Jesús Fortún

Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology.

Tuberculosis is a particularly important condition in solid-organ transplant recipients because of the delay in treatment caused by the difficulties involved in its diagnosis and because of the pharmacological toxicity associated with this treatment. Both treatment delay and toxicity are responsible for the many clinical complications of and high mortality associated with tuberculosis in this population. The Consensus Statement from the Spanish Group for the Study of Infectious Diseases in Transplant Recipients defines the indications for treatment of latent tuberculosis infection in solid-organ transplant recipients, especially in patients with a high risk of pharmacological toxicity, as is the case with liver recipients. We established a series of recommendations regarding the types of drugs and the duration of treatment of tuberculosis in solid-organ recipients, giving special attention to pharmacological interactions between rifampin and immunosuppressive drugs (cyclosporine, tacrolimus, rapamycin, and corticosteroids).

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.

Tuberculosis after Solid-Organ Transplant: Incidence, Risk Factors, and Clinical Characteristics in the RESITRA (Spanish Network of Infection in Transplantation) Cohort

BACKGROUND It is necessary to clarify the incidence of and risk factors for tuberculosis (TB) among solid-organ transplant (SOT) recipients as well as changes in the chronology, clinical presentation, and prognosis of the disease. METHODS A total of 4388 SOT recipients were monitored prospectively at 16 transplant centers included in the Spanish Network for Research in Infectious Diseases (REIPI). TB episodes were studied, and the incidence rate was calculated. Certain variables were analyzed, by Cox regression analysis, as potential risk factors for TB. RESULTS Among the 4388 SOT recipients, 21 cases of TB were reported (0.48%). The median duration of follow-up was 360 days (range, 0-720 days). The global incidence of TB was 512 cases per 10(5) patients per year (95% confidence interval [CI], 317-783), which was higher than that in the general population in Spain (18.9 cases per 10(5) inhabitants per year; relative risk [RR], 26.6). The highest incidence (2072 cases per 10(5) patients per year; 95% CI, 565-5306) was observed among lung transplant recipients (RR, 73.3). Of the TB cases, 95% occurred within the first year after transplant, and 76% were pulmonary forms. Crude mortality was 19.0%, and attributable mortality was 9.5%. Multivariate analysis identified recipient age (RR, 1.05; 95% CI, 1.0-1.1) and receipt of a lung transplant (RR, 5.6; 95%, 1.9-16.9) as independent risk factors. CONCLUSIONS TB incidence is increased among SOT recipients. The risk factors identified were age and receipt of a lung transplant. TB-attributable mortality (9.5%) is still high.

Bloodstream infections among transplant recipients: results of a nationwide surveillance in Spain.

Bloodstream infections (BSIs) are a major cause of morbidity and mortality in transplant recipients. The aim of this study is to describe the incidence, microbiology and outcomes of BSIs in transplant recipients in Spain. The Spanish Network for Research on Infection in Transplantation (RESITRA) is formed by 16 centers with transplant program in Spain. The incidence and characteristics of BSIs in transplant patients were obtained prospectively from the cohort. We included 3926 transplant recipients (2935 solid organ and 991 hematopoietic stem cell transplants). Overall, 730 episodes of BSIs were recorded with an incidence rate ranging from 3 episodes per 10 000 transplant days in kidney recipients to 44 episodes per 10 000 transplant days in allogeneic hematopoietic stem cell transplantation (HSCT). The most frequent sources were intravascular catheters and the most frequent microorganisms isolated were coagulase‐negative staphylococci. Crude mortality of BSIs was 7.8%, being highest in liver recipients (16%). Multidrug resistant nonfermentative gram‐negative BSIs had significantly worse prognosis than those caused by their susceptible counterparts (p = 0.015), but no differences were found between resistant and susceptible gram‐negative enteric bacilli, S. aureus or Candida spp. BSIs are still a major concern in transplant recipients. The increasing isolations of multiresistant microorganisms represent a challenge for the next years.

