Surgical Site Infections After Liver Transplantation: Emergence of Multidrug-Resistant Bacteria and Implications for Prophylaxis and Treatment Strategies.

BACKGROUND: Perioperative antimicrobial prophylaxis is administered to liver transplant (LTx) recipients to prevent surgical site infections (SSIs), but regimens are not standardized, and there are limited effectiveness data. Prevention and treatment of SSIs have been complicated by the emergence of multidrug-resistant (MDR) pathogens. METHODS: We retrospectively reviewed SSIs among 331 LTx recipients at our center in 2010 to 2014. RESULTS: Culture-proven superficial and deep SSIs occurred in 3% and 15% of patients, respectively, at median 12.5 and 13.5 days post-LTx. Recipients with superficial SSIs and those without SSIs were similar in demographics, clinical characteristics, length of hospital stay, and mortality. Deep SSIs included abscesses (58%), peritonitis (28%), deep incisional infections (8%), and cholangitis (6%). Rates of deep SSIs were comparable among patients receiving prophylaxis with ampicillin-sulbactam, aztreonam and vancomycin, or tigecycline (P = 0.61). Independent risk factors for deep SSIs were bile leak (P < 0.001) and operative time (P < 0.001). Enterobacteriaceae (42%), Enterococcus spp. (24%), and Candida spp. (15%) were predominant pathogens. Fifty-three percent of bacteria were MDR, including 95% of Enterococcus faecium and 55% of Enterobacteriaceae; 82% of deep SSIs were caused by bacteria resistant to antimicrobials used for prophylaxis, and 58% of patients were treated with an inactive empiric regimen. Deep SSIs were associated with longer lengths of stay (P < 0.001), and higher 90-day and long-term mortality rates (P < 0.001). CONCLUSIONS: Deep SSIs, including those caused by MDR bacteria, were common after LTx despite prophylaxis with broad-spectrum antimicrobials. Rather than altering prophylaxis regimens, programs should devise empiric treatment regimens that are directed against the most common local pathogens.

Ganciclovir-resistant cytomegalovirus infections among lung transplant recipients are associated with poor outcomes despite treatment with foscarnet-containing regimens.

Ganciclovir-resistant cytomegalovirus (CMV) infections are reported infrequently among lung transplant recipients receiving extended valganciclovir prophylaxis. We performed a single-center, retrospective review of ganciclovir-resistant CMV infections in a program that employed valganciclovir prophylaxis for ≥6 months after lung transplant. CMV infections were diagnosed in 28% (170/607) of patients. UL97 mutations were detected in 9.4% (16/170) of CMV-infected patients at a median of 8.5 months posttransplant (range, 5 to 21) and despite prophylaxis for a median of 7 months (range, 4 to 21). UL97 mutations were canonical; 25% (4/16) of strains carried concurrent UL54 mutations. Ganciclovir-resistant CMV was more likely with breakthrough infections (75% [12/16] versus 19% [30/154]; P = 0.00001) and donor positive/recipient negative (D+/R-) serostatus (75% versus 45% [69/154]; P = 0.03). The median whole-blood CMV load was 4.13 log10 copies/cm(3) (range, 2.54 to 5.53), and 93% (14/15) of patients had low-moderate immune responses (Cylex Immunoknow). Antiviral therapy was successful, failed, or eradicated viremia followed by relapse in 12% (2/16), 31% (5/16), and 56% (9/16) of patients, respectively. Eighty-seven percent (14/16) of patients were treated with foscarnet-containing regimens; toxicity developed in 78% (11/14) of these. Median viral load half-life and time to viremia eradication among foscarnet-treated patients were 2.6 and 23 days, respectively, and did not correlate with protection from relapse. Sixty-nine percent (11/16) of patients developed CMV pneumonitis, and 25% (4/16) died of it. Serum viral load was independently associated with death among foscarnet-treated patients (P = 0.04). In conclusion, ganciclovir-resistant CMV infections remained a major cause of morbidity and mortality following lung transplantation. Foscarnet-based regimens often eradicated viremia rapidly but were ineffective in the long term and limited by toxicity.

Staphylococcus aureus infections in the early period after lung transplantation: epidemiology, risk factors, and outcomes.

