Infectious complications of stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is an accepted treatment for a variety of hematologic malignancies. The profound immunosuppression these patients experience adversely affects their risk of infection. This risk is much higher than in the general population and requires aggressive diagnostic and therapeutic interventions. The chapter will outline the major infections after HSCT.

Combination therapeutic approaches for the management of invasive aspergillosis in organ transplant recipients.

Outcomes in organ transplant recipients with invasive aspergillosis remain sufficiently dismal that combination antifungal approaches present an attractive therapeutic option. The efficacy of such approaches has not been incontrovertibly documented. However, limited data suggest that combination antifungal therapy may be considered in subsets of high-risk patients e.g. those renal and replacement therapy in whom mortality rates have typically exceeded 90%. Synergistic interactions of antifungal agents with the immunosuppressants suggest a role for devising antifungal strategies that target novel signalling pathways. Finally, manipulating known predisposing immunological defects with immunotherapeutic agents is a potentially promising approach for the management of these challenging opportunistic mycoses.

Successful allogeneic transplantation of patients with suspected prior invasive mold infection.

Prior invasive fungal infection (IFI) has historically limited the use of allogeneic stem cell transplantation for patients with hematologic malignancies. Transplantation of such patients frequently resulted in recurrent infection and high mortality rates. Several new antifungal agents have been introduced over the past 5 years with broader spectra of activity against molds such as Aspergillus and a favorable toxicity profile. In this study, we present a series of 16 consecutive patients with hematologic malignancy and prior invasive fungal infection who underwent allogeneic transplantation. Of these patients, the majority of whom were treated with voriconazole and/or caspofungin, only four experienced recurrent fungal infection and recurrent fungal infection was the primary cause of death in only one patient. The estimated 45% 2-year survival in this series is similar to that for other patients with high risk hematologic malignancy undergoing stem cell transplantation. We conclude that suspected prior invasive fungal infection should not preclude the use of allogeneic stem cell transplantation.

Cobicistat Significantly Increases Tacrolimus Serum Concentrations in a Renal Transplant Recipient with Human Immunodeficiency Virus Infection.

Cobicistat is a pharmacokinetic booster in several fixed-dose combination products for treatment of human immunodeficiency virus (HIV) infection. As a potent inhibitor of cytochrome P450 (CYP) 3A enzymes, significant drug-drug interactions are expected between cobicistat and medications that are metabolized primarily through the CYP3A pathway, including calcineurin inhibitors (e.g., tacrolimus and cyclosporine). We describe a case of tacrolimus toxicity due to supratherapeutic tacrolimus concentrations when Stribild (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate) was initiated for newly diagnosed HIV infection in a 50-year-old renal transplant recipient who was previously receiving a stable tacrolimus regimen. Drug-drug interaction via CYP3A inhibition was acknowledged, and weekly labs were ordered to allow for close monitoring of renal function and tacrolimus serum concentrations as recommended by Stribild prescribing information. The patient reported headache, insomnia, stomachache, and decreased urine output within 1 week of starting Stribild and was found to have acute kidney injury (serum creatinine [Scr ]concentration increasing from 1.5-2.3 mg/dl) and a serum tacrolimus concentration of 111.2 ng/ml at 1 week follow-up (goal trough level 4-6 ng/ml). Both tacrolimus and Stribild were withheld. In 15 days, the patient's tacrolimus serum concentration returned to goal. In the interim, he required twice/week clinic visits for laboratory assessments and an emergency department visit for management of hyperkalemia (potassium 6.5 mEq/L). Triumeq (abacavir, dolutegravir, and lamivudine) was started about 4 weeks later after Scr returned to baseline, and his tacrolimus serum trough concentrations subsequently remained stable. To our knowledge, this is the first case report describing the extent, significance, and onset of cobicistat and tacrolimus drug-drug interaction in clinical practice. As more fixed-dose combination products including cobicistat as a pharmacokinetic booster come to market, clinicians should be reminded of its multitude of clinically significant drug-drug interactions.

