Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989-2003).

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Chamilos G, Luna M, Lewis RE, Bodey GP, Chemaly R, Tarrand JJ, Safdar A, Raad II, Kontoyiannis DP.

Haematologica. 2006 Jul;91(7):986-9. Epub 2006 Jun 1.

Abstract

We evaluated autopsy-proven invasive fungal infections (IFI) in patients with hematologic malignancies over three periods (1989-1993, 1994-1998, and 1999-2003). The autopsy rate declined significantly (67%-34%-26%, respectively p<0.0001). IFI were identified in 314 (31%) of 1017 autopsies. Most IFI (75%) were not diagnosed antemortem. The prevalence of invasive mold infections increased significantly (19%-24%-25% p=0.05) in parallel with the emergence of Zygomycetes (0.9%-4%-3%; p=0.03). The prevalence of all other IFI remained relatively constant. Among patients with invasive pulmonary aspergillosis, those with graft-versus-host disease had a histopathological pattern distinct from those with neutropenia. The complex and evolving epidemiology of IFI in severely immunocompromised patients is not well captured by current diagnostic methods.

Recombinant interferon gamma1b immune enhancement in 20 patients with hematologic malignancies and systemic opportunistic infections treated with donor granulocyte transfusions.

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Safdar A, Rodriguez GH, Lichtiger B, Dickey BF, Kontoyiannis DP, Freireich EJ, Shpall EJ, Raad II, Kantarjian HM, Champlin RE.

Cancer. 2006 Jun 15;106(12):2664-71.

Abstract

BACKGROUND:

The response to antifungal therapy alone often is suboptimal in patients with cancer who have therapy-refractory neutropenia, and even donor-derived granulocyte transfusions (GTX) are not always successful. The authors evaluated the safety and efficacy of immune enhancement using recombinant interferon gamma1b (rIFN-gamma1b) in patients with cancer who received GTX for refractory, systemic, opportunistic infections.

METHODS:

Twenty recipients of high-dose donor GTX ( approximately 5.5 x 10(10) neutrophils per transfusion) who had received concurrent rIFN-gamma1b between October 2001 and December 2004 were evaluated retrospectively.

RESULTS:

The median age (+/- standard deviation [SD]) was 45 +/- 17 years. Ten patients (50%) were men, 17 patients (85%) had leukemia, and 3 patients (15%) had myelodysplastic syndrome. The median +/- SD Acute Physiology and Chronic Health Evaluation II score was 15 +/- 4 (range, 7-22). Most patients (n = 18 patients; 90%) had recurrent or refractory cancer. In 6 patients (30%) who received allogeneic hematopoietic stem cell transplantation, GTX plus rIFN-gamma1b was given a median +/- SD of 26 +/- 100 days (range, 12-372 days) after transplantation. Seventeen patients (85%) had neutropenia during GTX therapy. Five patients (25%) had possible invasive fungal infection, 3 patients (15%) had probable invasive fungal infection, and 11 patients (55%) had proven invasive fungal infection. One patient (5%) had refractory Pseudomonas aeruginosa sepsis. Eight patients (40%) received corticosteroids during GTX plus rIFN-gamma1b therapy. Patients received a median +/- SD of 8 +/- 7 GTX doses (range, 4-28 doses) and 9 +/- 7 rIFN-gamma1b doses (range, 1-28 doses), for a mean +/- SD cumulative dose (CD) of 400 +/- 2621 microg. Other concomitant cytokines were granulocyte-colony stimulating factor (12 +/- 3 doses; CD, 6720 +/- 4721 microg) in 15 patients (75%) and granulocyte-macrophage-colony stimulating factor (12 +/- 9 doses; CD, 4750 +/- 4410 microg) in 14 patients (70%). Four patients (20%) developed fever, and 2 patients (10%) developed skin rashes. Reversible liver dysfunction (n = 3 patients; 15%) and tachycardia (n = 1 patients; 5%) were considered rIFN-gamma1b-associated adverse reactions; whereas, in 1 patient (5%), transient dyspnea was attributed to GTX. Four weeks after therapy started, 9 patients (45%) had complete or partial resolution of infection; and, in another 3 patients (15%), the invasive fungal infection had become stable.