BACKGROUND: Staphylococcus aureus infections among lung transplant recipients are poorly studied. METHODS: We conducted a 5-year retrospective study of the epidemiology, clinical manifestations, risk factors, and outcomes of patients infected with S aureus within the first 90 days after lung transplantation. RESULTS: An S aureus infection developed in 109 of 596 lung transplant (18%) recipients. Methicillin-susceptible S aureus (MSSA; 62%) was more common than methicillin-resistant S aureus (MRSA; 38%); however, the proportion of infections caused by MRSA increased over time. Pneumonia (48%) was the most common infection, followed by tracheobronchitis (26%), bacteremia (12%), intrathoracic infections (7%), and skin/soft tissue infections (7%). Risk factors included mechanical ventilation for > 5 days and isolation of S aureus from recipients' sterility cultures. Patients with MRSA cultured from the nares or respiratory tract at the time of transplant were at an increased risk for MRSA infection (p < 0.0001 and p = 0.02, respectively). Infected patients required longer hospital and intensive care unit stays (p < 0.0001 for both), but the 30- and 90-day mortality rates from the onset of infection were only 7% and 12%, respectively. However, infected patients had higher rates of acute and chronic rejection at 1 (p = 0.048) and 3 years (p = 0.002), and higher rates of mortality at 1 (p = 0.058) and 3 years (p = 0.009). CONCLUSIONS: S aureus infections within the first 90 days of lung transplant were associated with low short-term mortality but increased long-term rates of mortality and acute and chronic rejection. Future studies are needed to explore the utility of S aureus eradication strategies in reducing disease burden and improving outcomes.

Invasive aspergillosis among heart transplant recipients is rare but causes rapid death due to septic shock and multiple organ dysfunction syndrome.

Between 2000 and 2011, proven or probable invasive aspergillosis (IA) was diagnosed in 1.7% (8/455) of heart transplant (HTx) recipients at our center, in the absence of antifungal prophylaxis. All patients had invasive pulmonary infections and 75% (6/8) were diagnosed during 2 separate 3-month periods. Cases were notable for their association with septic shock and multiple organ dysfunction syndrome (MODS) (75%, 6/8 each), non-specific clinical and radiographic findings, and rapid mortality despite mould-active antifungal therapy (88%, 7/8; occuring at a median 11 days after diagnosis). All patients had predisposing conditions known to be risk factors for IA. For patients with early IA (within 90 days of HTx), conditions included hemodialysis, thoracic re-operation, and the presence of another case in the institution within the preceding 3 months. For late-onset IA, conditions included hemodialysis and receipt of augmented immunosuppression. Clinicians should suspect IA in HTx recipients with risk factors who present with non-specific and unexplained respiratory syndromes, including those in septic shock and MODS, and institute prompt antifungal therapy without waiting for the results of cultures or other diagnostic tests.

Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.

Voriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (n = 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (n = 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 µg/ml, respectively. The age of the patient directly correlated with initial troughs (P = 0.005). Patients that were ≥ 60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ≥ 2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ≤ 1.5 µg/ml or >1.5 µg/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 µg/ml (P = 0.07). Invasive fungal infections or colonization were more likely with troughs of ≤ 1.5 µg/ml (P = 0.01) and among patients with no trough of >1.5 µg/ml (P = 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (P = 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 µg/ml. A cutoff for toxicity was not identified, but troughs of >4 µg/ml were rare. The data support a target range of >1.5 to 4 µg/ml.

Ochroconis gallopava: a dematiaceous mold causing infections in transplant recipients.

The dematiaceous mold Ochroconis gallopava is increasingly recognized as a human pathogen. Infection is almost always associated with immunosuppression. We describe a case with a unique presentation in a kidney transplant recipient and retrospectively review all 10 cases of O. gallopava at our institution over 18 yr, all in organ transplant recipients. Sixty percent of infections at our institution occurred in the last five yr studied. Infection generally occurred late after transplantation, and pulmonary infection was the most common manifestation. Use of almetuzumab for induction was associated with infection in the first six months post-transplant (p = 0.03). Attributable mortality at six months was 20%. Ochroconis gallopava is a rare but important pathogen in immunosuppressed individuals and organ transplantation is the most common underlying condition. Pulmonary involvement is the most common manifestation among patients with organ transplant. Optimal therapy remains undefined. Prognosis in organ transplant recipients is good if infection is diagnosed prior to dissemination.

