Why don't we have more inhaled antibiotics to treat ventilator-associated pneumonia?

BACKGROUND: The increasing prevalence of ventilator-associated pneumonia (VAP) due to either multidrug-resistant (MDR) organisms or infections with limited treatment options (i.e. susceptible to only aminoglycosides or colisitin) coupled with a dearth of new antimicrobials has led clinicians to pursue alternative management strategies including the use of inhaled antibiotics (IA). OBJECTIVES: To review the evidence surrounding the use of IA in the treatment of VAP with a focus on establishing a path whereby adjunctive IA could become a standard therapy for the treatment of specific VAP patient populations. SOURCES: A meta-analysis performed by the 2016 IDSA/ATS Hospital-acquired Pneumonia Guideline Committee; a PubMed and clinicaltrials.gov search for subsequent trials of IA for the treatment of VAP. CONTENT: Based on a meta-analysis of nine studies (RR 1.29; 95% CI 1.13-1.47), the 2016 IDSA/ATS Hospital-acquired Pneumonia Guideline Committee recommended that adjunctive IA be used to treat VAP due to Gram-negative bacilli that are susceptible to only aminoglycosides or polymyxins. Two subsequent randomized trials of adjunctive IA for the treatment of mechanically ventilated patients with pneumonia failed to demonstrate a benefit. Despite these results, an updated meta-analysis (n = 11) including these two recent trials suggests a benefit of adjunctive IA for the treatment of VAP due to MDR and difficult-to-treat infections (RR 1.2; 95% CI 1.05-1.57). IMPLICATIONS: Patients with VAP and limited intravenous antibiotic options are the individuals most likely to benefit from adjunctive IA and should be the focus of future investigative studies. Although vibrating mesh nebulizers predominate in pharmaceutical company-sponsored trials, these devices have not been directly compared with the traditional jet nebulizers in terms of efficacy or safety.

Adenovirus-A Deadly Disease in the Solid Organ Transplant Population: Risk Factors and Outcomes.

BACKGROUND: The importance of adenoviruses (AdV) in the immunocompromised population has been more recognized in recent decades. We aimed to assess the risk factors and outcomes associated with AdV in solid organ transplant recipients. METHODS: This was a retrospective cohort study of solid organ transplant recipients who tested positive for AdV between January 1, 2004, and March 12, 2014. The subjects were divided in 2 groups: AdV asymptomatic infection and AdV disease. The characteristics and outcomes of the groups were compared using Wilcoxon rank-sum and Fisher exact tests; logistic regression was performed to evaluate risk factors. RESULTS: A total of 125 patients were included with a mean (SD) age of 9.79 years (16.54); 49.6% were male, and 20.8% had AdV disease. No significant risk factors were found for AdV disease by univariate analyses. Comparing patients with disease and with asymptomatic infection, rejections during the first year after testing positive for AdV were 7 (26.92%) vs 17 (17.17%); mortality at 1 year post-transplantation was 26.92% vs 6.06% (P = .006), respectively, and at 1 year after testing positive for AdV was 38.46% vs 11.11% (P = .002), respectively. CONCLUSION: No independent risk factor for AdV disease was identified, but patients with AdV disease had a significantly higher mortality compared with those with asymptomatic infection.

Risk Factors for the Development of Cytomegalovirus Resistance in Solid Organ Transplantation: A Retrospective Case-Control Study.

