistant. On the other hand, the organisms were susceptible to ciprofloxacin in the three patients receiving this antibiotic. Two of the three patients who responded to treatment with trimethoprim-sulfamethoxazole recovered from myelosuppression. The third patient responded despite persistent neutropenia. The remaining three patients died of causes unrelated to their persistent infection. Two of these patients had persistent neutropenia. Primary Cellulitis None of the five patients with primary cellulitis had leukemia, and none received antibiotics. Only two were receiving chemotherapy and had neutropenia; four were outpatients. All patients had tender cellulitis without clear demarcation of the borders. The lesion surrounded a neck mass in one patient and produced an exudate at catheter insertion sites in four patients. Response in the three patients receiving antimicrobial treatment, two of whom were neutropenic and recovered from myelosuppression, coincided with the removal of the catheter. Removal of the catheter was the only therapeutic maneuver required to achieve response in the remaining two patients. Discussion Several new findings emerged from our study: 1) Mucocutaneous and soft tissue infections caused by X. maltophilia are not uncommon; 2) X. maltophilia can cause metastatic nodular skin lesions that mimic disseminated fungal infections [this type of lesion has not been described previously]; 3) X. maltophilia causes serious morbidity and high mortality in patients with metastatic skin nodules; 4) X. maltophilia can cause superinfections in patients receiving broad-spectrum -lactam or quinolone antibiotics to which the organisms are susceptible at the time of the infections; and 5) catheter removal contributes to a favorable outcome in patients with catheter-associated X. maltophilia cellulitis without b

Parainfluenza virus infection in adult bone marrow transplant recipients

The clinical course of parainfluenza virus infection occurring in 8 of 265 (3 %) adult bone marrow transplant recipients during 1991 was reviewed. Parainfluenza virus type 3 was isolated from all eight patients. The clinical course ranged from self-limited upper respiratory tract infections (2 patients) to severe lower respiratory tract disease (6 patients) associated with a 50 % mortality. This study highlights the important role of community respiratory viruses such as parainfluenza virus in the etiology of pneumonia in immunocompromised adults.

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.