Epidemiology, clinical characteristics and outcomes of extensively drug-resistant Acinetobacter baumannii infections among solid organ transplant recipients.

BACKGROUND: Extensively drug-resistant Acinetobacter baumannii (XDR-Ab) has emerged as a major nosocomial pathogen, but optimal treatment regimens are unknown. Although solid organ transplant (SOT) recipients are particularly susceptible to XDR-Ab infections, studies in this population are limited. Our objectives were to determine the epidemiology, clinical characteristics and outcomes of XDR-Ab infections among SOT patients. METHODS: A retrospective study of SOT recipients at our center who were colonized or infected with XDR-Ab between November 2006 and December 2011 was conducted. Among infected patients, the primary outcome was survival at 28 days. Secondary outcomes included survival at 90 days and clinical success at 28 days, and XDR-Ab infection recurrence. RESULTS: XDR-Ab was isolated from 69 SOT patients, of whom 41% (28) and 59% (41) were colonized and infected, respectively. Infections were significantly more common among cardiothoracic than abdominal transplant recipients (p=0.0004). Ninety-eight percent (40/41) of patients had respiratory tract infections, most commonly ventilator-associated pneumonia (VAP; 88% [36/41]). Survival rates at 28 and 90 days were 54% (22/41) and 46% (19/41), respectively. Treatment with a colistin-carbapenem regimen was an independent predictor of 28-day survival (p=0.01; odds ratio=7.88 [95% CI: 1.60-38.76]). Clinical success at 28 days was achieved in 49% (18/37) of patients who received antimicrobial therapy, but 44% (8/18) of successes were associated with infection recurrence within 3 months. Colistin resistance emerged in 18% (2/11) and 100% (3/3) of patients treated with colistin-carbapenem and colistin-tigecycline, respectively (p=0.03). CONCLUSIONS: XDR-Ab causes VAP and other respiratory infections following SOT that are associated with significant recurrence and mortality rates. Cardiothoracic transplant recipients are at greatest risk. Results from this retrospective study suggest that colistin-carbapenem combinations may result in improved clinical responses and survival compared to other regimens and may also limit the emergence of colistin resistance.

High mortality rates among solid organ transplant recipients infected with extensively drug-resistant Acinetobacter baumannii: using in vitro antibiotic combination testing to identify the combination of a carbapenem and colistin as an effective treatment regimen.

Extensively drug-resistant (XDR) Acinetobacter baumannii infections caused 91% (10/11) mortality in transplant recipients. Isolates were colistin-susceptible initially, but susceptibility decreased during therapy in 40% (4/10). We tested antibiotic combinations against XDR Acinetobacter in vitro and demonstrated positive interactions for carbapenem-colistin. Subsequently, 80% (4/5) of transplant patients were treated successfully with carbepenem-colistin regimens.

A polymorphism linked to elevated levels of interferon-γ is associated with an increased risk of cytomegalovirus disease among Caucasian lung transplant recipients at a single center.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) associated with active cytomegalovirus (CMV) infections after lung transplantation have not been identified. METHODS: SNPs associated with varying levels of interferon (IFN)-γ (+874T/A), tumor necrosis factor-α (-308G/A), interleukin-10 (-1082G/A, -819C/T, -592C/A) and interleukin-6 (-174G/C) were characterized for 170 Caucasian lung transplant recipients who received alemtuzumab induction and valganciclovir prophylaxis against CMV. RESULTS: Patients were followed for a median of 34 months post-transplant, and 66% (113 of 170), 24% (40 of 170) and 10% (17 of 170) had no CMV infection, CMV viremia and CMV disease, respectively. Median times to CMV viremia and disease were 7 and 10 months, respectively. For each gene, there was no significant deviation from Hardy-Weinberg equilibrium. Independent risk factors for the development of CMV disease were IFN-γ +874 T/T genotype (associated with high levels of IFN-γ production), CMV donor-positive/recipient-negative (D(+)/R(-)) serostatus and acute cellular rejection requiring augmented immunosuppression (p = 0.001, 0.003 and 0.049, respectively). The association between IFN-γ +874 T/T genotype and CMV disease was most striking among R(+) patients (p = 0.02). D(+)/R(-) serostatus was also a significant risk factor for CMV viremia (p = 0.0005). IFN-γ +874 T/T genotype was associated with significantly lower peak CMV viral loads (p = 0.03). There were no associations between tumor necrosis factor-α, interleukin-10 or interleukin-6 SNPs and CMV infections. CONCLUSION: A genetic predisposition to elevated IFN-γ levels may play a dual role in controlling active CMV infection among lung transplant recipients receiving alemtuzumab induction and valganciclovir prophylaxis, limiting the extent of viral replication in serum but increasing the risk of CMV disease.