BACKGROUND: Cytomegalovirus (CMV) resistance is an emerging problem in solid organ transplant recipients. Risk factors are not well defined. METHODS: Recipients with CMV viremia of solid organ transplants who underwent CMV resistance testing between January 2010 and March 2016 were divided in 2 groups: proven CMV resistance and refractory CMV infection. A third group was added to compare patients with viremia during the study period with patients with no resistance proven or suspected. We aimed to identify risk factors associated with the occurrence of CMV genotypic resistance. RESULTS: Forty-nine patients underwent resistance testing. Eleven (22.45%) developed genotypic mutations. Group 1 vs groups 2 and 3 had higher prednisone (P = .01) and tacrolimus levels (P = .03); did not respond to antivirals (P < .0001); and had a higher rate of fungal infections (P = .03). CMV resistance was less common in liver and kidney vs heart, small bowel, and mutivisceral recipients (P = .0007). There was no difference in duration of antiviral prophylaxis, viremia while on antiviral prophylaxis, rate of end-organ disease, graft loss, and overall survival. Persistent clinical disease and viremia despite antiviral therapy was the most important risk factor for development of CMV resistance. CONCLUSION: Persistent clinical disease despite antiviral therapy is an important risk factor and may in part be due to a high degree of immunosuppression. Graft loss and survival were not impacted by CMV resistance.

Severe infections in critically ill solid organ transplant recipients.

BACKGROUND: Severe infections are among the most common causes of death in immunocompromised patients admitted to the intensive care unit. The epidemiology, diagnosis and treatment of these infections has evolved in the last decade. AIMS: We aim to provide a comprehensive review of these severe infections in this population. SOURCES: Review of the literature pertaining to severe infections in critically ill solid organ transplant recipients. PubMed and Embase databases were searched for documents published since database inception until November 2017. CONTENT: The epidemiology of severe infections has changed in the immunocompromised patients. This population is presenting to the intensive care unit with specific transplantation procedure-related infections, device-associated infections, a multitude of opportunistic viral infections, an increasing number of nosocomial infections and bacterial diseases with a more limited therapeutic armamentarium. Both molecular diagnostics and imaging techniques have had substantial progress in the last decade, which will, we hope, translate into faster and more precise diagnoses, as well as more optimal empirical treatment de-escalation. IMPLICATIONS: The key clinical elements to improve the outcome of critically ill solid organ transplant recipients depend on the knowledge of geographic epidemiology, specific surgical procedures, net state of immunosuppression, hospital microbial ecology, aggressive diagnostic strategy and search for source control, rapid initiation of antimicrobials and minimization of iatrogenic immunosuppression.

Risk factors for Clostridium difficile infection in intestinal transplant recipients during the first year post-transplant.

BACKGROUND: Clostridium difficile is the most common cause of healthcare-associated infectious diarrhea. Risk factors for C. difficile infections (CDI) in intestinal transplant recipients (ITR) are not well-defined. The aim of our study was to assess specific risk factors for CDI in ITR. METHODS: This is a 1:3 case-control study that included 29 ITR who developed CDI (cases) and 87 ITR without CDI (controls) observed during the first year post-transplantation. Wilcoxon rank sum and Fisher's exact tests were used to compare variables. Univariate and multivariable conditional logistic regressions analysis were performed to identify risk factors for CDI. RESULTS: The multivariable conditional logistic regression analysis showed that proton pump inhibitors (PPI) administration (odds ratio [OR] = 0.06; 95% confidence interval [CI]: 0.007-0.52; P = .01) was the only factor associated with lower rates of CDI. Outcomes for cases vs controls: rejection episodes 24.14% vs 20.69% (P = .7), graft loss 0% vs 2.3% (P = .99), and survival rate 1 year post-transplantation 79.3% (59.6-90.1%) vs 87.2% (78.1-92.7%) (P = .38). CONCLUSIONS: Proton pump inhibitor administration might be protective for CDI in ITR. Risks factors for CDI might be different in ITR compared to other populations; anatomical differences and medications administered in the post-transplantation period may affect intestinal microbiota.

Impact of Immunoglobulin Therapy in Intestinal Transplant Recipients With Posttransplantation Hypogammaglobulinemia.