Antifungal management practices and evolution of infection in organ transplant recipients with cryptococcus neoformans infection.

BACKGROUND: Therapeutic practices for Cryptococcus neoformans infection in transplant recipients vary, particularly with regards to antifungal agent employed, and duration of therapy. The risk of relapse and time to recurrence is not known. We assessed antifungal treatment practices for cryptococcosis in a cohort of prospectively followed organ transplant recipients. METHODS: The patients comprised 83 transplant recipients with cryptococcosis followed for a median of 2.1 and up to 5.2 years. RESULTS: Patients with central nervous system infection (69% vs. 16%, P = 0.00001), disseminated infection (82.7% vs. 20%, P = 0.00001), and fungemia (29% vs. 8%, P = 0.046) were more likely to receive regimens containing amphotericin B than fluconazole as primary therapy. The use of fluconazole, on the other hand, was more likely for infection limited to the lungs (64% vs. 14%, P = 0.00002). Survival at 6 months tended to be lower in patients whose CSF cultures at 2 weeks were positive compared to those whose CSF cultures were negative (50% vs. 91%, P = 0.06). Maintenance therapy was employed in 68% (54/79) of the patients who survived >3 weeks. The median duration of maintenance therapy was 183 days; 55% received maintenance for > or = 6 months and 25% for >1 year. Relapse was documented in 1.3% (1/79) of the patients. CONCLUSIONS: A majority of the organ transplant recipients with cryptococcosis receive maintenance antifungal therapy for 6 months with low risk of relapse. These data can assist in trials to assess the optimal therapeutic approach and duration of therapy for cryptococcosis in transplant recipients.

Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome.

BACKGROUND: Clinical characteristics, risks, and outcomes in solid organ transplant (SOT) recipients with zygomycosis in the era of modern immunosuppressive and newer antifungal agent use have not been defined. METHODS: In a matched case-controlled study, SOT recipients with zygomycosis were prospectively studied. The primary outcome measure was success (complete or partial response) at 90 days. RESULTS: Renal failure (odds ratio [OR], 3.17; P = .010), diabetes mellitus (OR, 8.11; P < .001), and prior voriconazole and/or caspofungin use (OR, 4.41; P = .033) were associated with a higher risk of zygomycosis, whereas tacrolimus (OR, 0.23; P = .002) was associated with a lower risk of zygomycosis. Liver transplant recipients were more likely to have disseminated disease (OR, 5.48; P = .021) and developed zygomycosis earlier after transplantation than did other SOT recipients (median, 0.8 vs 5.7 months; P < .001). Overall the treatment success rate was 60%. Renal failure (OR, 11.3; P = .023) and disseminated disease (OR, 14.6; P = .027) were independently predictive of treatment failure, whereas surgical resection was associated with treatment success (OR, 33.3; P = .003). The success rate with liposomal amphotericin B was 4-fold higher even when controlling for the aforementioned variables. CONCLUSIONS: The risks identified for zygomycosis and for disseminated disease, including those that were previously unrecognized, have implications for further elucidating the biologic basis and for optimizing outcomes in SOT recipients with zygomycosis.

Mycobacterium haemophilum: a rare cause of endophthalmitis.

Nontuberculous mycobacterial (NTM) infections are becoming an increasingly important complication in ophthalmology, particularly among immunocompromised patients. We report a case of NTM in a 66-year-old male immunosuppressed after cardiac transplantation. Chronic granulomatous iridocyclitis progressed to purulent endophthalmitis despite intraocular and systemic antimicrobial therapy. Direct immunoflourescent staining of the vitrectomy specimen revealed acid-fast bacilli. Biopsies of nodular skin lesions revealed non-caseating granulomas with acid-fast bacilli. Cultures of skin and eye biopsies yielded Mycobacterium haemophilum. Despite aggressive combination antimicrobial therapy, the eye was eventually enucleated. Resolution of systemic infection occurred with the addition of granulocyte macrophage-colony stimulating factor. This is the first reported case of M. haemophilum endophthalmitis.

