Hsiao Ju Lin

Impact of toxigenic Clostridium difficile colonization and infection among hospitalized adults at a district hospital in southern Taiwan.

Background The impact of toxigenic Clostridium difficile colonization (tCDC) in hospitalized patients is not clear. Aim To study the significance of tCDC in hospitalized patients. Methods A prospective study in the medical wards of a regional hospital was performed from January to June 2011. Fecal samples collected from patients at the time of admission were tested for tcdB by real-time polymerase chain reaction (PCR) and cultured for C. difficile. The patients were followed up weekly or when they developed diarrhea during hospitalization. If C. difficile was isolated, tcdA and tcdB would be tested by multiplex PCR. The primary outcome was the development of C. difficile-associated diarrhea (CDAD). Findings Of 168 patients enrolled, females predominated (87, 51.8%), and the mean patient age was 75.4 years old. Approximately 70% of the patients were nursing home residents, and one third had a recent hospitalization within the prior three months. Twenty-eight (16.7%) patients had tCDC, including 16 (9.5%) patients with tCDC at the time of admission and 12 (7.2%) with tCDC during the follow-up period. With regard to the medications taken during hospitalization, the patients were more likely to have tCDC if they had received more than one class of antibiotics than if they had received monotherapy (odds ratio [OR] 6.67, 95% confidence interval [CI] 1.41–31.56, P = 0.01), particularly if they received a glycopeptide in combination with a cephalosporin or penicillin or a cephalosporin and a carbapenem. More patients with tCDC developed CDAD than those without tCDC (17.9%, 5/28 vs. 1.4%, 2/140, P = 0.002). Overall 7 (4.2%) of the 168 patients developed CDAD, and crude mortality rate of those with and without tCDC was similar (21.4%, 6/28 vs. 19.4%, 27/140, P = 0.79). Conclusion Recent use of glycopeptides and β-lactam antibiotics is associated with toxigenic C. difficile colonization, which is a risk factor for developing C. difficile-associated diarrhea.

Clinical impact of Clostridium difficile colonization

Clostridium difficile can cause antibiotic-associated diarrhea in hospitalized patients. Asymptomatic colonization by C. difficile is common during the neonatal period and early infancy, ranging from 21% to 48%, and in childhood. The colonization rate of C. difficile in adult hospitalized patients shows geographic variation, ranging from 4.4% to 23.2%. Asymptomatic carriage in neonates caused no further disease in many studies, whereas adult patients colonized with toxigenic C. difficile were prone to the subsequent development of C. difficile-associated diarrhea (CDAD). However, the carriage of nontoxigenic C. difficile strains appears to prevent CDAD in hamsters and humans. Risk factors for C. difficile colonization include recent hospitalization, exposure to antimicrobial agents or gastric acid-suppressing drugs (such as proton-pump inhibitors and H2 blockers), a history of CDAD or cytomegalovirus infection, the presence of an underlying illness, receipt of immunosuppressants, the presence of antibodies against toxin B, and Toll-like receptor 4 polymorphisms. Asymptomatic C. difficile carriers are associated with significant skin and environmental contamination, similar to those with CDAD, and contact isolation and hand-washing practices should therefore be employed as infection control policies for the prevention of C. difficile spread. Treating patients with asymptomatic C. difficile colonization with metronidazole or vancomycin is not suggested by the currently available evidence. In conclusion, asymptomatic C. difficile colonization may lead to skin and environmental contamination by C. difficile, but more attention should be paid to the clinical impact of those with C. difficile colonization.

Risk factors for Clostridium difficile-associated diarrhea among hospitalized adults with fecal toxigenic C. difficile colonization.