BACKGROUND: Severe hypogammaglobulinemia (HGG) (IgG <400 mg/dL) following intestinal transplantation is common. Although IgG replacement therapy is commonly used, clinical outcomes associated with increasing IgG levels to >400 mg/dL are not well described. METHODS: Kaplan-Meier analysis was performed to estimate survival, the log-rank test to compare survival distributions between groups, and the Fisher exact test to determine the association between HGG and rejection. RESULTS: A total of 23 intestinal transplant (IT) recipients with a median age of 2.3 years (range, 0.7-41 years) at the time of HGG diagnosis were included. The types of transplants were liver-small bowel (73.9%), liver-small bowel-kidney (8.7%), and small bowel only (17.4%). The 3-year survival after the diagnosis of HGG was 50.2% (95% confidence interval [CI] = 28.2%-68.7%). There was no difference in survival (P = .67) when patients were dichotomized based upon IgG level at last follow-up (IgG ≥400 mg/dL, n = 14; and IgG <400 mg/dL, n = 9). There was no also evidence of an association between survival and: total dose (P = .58), frequency (P = .11), and number of IgG doses administered (P = .8). There was no difference in survival between patients receiving (n = 12) or not receiving (n = 11) cytomegalovirus hyperimmunoglobulin (P = .10). CONCLUSIONS: Improved survival rates were not found in our IT recipients with severe HGG with immunoglobulin therapy to IgG levels of ≥400 mg/dL, even when cytomegalovirus hyperimmunoglobulin was administered.

Colistin, an Old Drug in a New Territory, Solid Organ Transplantation.

BACKGROUND: The clinical experience with colistin therapy for multidrug-resistant Gram-negative pathogens in solid organ transplantation is limited. METHODS: Patients transplanted from January 2003 to July 2011 and treated with intravenous or nebulized colistin were included. Descriptive statistics were used to summarize patients' characteristics and Kaplan-Meier curves for survival analysis. RESULTS: Fifteen patients were included: 10 adults (median age, 54.6 y; range, 32.2-79.6 y) and 5 children (median age, 3.3 y; range, 1.1-10.4 y). Eight patients had intra-abdominal infections, 3 had pneumonia, and 4 had bacteremia. The infections were diagnosed at a median of 5.9 months (range, 0.8-49.8 mo) after transplantation. Eight patients had coinfections, mainly with enteric pathogens. Pseudomonas aeruginosa was isolated in 13 cases and ESBL Klebsiella oxytoca and ESBL Escherichia coli were isolated in 1 case each. Thirteen patients received concomitant antibiotics with colistin. The median dose of intravenous colistin (13 patients) was 2.7 mg/kg/d (range, 1-4.9 mg/kg/d) and nebulized colistin (2 patients) was 241.7 mg/d (range, 150-333.3 mg/d). Clinical cure was achieved in 9 patients (60%). Four-week survival rate after infection was 86.7% (95% confidence interval, 56.4%-96.5%). There was no difference in the median creatinine clearance in adults (P = .38) or children (P = .88) before and after colistin. One patient had both neurotoxicity and nephrotoxicity, and 1 patient had neurotoxicity only. CONCLUSIONS: Colistin might be used as an alternate therapy for transplant patients with multidrug-resistant Gram-negative pathogens.

What is the impact of hypogammaglobulinemia on the rate of infections and survival in solid organ transplantation? A meta-analysis.