CONCLUSIONS:

The current results indicated that no serious adverse events were associated with rIFN-gamma1b immune enhancement in patients with systemic opportunistic infections who received donor GTX therapy.

Relationship of colonization with vancomycin-resistant enterococci and risk of systemic infection in patients with cancer.

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Matar MJ, Safdar A, Rolston KV.

Clin Infect Dis. 2006 May 15;42(10):1506-7

Culture-positive and culture-negative endocarditis in patients with cancer: a retrospective observational study, 1994-2004.

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Yusuf SW, Ali SS, Swafford J, Durand JB, Bodey GP, Chemaly RF, Kontoyiannis DP, Tarrand J, Rolston KV, Yeh E, Raad II, Safdar A.

Medicine (Baltimore). 2006 Mar;85(2):86-94.

Abstract

Endocarditis is uncommon in patients with cancer. The characteristics of culture-positive (CPE) and culture-negative endocarditis (CNE) in high-risk cancer patients are not known; therefore we sought to evaluate the disease characteristics in patients with endocarditis at a comprehensive cancer center. We retrospectively reviewed the transthoracic (TTE) and transesophageal (TEE) echocardiograms obtained from 654 consecutive cancer patients in whom endocarditis was suspected between 1994 and 2004. Endocarditis was confirmed in 45 (7%) of 654 patients using modified Duke University criteria based on information obtained from hospital records and computerized data systems. In 21 (95%) of 22 cases, TEE examinations were diagnostic, and 16 (42%) of 38 patients with initially nondiagnostic TTE studies had the diagnosis confirmed by TEE study; this difference between diagnostic TEE and initial nondiagnostic TTE was significant (p < 0.0001). Among the 26 (58%) patients with CPE, Staphylococcus aureus (35%) was the most common organism isolated, followed by coagulase-negative Staphylococcus species (23%). Eighteen (78%) of 23 patients with a central venous catheter had CPE, whereas only 8 (36%) of 22 patients without a central venous catheter had CPE (odds ratio [OR], 6.3; 95% confidence interval [CI], 1.69-23.53; p < 0.006). Vegetations were larger in patients with CPE than in patients with CNE (median +/- standard deviation, 10 +/- 8.8 vs. 8.7 +/- 3.9 mm). Fifteen patients (58%) with CPE and 10 (53%) with CNE had embolic complications. We note that cutaneous and septic pulmonary emboli were more common in patients with CPE than in patients with CNE (31% vs. 11% and 15% vs. 0%, respectively), whereas embolic cerebrovascular and fatal embolic coronary events were more common in patients with CNE than in those with CPE (37% vs. 12% and 21% vs. 0%, respectively; p = 0.026). The 4-week endocarditis-attributable death rate did not differ significantly between the groups (CPE, 15% vs. CNE, 32%; p = 0.28). On stepwise multivariate regression analysis, patients with neutropenia (OR, 22.52; 95% CI, 2.25-225.48; p < 0.008) and those with embolic cerebrovascular events (OR, 17.07; 95% CI, 1.63-178.45; p < 0.01) had an increased probability of death due to endocarditis. The clinical spectrums of CPE and CNE differed in these patients with cancer. In patients with CNE, embolic cerebrovascular and fatal myocardial infarction were relatively common.

Aerosolized ribavirin-induced reversible hepatotoxicity in a hematopoietic stem cell transplant recipient with Hodgkin lymphoma.

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Chaves J, Huen A, Bueso-Ramos C, Safdar A, Vadhan-Raj S.