Posaconazole serum concentrations among cardiothoracic transplant recipients: factors impacting trough levels and correlation with clinical response to therapy.

Fifty-six serum posaconazole trough levels were measured in 17 cardiothoracic transplant recipients. Initial levels were ≤ 0.5, 0.51 to 0.99, and ≥ 1 µg/ml for 47, 29, and 24% of patients, respectively. Median trough levels associated with therapeutic success were higher than those associated with failure (1.55 versus 0.34 µg/ml; P = 0.006). Patients with levels consistently >0.5 µg/ml were more likely to have successful outcome (P = 0.055). Age ≥ 65 years, oral administration, and absence of proton pump inhibitors were associated with higher levels of posaconazole (P = 0.006, 0.006, and 0.001, respectively).

Age-specific complications among lung transplant recipients 60 years and older.

BACKGROUND: An age limit of 65 years has been suggested for lung transplantation (LTx). METHODS: We conducted a retrospective study of LTx recipients at our institution and compared survival rates among patients aged <60, 60 to 65, and >65 years. We identified common complications and risk factors for death among patients aged ≥ 60 years. RESULTS: Between January 2006 and May 2008, 126 of 268 (47%) of LTx recipients were aged >60 years, among whom 36% were 60 to 65 and 64% were >65 years. There were no differences in survival among patients aged <60, 60 to 65, and >65 years. Among older patients, the major complications were infections (78%), rejection (36%), thromboembolism (21%), bone fractures (12%), malignancies (10%), and drug toxicity (10%). Rejection was more common among patients who were aged 60 to 65, and malignancies and drug toxicity were more common among patients >65 years. Other complications did not differ by age group. Infections accounted for 69% of deaths within 12 months, and infection-related deaths did not differ among the groups. Major infections were the strongest independent risk factors for death (hazard ratio, 4.37), followed by cytomegalovirus mismatch (hazard ratio, 3.69) and pre-transplant coronary artery disease (hazard ratio, 2.43). CONCLUSIONS: Survival rates among LTx recipients were similar regardless of age, but specific complications among older patients differed by age. Selection for LTx should not be based strictly on an age cutoff, but rather individualized according to general health status and other risk factors. Further research on risk factors affecting outcomes, pharmacokinetics and dynamics, quality of life, and mechanisms of untoward events is needed among older LTx recipients.

Cytomegalovirus disease among donor-positive/recipient-negative lung transplant recipients in the era of valganciclovir prophylaxis.

BACKGROUND: Valganciclovir prophylaxis is advocated for lung transplant recipients, but its efficacy is unknown. METHODS: Retrospective review was done of 109 donor-positive/recipient-negative lung transplant patients who received alemtuzumab induction and valganciclovir for cytomegalovirus prophylaxis. RESULTS: Median duration of follow-up after transplant was 27 months. Valganciclovir dose reductions (< 900 mg/day or renal-equivalent) were required for 18 patients (17%) due to toxicity, most commonly for neutropenia (n = 15) or gastrointestinal symptoms (n = 2). Of the 109 patients, 34 (31%) had no CMV infections, 45 (41%) had asymptomatic viremia, and 30 (27%) had CMV disease. CMV disease developed off prophylaxis in 10 patients (18%) at a median of 8.7 months after transplant and 2 months after valganciclovir discontinuation. Breakthrough disease occurred during prophylaxis in 10 patients (9%) at a median of 6.7 months. Patients with asymptomatic viremia or no CMV infection received prophylaxis for median 8.6 and 8.7 months, respectively. Risk factors for CMV disease by univariate analysis were increased age (p = 0.01), single-lung transplant (p = 0.03), chronic obstructive pulmonary disease (p = 0.05), reduced-dose valganciclovir (p = 0.001), and less than 6 months of prophylaxis (p = 0.005). By multivariate analysis, advanced age (p = 0.01) and reduced-dose valganciclovir (p = 0.0006) were independent risk factors for CMV disease. CMV disease developed in 4 patients (4%) due to ganciclovir-resistant viruses. CMV-attributable mortality was 5% (5 of 109), including 100% (4 of 4) with ganciclovir-resistant disease. CONCLUSIONS: Valganciclovir prophylaxis among donor-positive/recipient-negative lung transplant recipients delayed but did not eliminate CMV disease or CMV-related deaths and was limited by toxicity and ganciclovir-resistance. Our experience suggests that valganciclovir at reduced-doses or for less than 6 months is sub-optimal in preventing CMV disease.

Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients.

BACKGROUND: Skin cancer, in particular squamous cell carcinoma (SCC), is the most common malignancy after solid-organ transplantation. SCC has been reported in immunosuppressed patients receiving voriconazole, but the agent has not been shown to be a risk factor. Universal voriconazole prophylaxis and alemtuzumab induction are standard in our lung transplant program. METHODS: We performed a retrospective, case-control study (matched 1:3) among lung transplant recipients at our center from 2003 to 2008. RESULTS: SCC was diagnosed in 3.1% (17 of 543) of patients at a median follow-up of 36 months. Median time to development of SCC was 19 months post-transplant. Risk factors for SCC by univariate analysis included older age (p = 0.02), residence in locations with high levels of sun exposure (p = 0.0001), single-lung transplant (p = 0.02) and duration (p = 0.03) and cumulative dose (p = 0.03) of voriconazole. Duration of voriconazole (hazard ratio [HR] = 2.1; p = 0.04) and residence in locations with high sun exposure (HR = 3.8; p = 0.0004) were independent risk factors by multivariate analysis. SCC lesions were located on the head and neck in 94% of cases, and 53% had multiple lesions. All patients were treated with surgery. At least one independent lesion developed subsequently in 47% of patients. Local spread and distant metastases each occurred in 7% of cases. There were no deaths among the cases. CONCLUSIONS: Voriconazole exposure is a risk factor for SCC after lung transplantation, particularly among older patients living in areas with high sun exposure. Voriconazole should be used cautiously in these patients.

Impact of mold infections in explanted lungs on outcomes of lung transplantation.

INTRODUCTION: Little is known about the incidence or significance of mold infections in the explanted lungs of lung transplant recipients. METHOD: We reviewed the histopathology of the explanted lungs from 304 patients who underwent lung transplantation at our institution from 2005 to 2007 and received alemtuzumab induction therapy and posttransplant voriconazole prophylaxis. RESULTS: Invasive mold infections were present in the explanted lungs of 5% (14 of 304) of patients, including chronic necrotizing pneumonias (n=7), mycetomas (n=4), and invasive fungal pneumonias (n=3). Only 21% (3 of 14) received immunosuppressive therapy within 1 year before lung transplantation, suggesting that lung damage itself predisposed patients to mold infections. The risk of mold infection was higher in patients with cystic fibrosis (11%, 4 of 35) than other underlying lung diseases (4%, 10 of 269). Pulmonary mold infections were not diagnosed or suspected in 57% (8 of 14) of patients. Despite secondary voriconazole prophylaxis, fungal infections developed in 43% (6 of 14) of patients with mold infections of the explanted lungs compared with 14% (42 of 290) of patients without mold infections (P=0.01). Three patients developed invasive fungal infections while on voriconazole prophylaxis and three developed fungal infections more than 8 months after the discontinuation of voriconazole. The mortality attributable to invasive fungal infections among patients with mold infections of the explanted lungs was 29% (4 of 14). CONCLUSION: Invasive mold infections in the explanted lungs are often not recognized before lung transplantation and are associated with poor outcomes.

Post-transplant colonization with non-Aspergillus molds and risk of development of invasive fungal disease in lung transplant recipients.