Infections and severe sepsis in solid-organ transplant patients admitted from a university-based ED.

The objective was to provide a descriptive analysis of infectious processes in transplant patients admitted from the emergency department (ED). A database of all adult transplant patients at a university medical center was cross-referenced with a computerized record of all ED visits over an 18-month period. ED charts, inpatient records, and microbiology data were retrospectively reviewed. Final diagnoses and outcomes were analyzed. There were 352 ED visits by transplant patients (kidney 66%, kidney/pancreas 15%, liver 13%, lung 3%, heart 3%). Infections were the most common indications for admission (77/217, 35%). Urinary tract infection and pneumonia were the most common infections. Nine of 77 patients (11.7%) with documented infections developed severe sepsis, which was the most common reason for ICU utilization. Thirty-five percent of transplant patients admitted from the ED had acute infections, and 11.7% of these patients had severe sepsis. The emergency physician must have a high index of suspicion for infections when evaluating organ transplant recipients.

A standardized protocol for the treatment of severe pneumonia in kidney transplant recipients.

Although the incidence of pneumonia after kidney transplantation is the lowest among all solid organ transplants, it is associated with high mortality rate (40-50%). We evaluated the efficacy of a protocol consisting of bronco-alveolar-lavage (BAL) for early microbiological diagnosis, reduction of the immunosuppressive therapy, and prompt administration of standardized antibiotic regimen in renal transplant recipients with severe pneumonia. Between 6/1989 and 5/1999, 40 kidney transplant recipients developed 46 episodes of severe pneumonia (hypoxia and/or infiltrate on the chest X-ray). According to protocol, in all these cases, a BAL was immediately performed and empirical antibiotic therapy was initiated with erythromycin and trimethoprim-sulfamethoxazole i.v. Furthermore, the immunosuppressive therapy was drastically reduced. Analyses of BAL fluid included cell differential count, cytopathologic examination and cultures for bacteria, fungi and viruses. Within 48 h, the therapy was switched to proper i.v. antibiotics, if necessary, according to the results of sensitivity testing of BAL specimens. The mortality rate was 12.5% (5 of 40). Mechanical ventilation was required in 20 cases (34.5%) and four of the patients that required intubation died. BAL alone established a diagnosis in 67.4% (31 of 46) of the patients. Bacteria were responsible for 61% of the episodes, with fungi responsible for 29% and viruses for 10%. Seven cases of Pneumocystis carinii pneumonia were treated with the prolongation of the initial therapy. We conclude that a combination of early detection of the responsible pathogen by BAL, aggressive reduction of the immunosuppressive therapy and the immediate empirical administration of erythromycin and trimethoprim-sulfamethoxazole is an effective strategy to treat pneumonia kidney transplantation (KTX) recipients.

Analysis and characterization of antiviral drug-resistant cytomegalovirus isolates from solid organ transplant recipients.

The development of cytomegalovirus (CMV) disease and subsequent emergence of drug-resistant strains was examined in a large group of solid organ transplant recipients; drug-resistant CMV was detected in a total of 30 transplant recipients (20 lung, 5 kidney, 4 heart, and 1 liver). Drug resistance was confirmed both phenotypically and genotypically. The sequences of drug-resistant CMV strains from the same patient differed from drug-susceptible baseline sequences only at single sites previously confirmed to confer drug resistance. At least 1 isolate from each patient had a mutation in the UL97 phosphotransferase coding sequence. Mutations in the DNA polymerase gene were found in 6 of 38 sequenced strains. Lung transplant recipients had the highest incidence of drug-resistant virus: of the 30 patients, 28 were CMV-seronegative transplant recipients of CMV-seropositive organs, which strongly supports the premise that drug resistance is most prevalent in that transplant population.