Hypogammaglobulinemia has been described after solid organ transplantation and has been associated with increased risk of infections. The aim of the study was to evaluate the rate of severe hypogammaglobulinemia and its relationship with the risk of infections during the first year posttransplantation. Eighteen studies (1756 patients) that evaluated hypogammaglobulinemia and posttransplant infections were included. The data were pooled using the DerSimonian and Laird random-effects model. Q statistic method was used to assess statistical heterogeneity. Within the first year posttransplantation, the rate of hypogammaglobulinemia (IgG < 700 mg/dL) was 45% (95% CI: 0.34-0.55; Q = 330.1, p < 0.0001), the rate of mild hypogammaglobulinemia (IgG = 400-700 mg/dL) was 39% (95% CI: 0.22-0.56; Q = 210.09, p < 0.0001) and the rate of severe hypogammaglobulinemia (IgG < 400 mg/dL) was 15% (95% CI: 0.08-0.22; Q = 50.15, p < 0.0001). The rate of hypogammaglobulinemia by allograft type: heart 49% (21%-78%; Q = 131.16, p < 0.0001); kidney 40% (30%-49%; Q = 24.55, p = 0.0002); liver 16% (0.001%-35%; Q = 14.31, p = 0.0002) and lung 63% (53%-74%; Q = 6.85, p = 0.08). The odds of respiratory infection (OR = 4.83; 95% CI: 1.66-14.05; p = 0.004; I(2) = 0%), CMV (OR = 2.40; 95% CI: 1.16-4.96; p = 0.02; I(2) = 26.66%), Aspergillus (OR = 8.19; 95% CI: 2.38-28.21; p = 0.0009; I(2) = 17.02%) and other fungal infections (OR = 3.69; 95% CI: 1.11-12.33; p = 0.03; I(2) = 0%) for patients with IgG < 400 mg/dL were higher than the odds for patients with IgG > 400 mg/dL. The odds for 1-year all-cause mortality for severe hypogammaglobulinemia group was 21.91 times higher than those for IgG > 400 mg/dL group (95% CI: 2.49-192.55; p = 0.005; I(2) = 0%). Severe hypogammaglobulinemia during the first year posttransplantation significantly increased the risk of CMV, fungal and respiratory infections, and was associated with higher 1-year all-cause mortality.

What is the efficacy and safety of colistin for the treatment of ventilator-associated pneumonia? A systematic review and meta-regression.

BACKGROUND: Experience with intravenous and aerosolized forms of colistin for the treatment of ventilator-associated pneumonia (VAP) in patients without cystic fibrosis is limited. We aimed to assess the safety and efficacy of colistin for the treatment of VAP. METHODS: We searched MEDLINE and Cochrane Database of Systematic Reviews for studies comparing colistin vs other antibiotics for treatment of VAP in patients without cystic fibrosis. QUOROM guidelines were followed, the I(2) method was used for heterogeneity, and a random-effects model for odds ratio (OR) estimates. RESULTS: Six controlled studies met the inclusion criteria. Clinical response did not differ significantly between colistin and control groups (OR, 1.14; 95% confidence interval [CI], .74-1.77; P = .56; I(2) = 0%). The efficacy of colistin was independent of study design (prospective OR, 0.89 [95% CI, .48-1.66; P = .71; I(2) = 0%]; retrospective OR, 1.45 [95% CI, .79-2.68; P = .23; I(2) = 0%]); randomized trials OR, 0.86 [95% CI, .43-1.74; P = .68; I(2) = 0%]). There was no indication of a significant change in clinical response after controlling for concomitant antibiotic treatment (intercept, 0.121; slope, 0.0315; P = .95). Treatment with colistin vs controls did not affect hospital mortality (OR, 0.92; 95% CI, .50-1.67; P = .78; I(2) = 34.59%) or nephrotoxicity (OR, 1.14; 95% CI, .59-2.20; P = .69; I(2) = 0%). Fourteen single-arm studies have been analyzed, and the results were in concordance with the findings of the controlled studies. CONCLUSIONS: Our results suggest that colistin may be as safe and as efficacious as standard antibiotics for the treatment of VAP.

Incidence, risk factors, and outcomes associated with cytomegalovirus disease in small bowel transplant recipients.

Despite improved prophylaxis, monitoring, and more efficient immunosuppression, CMV infection remains a common opportunistic infection in transplant recipients. We assessed the incidence of CMV disease in pediatric SBT recipients, the timing of CMV disease after transplantation, and its impact on patient outcome. The medical records of 98 SBT recipients were reviewed. We performed descriptive analysis, regression analysis, and Kaplan-Meier curves to determine the time-to-event after transplantation. Fifty-three percent patients were male and 47% female, with a mean age of 38.3 months. Thirty-five percent of patients received prophylactic VGC, 55% GCV, 10% a combination of GCV/VGC, and 99% CMV immunoglobulins. A total of 24.5% recipients were CMV D+/R- (CMV serostatus donor positive/recipient negative). Seven (c. 7%) patients developed CMV disease. CMV disease was associated with 2.5 times (0.52-12.1; p = 0.25) higher rate of CMV mismatch and 11.1 times (1.3-95.9; p = 0.03) higher risk of death. CMV prophylaxis increased time-to-death (p = 0.074). Time-to-CMV disease was shorter in patients with enteritis (p < 0.0001), and CMV disease was associated with shorter time-to-death after transplantation (p = 0.001). CMV disease in SBT recipients was associated with an 11-fold mortality increase and a fourfold faster time-to-death. Time-to-death was significantly shorter with CMV enteritis.