BACKGROUND Patients with toxigenic Clostridium difficile colonization (tCDC) are at risk of developing C. difficile-associated diarrhea (CDAD). However, the risk factors of hospitalized patients with tCDC developing CDAD are not clear. METHODS We conducted an 18-month prospective study at a medical ward in a district hospital in southern Taiwan. Within 48 hours of admission, weekly stool samples from asymptomatic hospitalized patients were obtained to detect fecal CDC. A polymerase chain reaction for tcdB was performed to determine toxigenic isolates. CDAD was diagnosed if the patient had diarrhea and toxigenic C. difficile present in a stool sample. RESULTS A total 483 patients with stool samples were eligible for the study. Eighty-six (17.8%) patients had tCDC after screening, of whom 14 (16.3%) developed CDAD during follow-up. Among those with tCDC, patients with subsequent CDAD were more likely to have diabetes mellitus (p = 0.01) and to have received piperacillin-tazobactam (p = 0.04), or proton-pump inhibitors (PPIs; p = 0.04) than those without developing CDAD. The variables were statistically significant as determined by multivariate analysis. However, the 60-day crude mortality rates among tCDC patients with and without subsequent development of CDAD were similar. CONCLUSION Diabetes mellitus and recent receipt of piperacillin-tazobactam or PPIs are independent risk factors for the development of CDAD among hospitalized patients with tCDC.

Risk Factors of Fecal Toxigenic or Non-Toxigenic Clostridium difficile Colonization: Impact of Toll-Like Receptor Polymorphisms and Prior Antibiotic Exposure

Background This study is to investigate the significance and risk factors of fecal toxigenic (tCdC) or non-toxigenic Clostridium difficile colonization (ntCdC) among hospitalized patients. Methods Adults admitted to medical wards in a district hospital between January 2011 and June 2012 were enrolled, and those with a history of colectomy, C. difficile fecal colonization or infection or receipt of either metronidazole or oral vancomycin within 3 months, were excluded. Stools collected within 48 hours after admission and every week during hospitalization were cultured for C. difficile. Findings Among the 441 enrolled patients, 84 (20.0%) had CdC at initial screening, including 58 (13.2%) with tCdC and 26 (6.8%) with ntCdC. Among patients with initial negative fecal screening for CdC, it took an average of 70.6 days or 66.5 days to develop tCdC or ntCdC during the study period. Finally 78 (17.7%) had tCdC and 34 (7.7%) had ntCdC. During the follow-up period, the patients with tCdC had a higher risk of CDAD (11/79, 14.1%) than those without CdC (3/328, 0.9%) and those with ntCdC (0/34, 0%) (P<0.001). In multivariate analysis, the TLR4 rs1927914 polymorphism (GG genotype) (odds ratio [OR] 4.4, 95% confidence interval [CI] 1.6–11.8, P = 0.003) and recent cefepime therapy (OR 5.3, 95% CI 2.1–13.2, P<0.001) were independently associated with tCdC, whereas recent cefuroxime (OR 11.7, 95% CI 2.3–60.2, P = 0.003) and glycopeptide therapy (OR 10.9, CI: 2.1–57.2, P = 0.005) associated with ntCdC. Conclusion The incidence of CDAD is highest in patients with tCdC and lowest in patients with ntCdC, and the TLR4 rs1927914 polymorphism GG genotype and recent cefepime therapy were independently associated with tCdC.

Cytomegalovirus disease in nonimmunocompromised, human immunodeficiency virus-negative adults with chronic kidney disease

BACKGROUND/PURPOSE(S) To identify the clinical characteristics of cytomegalovirus (CMV) disease in chronic kidney disease (CKD) patients. METHODS Patients from two sources were reviewed: (1) a retrospective study of hospitalized patients admitted between January 1990 and February 2009 was performed at a tertiary hospital in Taiwan; (2) the English literature from 1990 to 2009 was reviewed for additional cases, and adults with CKD and histopathologically documented cytomegalovirus disease were included. RESULTS Seven CKD patients from our hospital and seven from the literature were included. Nine (64.3%) patients were males, and the mean age was 66 years. Histopathologically proven CMV disease was present in the gastrointestinal (GI) tract of 13 (92.9%) and in the skin of one (7.1%) patient. GI symptoms included bleeding (78.6%), abdominal pain (35.7%), and diarrhea (28.6%).The most common comorbidities were diabetes mellitus (7, 50%) and hypertension (8, 57.1%). Thirteen patients had CMV GI disease. The endoscopic gross features of the GI tract lesions included single or multiple ulcers and a large polypoid or uneven surface mass. Of the seven cases with available data, a low body mass index (22.3 ± 1.3 kg/m(2)) and hypoalbuminemia (25 ± 7.0 g/L) were noted. Twelve patients had received ganciclovir or valganciclovir therapy. Five (35.7%) patients died, and the death of two patients was directly related to bowel perforation caused by CMV colitis. CONCLUSION CMV disease may occur in CKD patients without the presence of overt immunodeficiency. The gastrointestinal tract is the most common site of involvement. Clinicians should be aware of this possibility in CKD patients who have GI symptoms.