Nosocomial transmission of Mycobacterium bovis resistant to 11 drugs in people with advanced HIV-1 infection

BACKGROUND Since 1990, several nosocomial outbreaks of multidrug-resistant (MDR) tuberculosis have occurred, none of which have involved Mycobacterium bovis. We describe an epidemic of nosocomial and primary MDR M bovis tuberculosis from December, 1993, to February, 1995, among HIV-1-infected patients in a district of Madrid. METHODS We undertook genetic characterisation of the M bovis strain and investigated its presence in a tuberculosis epidemic in a Madrid hospital in a case-controlled study. We assessed 19 cases diagnosed with MDR tuberculosis due to M bovis during the study period. For the control group, we randomly selected 33 patients with HIV-1 infection and isolation of a strain of M tuberculosis susceptible to isoniazid, rifampicin, or both, who were treated in Ramón y Cajal Hospital. Infection-control policies and practices were implemented. FINDINGS We detected 19 cases in HIV-1-infected patients of primary MDR tuberculosis produced by M bovis resistant to 11 antituberculosis drugs. We found phenotypic and genotypic similarities in the strains of M bovis. In the case group, the index case and two other cases had had previous contact with another hospital that had had an MDR tuberculosis outbreak. All patients died after a mean of 44 days (range 2-116), despite multidrug treatment with first-line and second-line antituberculosis drugs. The cases with M bovis MDR tuberculosis were significantly more likely than controls to have been admitted to a hospital ward at the same time as patients already infected with MDR tuberculosis during the 10 months before their diagnosis (adjusted odds ratio 94.6 [95% CI 9.4-956.3], p < 0.0001). Advanced HIV-1 immunosuppression was associated with the development of MDR tuberculosis. Implementation of control measures stopped the epidemic. INTERPRETATION An M bovis primary MDR tuberculosis epidemic that cannot be treated effectively and with high mortality has emerged in Europe and has been transmitted between hospitals.

Impact of Current Transplantation Management on the Development of Cytomegalovirus Disease after Renal Transplantation

BACKGROUND Current advances in transplantation practices may influence the development of cytomegalovirus (CMV) disease after renal transplantation. METHODS From September 2003 through February 2005, 1470 renal transplant recipients (55 of whom were kidney-pancreas transplant recipients) were prospectively studied in the 16 transplant centers affiliated with the Spanish Network of Infection in Transplantation, with use of an ad hoc-designed online database. Univariate and multivariate analyses with logistic regression were performed to detect risk factors for CMV disease. RESULTS A total of 105 episodes of CMV disease (37 with visceral involvement) developed in 99 (6.7%) of 1470 patients. Attributable mortality appeared in 1 (1.0%) of 105 cases. Multivariate analysis showed that, apart from CMV serological mismatch, presence of rejection episodes, and the use of antilymphocitic drugs, a simultaneous pancreas transplantation (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.5-9), use of cyclosporine (OR, 1.7; 95% CI, 1.18-2.9), a donor >60 years of age (OR, 2.3; 95% CI, 1.5-3.7), and chronic graft malfunction (OR, 1.8; 95% CI, 1.14-2.9) were independently associated with CMV disease, whereas use of sirolimus had a protective effect (OR, 0.27; 95% CI, 0.1-0.78). CONCLUSIONS Additional risk factors related to current transplantation practices influence the epidemiology of CMV after renal transplantation and should be taken into account in the design of prophylactic strategies in this population of kidney or kidney-pancreas recipients.

Short-Course Therapy for Right-Side Endocarditis Due to Staphylococcus aureus in Drug Abusers: Cloxacillin versus Glycopeptides in Combination with Gentamicin

A prospective, randomized clinical trial among drug abusers was conducted to assess the efficacy and safety of a short course of a combination of a glycopeptide (vancomycin or teicoplanin) and gentamicin compared with a combination of cloxacillin and gentamicin for treatment of right-side endocarditis caused by Staphylococcus aureus. Therapeutic success was significantly more frequent with cloxacillin than with a glycopeptide. No adverse effects were noted among patients in the cloxacillin group. A 14-day course of vancomycin or teicoplanin plus gentamicin is ineffective in this instance because it is associated with a high rate of clinical and microbiological failure.