Staphylococcus aureus infections after liver transplantation.

BACKGROUND: More data on the risk factors and outcomes after Staphylococcus aureus infections in liver transplantation are needed. METHODS: Liver recipients with S. aureus infections (cases) were retrospectively identified and compared to gender-, age-, and transplant type-matched (1:2) non-S. aureus-infected controls. Risk factors associated with S. aureus infections were identified by conditional logistic regression analysis. RESULTS: We evaluated 51 patients (median age 52 years). First S. aureus infections developed at a median time of 29 days after transplantation, with 52.94% of them in the first month; 88.24% were nosocomial, 41.18% were polymicrobial, and 47.06% were caused by methicillin-resistant S. aureus (MRSA). Surgical site infections represented 58.82% and bacteremia 23.53%. By univariate analysis, patients with S. aureus infections were intubated more frequently (odds ratio [OR] 26.92, 95% confidence interval [CI] 3.23-3,504.15, p = 0.0006), had a central line (OR 11.69, 95% CI 1.42-95.9, p = 0.02), or recent surgery (OR 26.92, 95% CI 3.23-3,504.15, p = 0.0006) compared with controls. By multivariate analysis, subjects who underwent surgery within 2 weeks prior to infection had a 26.9 times higher risk of developing S. aureus infection (95% CI 3.23-3,504.15, p = 0.0006); these results were adjusted for matched criteria. S. aureus infections did not affect graft or patient survival, but the study was not powered for such outcomes. CONCLUSION: Only recent surgical procedure was found to be a significant independent risk factor for S. aureus infections after liver transplantation.

Clostridium difficile and cytomegalovirus colitis co-infection: search for the hidden 'bug'.

Few cases of co-infection with cytomegalovirus (CMV) and Clostridium difficile colitis have been reported previously. We describe 2 cases of CMV and C. difficile colitis, and review 7 previously published reports. We aim to raise awareness of possible CMV-C. difficile co-infection, especially in refractory cases of C. difficile colitis.

IMPACT trial results should not change current standard of care of 100 days for cytomegalovirus prophylaxis.

The results of the IMPACT trial showed a significant reduction in cytomegalovirus disease with 200-day valganciclovir prophylaxis compared to the standard 100-day regimen with the same drug. These results may have the potential to change the standard of care in most transplant centers. However, we have concerns with the design, execution and statistical analysis of this trial. Our study aimed to describe each of these issues and to provide possible solutions for the better understanding of the IMPACT trial. We conclude that the IMPACT trial does not have the strength of evidence to change current clinical practice of 100-day cytomegalovirus prophylaxis. Further, based on all available evidence, we consider that another clinical trial to test 200-day CMV prophylaxis is not necessary.

Recommendations for the assessment and reporting of multivariable logistic regression in transplantation literature.

Multivariable logistic regression is an important method to evaluate risk factors and prognosis in solid organ transplant literature. We aimed to assess the quality of this method in six major transplantation journals. Eleven analytical criteria and four documentation criteria were analyzed for each selected article that used logistic regression. A total of 106 studies (6%) out of 1,701 original articles used logistic regression analyses from January 1, 2005 to January 1, 2006. The analytical criteria and their respective reporting percentage among the six journals were: Linearity (25%); Beta coefficient (48%); Interaction tests (19%); Main estimates (98%); Ovefitting prevention (84%); Goodness-of-fit (3.8%); Multicolinearity (4.7%); Internal validation (3.8%); External validation (8.5%). The documentation criteria were reported as follows: Selection of independent variables (73%); Coding of variables (9%); Fitting procedures (49%); Statistical program (65%). No significant differences were found among different journals or between general versus subspecialty journals with respect to reporting quality. We found that the report of logistic regression is unsatisfactory in transplantation journals. Because our findings may have major consequences for the care of transplant patients and for the design of transplant clinical trials, we recommend a practical solution for the use and reporting of logistic regression in transplantation journals.