BACKGROUND: The clinical significance and risk of progression to invasive disease of the non-Aspergillus molds from the bronchoalveolar lavage (BAL) of lung transplant (LTx) recipients are not known. METHODS: We reviewed the medical records from March 1996 to March 2006 of all LTx recipients whose BAL culture grew non-Aspergillus mold. The clinical characteristics, administration of prophylaxis, and outcomes were recorded. RESULTS: Eighty-five non-Aspergillus molds were isolated from the BAL of 75 patients. Of these LTx recipients, 14.5% had a BAL with non-Aspergillus mold. Emphysema was the most common underlying diagnosis for transplantation (41.3%) and the most common isolate was Cladosporium. Isolation of a non-Aspergillus mold occurred at a median of 415 days after LTx. Prophylaxis with an anti-mold agent was noted in 44.7% (38 of 85) of the isolates. Median follow-up was 765 days. There were no cases of proven invasive fungal infection up to 1 year after isolation of the mold; and only 1 case of probable zygomycosis. CONCLUSIONS: Isolation of non-Aspergillus molds in the BAL of LTx recipients may not be associated with the development of invasive disease, irrespective of anti-fungal prophylaxis. These results suggest that initiation of targeted anti-fungal prophylaxis after isolation of non-Aspergillus molds from BAL may not be warranted.

Relationship of cytomegalovirus load assessed by real-time PCR to pp65 antigenemia in organ transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection in immunocompromised patients can lead to viremia associated with morbidity and mortality. Monitoring of viral loads in blood is critical for initiating and monitoring antiviral treatment. OBJECTIVES: Validate quantitative real-time PCR assay targeting the US17 and UL54 regions of the CMV genome for automated DNA and extraction and amplification. STUDY DESIGN: 3422 blood specimens from organ transplant recipients, including longitudinal specimens from 12 organ transplant recipients, were tested by CMV PCR and pp65 antigenemia. RESULTS: CMV PCR for both US17 and UL54, was more sensitive and detected CMV DNA earlier and for longer than the CMV pp65 antigenemia test. Using antigenemia results as a reference standard, an optimal cutoff of 500 normalized copies was calculated for both US17 and UL54 PCR targets based on high sensitivity, specificity, and positive and negative predictive values. CMV DNA levels tracked well with clinical symptoms, response to treatment, and antigenemia. CONCLUSIONS: Detection of persistent increases in CMV DNA levels above 500 normalized copies by this real-time PCR assay is indicative of symptomatic CMV disease in organ transplant recipients. Quantitative real-time PCR for CMV DNA can be used in lieu of antigenemia for monitoring CMV infection and determining when to initiate preemptive treatment.

Successful outcome of human metapneumovirus (hMPV) pneumonia in a lung transplant recipient treated with intravenous ribavirin.

Human metapneumovirus (hMPV) has recently been shown to be a prominent cause of respiratory infections in immunocompromised hosts, and is associated with high morbidity and mortality. We report a case of hMPV pneumonia in a lung transplant recipient presenting with respiratory failure and sepsis syndrome. hMPV was diagnosed by polymerase chain reaction, and treated with intravenous ribavirin with a successful outcome.

Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study.

BACKGROUND: Risk factors for Nocardia infection in organ transplant recipients have not been formally assessed in the current era of transplantation. METHODS: We performed a matched case-control study (1:2 ratio) between January 1995 and December 2005. Control subjects were matched for transplant type and timing. Univariate matched odds ratios were determined and conditional logistic regression was performed to identify independent risk factors. Clinical and microbiological characteristics of all case patients were reviewed. RESULTS: Among 5126 organ transplant recipients, 35 (0.6%) were identified as having cases of Nocardia infection. The highest frequency was among recipients of lung transplants (18 [3.5%] of 521 patients), followed by recipients of heart (10 [2.5%] of 392), intestinal (2 [1.3%] of 155), kidney (3 [0.2%] of 1717), and liver (2 [0.1%] of 1840) transplants. In a comparison of case patients with 70 matched control subjects, receipt of high-dose steroids (odds ratio, 27; 95% confidence interval, 3.2-235; P=.003) and cytomegalovirus disease (odds ratio, 6.9; 95% confidence interval, 1.02-46; P=.047) in the preceding 6 months and a high median calcineurin inhibitor level in the preceding 30 days (odds ratio, 5.8; 95% confidence interval, 1.5-22; P=.012) were found to be independent risk factors for Nocardia infection. The majority of case patients (27 [77%] of 35) had pulmonary disease only. Seven transplant recipients (20%) had disseminated disease. Nocardia nova was the most common species (found in 17 [49%] of the patients), followed by Nocardia farcinica (9 [28%]), Nocardia asteroides (8 [23%]), and Nocardia brasiliensis (1 [3%]). Of the 35 case patients, 24 (69%) were receiving trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis. Thirty-one case patients (89%) experienced cure of their Nocardia infection. CONCLUSIONS: Receipt of high-dose steroids, history of cytomegalovirus disease, and high levels of calcineurin inhibitors are independent risk factors for Nocardia infection in organ transplant recipients. Our study provides insights into the epidemiology of Nocardia infection in the current era, a period in which immunosuppressive and prophylactic regimens have greatly evolved.