Clin Infect Dis. 2006 Apr 15;42(8):e72-5. Epub 2006 Mar 13. Erratum in: Clin Infect Dis. 2006 May 15;42(10):1512. 

Abstract

We describe a case of acute hepatic toxicity associated with aerosolized ribavirin in a bone marrow transplant recipient with documented respiratory syncytial virus infection. The temporal relationship with drug administration and the liver biopsy results suggested drug-induced hepatic injury. As the use of aerosolized ribavirin to treat respiratory syncytial virus infections continues, it is imperative that careful attention be paid to possible adverse effects of therapy in the high-risk population of immunosuppressed patients.

Central venous catheter and Stenotrophomonas maltophilia bacteremia in cancer patients.

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Boktour M, Hanna H, Ansari S, Bahna B, Hachem R, Tarrand J, Rolston K, Safdar A, Raad I.

Cancer. 2006 May 1;106(9):1967-73.

Abstract

BACKGROUND:

Stenotrophomonas maltophilia bacteremia is frequently found in cancer patients. This study attempted to determine how often the catheters were the source of this infection and the risk factors associated with catheter-related bacteremias.

METHODS:

The microbiology records were retrospectively reviewed of all cancer patients having S. maltophilia bacteremia and indwelling central venous catheters seen between January 1998 and January 2004. In a multivariate analysis the patients’ clinical characteristics, antimicrobial therapy, outcome, and source of bacteremia that were significantly associated with definite catheter-related S. maltophilia bacteremia as opposed to secondary bacteremia were identified.

RESULTS:

A total of 217 bacteremias were identified in 207 patients: 159 (73%) were primary catheter-related (53 definite, 89 probable, and 17 possible), 11 (5%) were primary noncatheter-related, and 47 (22%) were secondary. Multivariate analysis showed the following factors to be independently associated with definite catheter-related bacteremias: 1) polymicrobial bacteremia (odds ratio [OR], 7.6; 95% confidence interval [95% CI], 1.3-45.5); 2) no prior intensive care unit admission (OR, 0.06; 95% CI, 0.005-0.578); and 3) nonneutropenic status at onset (OR, 0.07; 95% CI, 0.013-0.419). The response rate to appropriate antibiotics and catheter removal was 95% in the patients with definite catheter-related bloodstream infections, compared with only 56% in the patients with secondary bacteremias (P = .001).

CONCLUSIONS:

The majority of the S. maltophilia bacteremias occurring in cancer patients with indwelling central venous catheters appear to be catheter-related and are often polymicrobial. Catheter-related S. maltophilia bacteremias occurred more frequently in noncritically ill, nonneutropenic patients, and prompt removal of the catheter was found to be associated with a better prognosis.

Vancomycin tolerance, a potential mechanism for refractory gram-positive bacteremia observational study in patients with cancer.

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Safdar A, Rolston KV.

Cancer. 2006 Apr 15;106(8):1815-20.

Abstract

BACKGROUND:

The clinical significance of infections caused by vancomycin-tolerant (Vt) gram-positive organisms in patients with cancer remains unclear.

METHODS:

Twenty-five patients with nonenterococcal gram-positive bloodstream infection, which was refractory to vancomycin therapy, were identified by reviewing the Infectious Diseases consultation database at the tertiary care cancer center. Among these, 8 patients in whom vancomycin-tolerance was documented are described. Antibiotic tolerance was defined as a > 32 times increase in minimum bactericidal concentration compared with minimum inhibitory concentration.