Incidence and outcome of fungal infections in pediatric small bowel transplant recipients.

BACKGROUND: Data on the incidence, timing, and outcome of fungal infections in pediatric small bowel transplantation (SBT) are lacking. METHODS: Cases of pediatric SBT from January 2003 through December 2007 were collected. Standard induction was with thymoglobulin and/or basiliximab and maintenance immunosuppression was a tacrolimus-based regimen. Chi-square was used for categorical variables and Kaplan-Meier for survival analyses. RESULTS: A total 98 recipients were included; 25 patients developed 59 episodes of Candida infections and 4 episodes of invasive aspergillosis (incidence 25.5%, 95% confidence interval [CI] 17%, 34%). Of the Candida species, 37.3% were Candida albicans and 62.7% non-albicans Candida. Of all yeast infections, 66.1% were fungemia, 28.8% intra-abdominal infections, 1.7% empyema, and 3.4% urinary tract infection. Of the Candida intra-abdominal infections, 41.2% developed in the first month post transplantation, while 79.5% of candidemia developed after >6 months. Median time from transplantation to fungal infection was significantly shorter for abdominal infections compared with fungemia (9 versus 163 days; P=0.004). All-cause mortality was not significantly different between patients with and without fungal infections (32.3% versus 29.8%; odds ratio=1.12, 95% CI 0.45, 2.8). CONCLUSION: Fungal infections occurred in 25% of SBT recipients and C. albicans was the most common species. Intra-abdominal fungal infections occurred earlier (<1 month) than fungemia (>6 months) post transplantation.

Seroprevalence of West Nile virus infection in solid organ transplant recipients.

BACKGROUND: Of people infected with mosquito-borne West Nile virus (WNV), <1% develop neuroinvasive disease (NID). Population studies suggest that people older than 65 years may be at higher risk for neurologic symptoms. It has been suggested that solid organ transplant (SOT) recipients are also at higher risk for WNV NID, but definitive serologic and epidemiologic data are lacking. METHODS: A serologic screening survey, using a US Food & Drug Administration-approved enzyme-linked immunosorbant assay to detect WNV immunoglobulin-G (IgG) antibody responses in cohorts of SOT recipients and non-immunocompromised controls, was undertaken at a large Midwestern university organ transplant center in the aftermath of the summer 2003 WNV regional outbreak. Hemagglutination-inhibition testing was used to confirm WNV IgG-positive results and differentiate them from positive results caused by Saint Louis encephalitis virus, another flavivirus that is endemic in the Midwestern US. FINDINGS: The rate of WNV IgG-seropositive responses did not differ between SOT recipients and non-immunocompromised controls, and were 12% and 10%, respectively. Retrospective chart review showed no documented WNV NID in the seropositive SOT recipients, suggesting an incidence of WNV NID may be as low as 0.7% in this population. INTERPRETATION: Asymptomatic WNV infection is common among immunocompromised SOT patients, occurring as often as it does in non-immunocompromised controls. Our data indicated that severe WNV NID is less frequent in SOT patients, contrary to what has been suggested in other studies.

Enterococcus pneumonia complicated with empyema and lung abscess in an HIV-positive patient. Case report and review of the literature.

This report describes the first case of vancomycin-resistant Enterococcus pneumonia complicated with empyema and lung abscess in an HIV patient and reviews previously published cases of Enterococcus pleuro-pulmonary infection. Our case highlights the rarity of this entity and reviews the risk factors for Enterococcus pleuro-pulmonary infections.