Proton-Pump Inhibitor Exposure Aggravates Clostridium difficile–Associated Colitis: Evidence From a Mouse Model

BACKGROUND Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients. In addition to the infection due to toxigenic C. difficile in the gastrointestinal tract of susceptible hosts, other predisposing factors for C. difficile infection (CDI) are identified, including advanced age, a prolonged hospital stay, and use of acid-suppressive drugs. Of note, exposure to gastric acid-reducing agents, such as H2 blockers and proton pump inhibitors (PPIs), remains a controversial risk factor, and has been associated with CDI in some studies but not in others. A mouse model of antibiotic-associated clostridial colitis was established to examine the role of PPIs for CDI. MATERIALS AND METHODS A mouse model of antibiotic-associated clostridial colitis was set up. NF-κB reporter mice were used to address the in vivo spatial and temporal inflammatory patterns of C. difficile-associated colitis. Serum levels of lipopolysaccharide and dextran-FITC were measured to reflect the barrier permeability of affected intestines. RESULTS Mice with CDI that were exposed to PPI exhibited greater losses of stool consistency and body and cecal weights than those that were not exposed to PPI. Further, more neutrophilic infiltrations, epithelial damage, and inflammatory cytokine expression were noted in colon specimens of the mice with PPI exposure. More-evident inflammatory responses were detected by in vivo imaging of NF-κB reporter mice with CDI that were exposed to PPI. Gut barrier permeability was increased to a greater extent, as reflected by higher serum levels of lipopolysaccharide and dextran-FITC in mice with CDI that were exposed to PPI. CONCLUSIONS Our mouse model demonstrates that PPI exposure increases the severity of intestinal inflammation in mice with C. difficile-associated colitis.

Doxycycline and Tigecycline: Two Friendly Drugs with a Low Association with Clostridium Difficile Infection

Clostridium difficile infection (CDI) is known to be associated with prior exposure to many classes of antibiotics. Standard therapy for CDI (i.e., metronidazole and vancomycin) is associated with high recurrence rates. Although tetracycline derivatives such as tetracycline, doxycycline or tigecycline are not the standard therapeutic choices for CDI, they may serve as an alternative or a component of combination therapy. Previous tetracycline or doxycycline usage had been shown to have less association with CDI development. Tigecycline, a broad-spectrum glycylcycline with potency against many gram-positive or gram-negative pathogens, had been successfully used to treat severe or refractory CDI. The in vitro susceptibility of C. difficile clinical isolates to tigecycline in many studies showed low minimal inhibitory concentrations. Tigecycline can suppress in vitro toxin production in both historical and hypervirulent C. difficile strains and reduce spore production in a dose-dependent manner. Tetracycline compounds such as doxycycline, minocycline, and tigecycline possess anti-inflammatory properties that are independent of their antibiotic activity and may contribute to their therapeutic effect for CDI. Although clinical data are limited, doxycycline is less likely to induce CDI, and tigecycline can be considered one of the therapeutic choices for severe or refractory CDI.

The first case of severe Clostridium difficile ribotype 027 infection in Taiwan.