Acinetobacter baumannii bloodstream infection while receiving tigecycline: a cautionary report.

OBJECTIVES: Tigecycline has shown in vitro activity against Acinetobacter baumannii. Yet, published clinical experience with tigecycline use outside clinical trials is lacking. We describe, for the first time, bloodstream infection caused by tigecycline-non-susceptible A. baumannii occurring in patients receiving tigecycline for other indications. The possible mechanisms of resistance and pharmacokinetic limitations of the drug are addressed. METHODS: The clinical records of involved patients were systematically reviewed. Tigecycline susceptibility testing was initially performed using the Etest method and confirmed by agar dilution. Involved isolates underwent PFGE and exposure to phenyl-arginine-beta-naphthylamide (PAbetaN), an efflux pump inhibitor. RESULTS: Two patients developed A. baumannii bloodstream infection while receiving tigecycline. Tigecycline was administered for other indications for 9 and 16 days, respectively, before the onset of A. baumannii infection. Patient 1 died of overwhelming A. baumannii infection and Patient 2 recovered after a change in antibiotic therapy. The MICs of tigecycline were 4 and 16 mg/L, respectively. Both isolates had a multidrug-resistant phenotype and were genotypically unrelated. After exposure to PAbetaN, the MICs reduced to 1 and 4 mg/L, respectively. CONCLUSIONS: To our knowledge, this is the first clinical description of bloodstream infection caused by tigecycline-non-susceptible A. baumannii. Such resistance appears to be at least partly attributable to an efflux pump mechanism. Given the reported low serum tigecycline levels, we urge caution when using this drug for treatment of A. baumannii bloodstream infection.

Opportunistic infections in 547 organ transplant recipients receiving alemtuzumab, a humanized monoclonal CD-52 antibody.

BACKGROUND: Alemtuzumab is being increasingly used for the prevention and/or treatment of acute allograft rejection in organ transplant recipients. We assessed the risks of infection in, to our knowledge, the largest cohort and broadest range of organ transplant recipients yet reported to have received alemtuzumab. METHODS: All patients who received alemtuzumab from September 2002 through March 2004, either as induction therapy at the time of transplantation or for the treatment of rejection, were evaluated for the development of an opportunistic infection (OI) until death or for 12 months after receipt of the last dose of alemtuzumab. RESULTS: A total of 547 recipients were included, 65% of whom received alemtuzumab for induction therapy only. Overall, 56 recipients (10%) developed 62 OIs, including cytomegalovirus disease (n = 16), BK virus infection (n=12), posttransplantation lymphoproliferative disease (n=5), human herpesvirus 6 infection (n=1), parvovirus infection (n=1), esophageal candidiasis (n=12), cryptococcosis (n=2), invasive mold infection (n=4), Nocardia infection (n=4), mycobacterial infection (n=3), Balamuthia mandrillaris infection (n=1), and toxoplasmosis (n=1). Patients who received alemtuzumab for induction therapy were significantly less likely to develop an OI, compared with patients who received alemtuzumab for rejection therapy (4.5% vs. 21%; P<.001). Independent predictors of the development of an OI were administration of alemtuzumab for rejection therapy (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.8-6.8; P<.001), allograft failure (OR, 2.1; 95% CI, 1.1-4.4; P=.04), and receipt of a lung transplant (OR, 3.7; 95% CI, 1.7-8.0; P=.001) or an intestinal transplant (OR, 8.3; 95% CI, 3.5-19.5; P<.001). CONCLUSIONS: Patients who received alemtuzumab for the treatment of allograft rejection were significantly more likely to develop an OI, compared with patients who received alemtuzumab for induction therapy only. Such data have implications for new antimicrobial prophylactic strategies.