RESULTS:

Eight patients with persistent fever and bacteremia of > 72 hours’ duration after the initiation of vancomycin therapy were treated. The median age of these patients, which included 3 men and 5 women, was 44 years +/- 11 years. Solid tumors were more common (6 patients) and 2 patients had acute leukemia. Six patients (75%) were neutropenic (absolute neutrophil count < 500/mm3), including 2 breast cancer patients who had undergone autologous stem cell transplantation. The causative organisms were Staphylococcus aureus (n = 3 patients), group G streptococci (n = 2 patients), and Staphylococcus epidermidis, Streptococcus mitis, and Streptococcus sanguis (1 patient each). All isolates demonstrated a minimum bactericidal concentration for vancomycin that was at least 32 times greater than the minimum inhibitory concentration. Rapid defervescence (< or = 24 h) and resolution of bacteremia occurred with the addition of gentamicin (4 patients) or gentamicin plus rifampin (4 patients). None of these infections recurred after discontinuation of therapy.

CONCLUSIONS:

Lack of clinical and/or microbiologic response to vancomycin should raise the suspicion of possible infection due to Vt gram-positive bacteria, and alternative bactericidal therapy should be instituted early, especially in patients with underlying immune suppression.

Extrapulmonary tuberculosis active infection misdiagnosed as cancer: Mycobacterium tuberculosis disease in patients at a Comprehensive Cancer Center (2001-2005).

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Aisenberg GM, Jacobson K, Chemaly RF, Rolston KV, Raad II, Safdar A.

Cancer. 2005 Dec 15;104(12):2882-7.

Abstract

BACKGROUND:

Extrapulmonary tuberculosis is an uncommon disease in the U.S., even in immunosuppressed cancer patients. This study evaluated characteristics and frequency of extrapulmonary tuberculosis in patients at a tertiary care referral cancer center.

METHODS:

The records of all consecutive patients with Mycobacterium tuberculosis diagnosed during January 2001 through April 2005 at the M. D. Anderson Cancer Center were reviewed after obtaining institutional review board approval.

RESULTS:

There were 26 patients with active tuberculosis during the period studied; 18 of them were cancer patients and the others had been referred for a presumed cancer but did not have cancer. The overall rate of active tuberculosis during this period was 0.2 in 1000 new cancer diagnoses. There were 18 men (69%), the median age was 54 years (range, 3-84 yrs), and 16 patients (62%) were born in the U.S. Thirteen (72%) of the 18 cancer patients had solid-organ tumors; 3 of the 5 patients with a hematologic malignancy had non-Hodgkin lymphoma. Three patients (12%) had diabetes mellitus, and 2 patients (8%) had received high-dose (>1 mg/kg of prednisone daily) corticosteroids in the previous week. No patient had a recent history (within the past 4 wks) of chemotherapy; 4 patients had neutropenia. Cough was a prominent symptom (31%), followed by bone pain (19%), dyspnea (15%), and fever (12%). Fifteen patients (58%) had extrapulmonary infection, including 5 patients with concurrent pulmonary involvement; 7 noncancer patients (88%) and 8 cancer patients (44%, P = 0.22) had extrapulmonary disease. In 11 patients (42%), the lungs were the only site of active tuberculosis. Cavitary pneumonia was seen radiographically in 3 of 16 patients (19%) with pulmonary tuberculosis. All M. tuberculosis isolates were susceptible to isoniazid, rifampin, ethambutol, and pyrazinamide; streptomycin resistance was noted in 1 of 22 (5%) isolates tested. Twenty-two patients (85%) received appropriate antituberculosis treatment; all had a clinical and radiographic response. In 3 patients (12%) the cause of death was attributed to M. tuberculosis disease; 2 of 18 cancer patients (11%) died of progressive M. tuberculosis, and they had advanced solid-organ cancer, whereas 1 of 8 patients (13%) without cancer died and the tuberculosis diagnosis was made only on postmortem examination. Univariate analysis showed no significant differences in patients or disease characteristics between non-U.S.-born and U.S.-born patients, whereas noncancer patients (age 52 yrs) and those with extrapulmonary tuberculosis (age 53 yrs) were younger compared with cancer patients (63 yrs; P < 0.007) and those with pulmonary disease (age 60 yrs; P = 0.09).

CONCLUSIONS:

Extrapulmonary tuberculosis was relatively common in younger patients with active M. tuberculosis infection, and was often initially misdiagnosed as cancer.