The authors are grateful to Dr. Evelina Menna and Dr. Fabio Soldani (Department of Pathology and Diagnostics, Section of Infectious Diseases, Verona) and to all the nurses working at the Section of Infectious Diseases of the “G.B. Rossi” Hospital of Verona for their invaluable help in carrying out this study. The authors also acknowledge Dr. Stanley Pang (Centre d’Immunologie et des Maladies Infectieuses, E13, Paris) for its contribution.

Effects of PPARγ and RBP4 Gene Variants on Metabolic Syndrome in HIV-Infected Patients with Anti-Retroviral Therapy

Background PPARγ and RBP4 are known to regulate lipid and glucose metabolism and insulin resistance. The influences of PPARγ (C1431T and Pro12Ala) and RBP4 (−803GA) polymorphisms on metabolic syndrome in HIV-infected patients receiving anti-retroviral therapy were examined in this study. Materials and Methods A cross-sectional study of HIV-1 infected adults with antiretroviral therapy for more than one year in the National Cheng Kung University Hospital was conducted. The gene polymorphisms were determined by quantitative PCR. Results Ninety-one patients were included in the study. Eighty-two (90.1%) patients were males with a mean age of 44.4 years. For the C1431T polymorphism in PPARγ, while patients with the T allele (48.4%) had trends toward lower rate of hypertriglyceridemia, the borderline significance together with insignificant power did not support the protective effect of the T allele against development of hypertriglyceridemia. For the Pro12Ala polymorphism in PPARγ, although patients with the Pro/Ala genotype (8.8%) had a higher level of serum LDL (138.0 vs. 111.5 mg/dl, P = 0.04) and trends toward higher rates of hypercholesterolemia and serum LDL>110 mg/dl, these variables were found to be independent of the Pro/Ala genotype in the multivariate analysis. For the −803GA polymorphism in RBP4, patients with the A allele (23.1%) more often had insulin resistance (HOMA>3.8; 33.3 vs. 8.7%, P = 0.01) and more often received anti-hypoglycemic drugs (14.3 vs. 1.4%, P = 0.04). The detrimental effect of the A allele in RBP4 −803GA polymorphism on development of insulin resistance was supported by the multivariate analysis adjusting for covariates. Conclusion The impacts of PPARγ C1431T and Pro12Ala polymorphisms on metabolism in HIV-infected patients are not significant. RBP4 −803GA polymorphism has increased risk of insulin resistance in HIV-infected patients with anti-retroviral therapy.

Clostridium difficile infections in medical intensive care units of a medical center in Southern Taiwan: Variable seasonality and disease severity

Critical patients are susceptible to Clostridium difficile infections (CDIs), which cause significant morbidity and mortality in the hospital. In Taiwan, the epidemiology of CDI in intensive care units (ICUs) is not well understood. This study was aimed to describe the incidence and the characteristics of CDI in the ICUs of a medical center in southern Taiwan. Adult patients with diarrhea but without colostomy/colectomy or laxative use were enrolled. Stool samples were collected with or without 5 ml alcohol and were plated on cycloserine-cefoxitin-fructose agar. C. difficile identification was confirmed by polymerase chain reaction. There were 1,551 patients admitted to ICUs, 1,488 screened, and 145 with diarrhea. A total of 75 patients were excluded due either to laxative use, a lack of stool samples, or refusal. Overall, 70 patients were included, and 14 (20%) were diagnosed with CDI, with an incidence of 8.8 cases per 10,000 patient-days. The incidence of CDI was found to be highest in March 2013 and lowest in the last quarter of 2013. The cases were categorized as the following: 5 severe, complicated, 5 severe, and 4 mild or moderate diseases. Among the 14 cases of CDI, the median patient age was 74 (range: 47–94) years, and the median time from admission to diarrhea onset was 16.5 (4–53) days. Eight cases received antimicrobial treatment (primarily metronidazole), and the time to diarrheal resolution was 11.5 days. Though 6 cases were left untreated, no patients died of CDI. The in-hospital mortality of CDI cases was 50%, similar to that of patients without CDI (46.4%; P = 1.0). We concluded that the overall incidence of CDI in our medical ICUs was low and there were variable seasonal incidences and disease severities of CDI.