Risk Factors, Clinical Features, and Outcomes of Listeriosis in Solid-Organ Transplant Recipients: A Matched Case-Control Study

BACKGROUND Solid-organ transplant (SOT) recipients are classically considered to be at increased risk for listeriosis. However, risk factors for this infection have not been assessed. METHODS We carried out a multicenter, matched case-control study (1:2 ratio) from January 1995 through December 2007. Control subjects were matched for center, transplant type, and timing. Conditional logistic regression was performed to identify independent risk factors. Clinical features and outcomes for all case patients were reviewed. RESULTS Thirty patients (0.12%) with cases of listeriosis were identified among 25,997 SOT recipients at 15 Spanish transplant centers. In a comparison of case patients with 60 matched control subjects, the following independent risk factors for listeriosis were identified: diabetes mellitus (odds ratio [OR], 5.6; 95% confidence interval [CI], 1.6-19.6; ), P = .007 history of cytomegalovirus infection or disease within the preceding 6 months (OR, 35.9; 95% CI, 2.1-620; P = .014), receipt of high-dose prednisone within the preceding 6 months (OR, 6.2; 95% CI, 1.8-21.1; P = .003), and trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis (OR, 0.07; 95% CI, 0.006-0.76; P = .029). Twenty-six patients (86.7%) had bacteremia, and 7 had shock at presentation. Other manifestations included meningoencephalitis (10 cases), spontaneous peritonitis (2), pleural empyema (1), brain abscesses (1), and liver abscesses (1). The 30-day mortality rate was 26.7% (8 of 30 patients died). CONCLUSIONS Listeriosis in SOT recipients is uncommon but causes high mortality. Diabetes mellitus, cytomegalovirus infection or disease, and receipt of high-dose steroids are independent risk factors for this infection, whereas TMP-SMZ prophylaxis is a protective factor.

Population Structure of Enterococcus faecium Causing Bacteremia in a Spanish University Hospital: Setting the Scene for a Future Increase in Vancomycin Resistance?

ABSTRACT Over an 8-year period (1995 to 2002), 86 Enterococcus faecium blood isolates from 84 patients, of which 54 were ampicillin resistant (AREF) and 32 were ampicillin susceptible (ASEF), were studied in a university hospital (1,200 beds; serving a population of 600,000) in Spain, a country characterized by a near-absence of resistance to vancomycin and very high rates of ampicillin resistance among enterococci. Clonal relatedness by pulsed-field gel electrophoresis (PFGE), antibiotic susceptibility, presence of the virulence/epidemicity genes espEfm and hylEfm, and identification of purK alleles were studied. A group of isolates was also analyzed by amplified fragment length polymorphism (AFLP) and multilocus sequence typing. Medical charts (30 variables collected) were reviewed for 60/84 patients. ASEF showed high clonal diversity (32 PFGE types, 11 purK alleles, 4 AFLP genogroups), did not harbor putative virulence genes, and had no specific association with hospital acquisition. AREF isolates belonged to a clonal complex (CC) of genetically related strains (purK-1, AFLP genogroup C), occasionally harboring putative virulence traits, and were from patients with particular risk factors. Within this CC, previously associated with vancomycin-resistant E. faecium isolates causing outbreaks worldwide (W. L. Homan et al., J. Clin. Microbiol. 40:1963-1971, 2002), a great genetic diversity of antibiotic resistance and virulence/epidemicity profiles was found. Associations between esp and a >7-day hospital stay and between purK-1, hospital location, and nosocomial acquisition were noted (P < 0.001). These findings reflect the importance of local environmental differences in the evolution of this CC, suggesting that the emergence of vancomycin resistance among AREF strains in Spain may be a question of time.

Prophylaxis With Caspofungin for Invasive Fungal Infections in High-Risk Liver Transplant Recipients

Objective. The aim of this prospective, multicenter, noncomparative, open-label trial was to evaluate the prophylactic use of caspofungin in adult liver transplant recipients at high risk of developing invasive fungal infections (IFI). Methods. Patients received caspofungin for at least 21 days. A successful treatment outcome was defined as the absence of breakthrough IFI during the first 100 days after the onset of caspofungin. Results. According to study design, 71 patients were included. In the modified intention-to-treat analysis, successful treatment outcome was obtained in 88.7%. Two patients developed IFI: a Mucor and a Candida albicans surgical wound infections, respectively. Six more patients discontinued caspofungin because of drug-related altered liver function. No clinical side effects were related to caspofungin. Altered analytical data compatible with grade IV toxicity, irrespective of caspofungin attribution, were observed in 27.7% of patients at the end of caspofungin prophylaxis and in 15.4% of patients in safety visit (14 days after ending caspofungin administration) (P=0.13). Eight patients died, six during caspofungin administration and two during follow-up period, but none were attributed to IFI or caspofungin toxicity. Conclusion. These results show that caspofungin could be considered an efficacious and well-tolerated drug as antifungal prophylaxis in high-risk liver transplant recipients.