Inactive pulmonary tuberculosis mimicking metastasis from papillary thyroid carcinoma in diagnostic radioiodine whole-body scintigraphy.

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Picolos MK, Habra M, Safdar A, Sarlis NJ.

Thyroid. 2005 Sep;15(9):1105-6.

Streptococcus pneumoniae bacteremia in patients with cancer: disease characteristics and outcomes in the era of escalating drug resistance (1998-2002).

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Kumashi P, Girgawy E, Tarrand JJ, Rolston KV, Raad II, Safdar A.

Medicine (Baltimore). 2005 Sep;84(5):303-12.

Abstract

In the current era of multidrug-resistant organisms, the clinical spectrum of Streptococcus pneumoniae infection remains unclear, especially in immunosuppressed patients with cancer. We sought to define the characteristics of pneumococcal bacteremia in patients who were receiving care at a comprehensive cancer center. All consecutive episodes of S. pneumoniae bacteremia between January 1998 and December 2002 were evaluated retrospectively. One hundred thirty-five episodes of pneumococcal bacteremia occurred in 122 patients. Sixty-three (52%) of 122 patients had hematologic malignancies; the others had solid tumors. The median Acute Physiology and Chronic Health Evaluation II score was 14 +/- 5. Twenty-four episodes (18%) occurred during neutropenia (<500 cells/microL). Sixty-five patients (53%) were receiving antineoplastic therapy, and 36 (30%) were receiving systemic corticosteroids. Twelve (41%) of 29 hematopoietic stem cell transplant (HSCT) recipients had received transplantation within 12 months of the infection diagnosis; 11 patients had graft-versus-host disease (chronic in 10). In 27 episodes (22%), S. pneumoniae bacteremia was considered as a breakthrough infection. Nine (56%) of 16 hospital-acquired episodes of S. pneumoniae bloodstream infection occurred in patients with profound neutropenia, whereas 15 (13%) of 119 episodes of community-acquired infection occurred during neutropenia (p < 0.0002). In 91 episodes (67%), patients had radiographic evidence of pneumonia. Infected catheters were associated with 21 episodes (16%). Forty-eight (36%) of 135 isolates were not susceptible to penicillin (minimum inhibitory concentration [MIC] > or = 2 microg/mL); 9 (7%) showed intermediate susceptibility to ceftriaxone (MIC >0.5 and <2.0 microg/mL). Nineteen patients (16%) died within 2 weeks of diagnosis; 18 deaths were attributed to systemic pneumococcal infection. Univariate analysis showed no significant increase in the risk of short-term death in patients with infection due to penicillin non-susceptible organisms (OR [odds ratio], 1.47; 95% confidence intervals [CI], 0.53-4.05; p < 0.46), initially discordant treatment (OR, 1.0; 95% CI, 0.62-665.4; p < 0.16), presence of pneumonia (OR, 1.19; 95% CI, 0.39-3.62; p < 0.76), neutropenia (OR, 1.0; 95% CI, 0.28-4.09; p < 0.92), systemic corticosteroid use (OR, 1.96; 95% CI, 0.69-5.60; p < 0.21), or antineoplastic therapy (OR, 1.45; 95% CI, 1.52-4.05; p < 0.47). Similarly, patients with hematologic cancers compared to those with solid cancers (OR, 1.0; 95% CI, 0.49-3.70; p < 0.56) and recipients of HSCT compared to those with no history of transplantation (OR, 1.0; 95% CI 0.59-12.71; p < 0.20) did not have a less favorable outcome. In conclusion, most pneumococcal bloodstream infections were community acquired, although hospital-acquired infections were common in neutropenic patients. It is noteworthy that initially discordant therapy, penicillin non-susceptible S. pneumoniae, and other conventional predictors of unfavorable outcome were not associated with increased mortality rates in these high-risk patients with cancer.