Review article: antibiotic-induced Clostridium difficile infection

The great majority of cases of Clostridium difficile infection are hospital-acquired, and the reported incidence in England and Wales has increased sixfold between 1990 and 1993, with at least 17 patients dying in a recent large nosocomial outbreak. C. difficile infection accounts for an average 3-week increased length of stay in hospital. Acquisition of a toxigenic strain of Clostridium difficile may be followed by asymptomatic carriage, diarrhoea, colitis or pseudomembranous colitis. Antibiotic treatment and older age are major risk factors for the development of symptomatic disease, but less well-defined differences in strain virulence and host susceptibility are also probably important. Accurate data on the relative risks of different antibiotics to induce symptomatic C. difficile infection are scarce, but third-generation cephalosporins are frequently implicated. New kits are becoming available for the laboratory diagnosis of C. difficile infection but many of these lack sensitivity. Oral metronidazole or vancomycin are the main treatment options but avoidance of further antibiotics should also be encouraged where possible. The role of environmental C. difficile spores, which are highly resistant to conventional disinfectants, needs to be defined. Proven strategies for the prevention of C. difficile infection are required, in particular protocols to ensure that cross-infection does not occur.     

Clostridium difficile colitis associated with treatment of Helicobacter pylori infection

Helicobacter pylori infection of the stomach is being detected and treated more often now than ever before. This is likely to result in an increase in complications such as antibiotic-associated diarrhea. However, there is no literature on the incidence of such diarrhea, particularly Clostridium difficile colitis, in patients treated for Helicobacter pylori infection. We report the case of a patient who developed Clostridium difficile colitis after treatment for Helicobacter pylori infection with metronidazole, amoxicillin, H2 blockers, and bismuth subsalicylate. This patient presented with severe diarrhea that responded to a course of metronidazole with rapid disappearance of symptoms. The incidence of Clostridium difficile colitis in patients treated for Helicobacter pylori infection has not been studied. This unique association, although not unexpected, has not yet been reported in the literature. The increasing number of patients being diagnosed and treated for this infection requires a heightened awareness on the part of physicians, to assure early diagnosis and treatment of this treatable, yet potentially dangerous, complication.     

Some aspects of the Clostridium difficile infection

Clostridium difficile is now regarded as the most common nosocomial enteric pathogen. C. difficile infection has a wide spectrum of a clinical presentation ranging from asymptomatic carriage to the fulminant colitis. Antibiotic therapy is the most important risk factor in pathogen contagion, however other factors are also involved. Typical pathophysiology: 1. alteration of the indigenous colonic flora by antibodies, 2. ingestion of spores, 3. colonization by Clostridium difficile, 4. production of its toxins. Both entherotoxin A and cytotoxin B are active in human colon. The mode of action of these toxins is already quite well known. The main treatment includes withdrawal of the inducing agents, supported occasionally by oral Vancomycin and Metronidazole. Relapse is a major complication.     

Guidelines for optimal surveillance of Clostridium difficile infection in hospitals

The availability of surveillance data on C. difficile infection in hospitals in England and Wales is being jeopardised by the trend not to culture the organism for diagnostic purposes. NHS trust laboratories that no longer have the ability to isolate C. difficile cannot investigate putative outbreaks or monitor antimicrobial susceptibilities. These laboratories may now need to rely on their local public health laboratory for such investigations. Recent recommendations from the Department of Health(DH)/PHLS have highlighted the need for culture in outbreak investigations, for surveillance purposes, and for monitoring antimicrobial susceptibilities. It is important, therefore, that NHS diagnostic laboratories and public health laboratories, in particular, retain the ability to isolate C. difficile. A cost-effective approach is described that will facilitate surveillance by typing of strains and also enable their antimicrobial susceptibilities to be monitored.     

Clostridium difficile infection in patients with reactive arthritis of undetermined etiology

BACKGROUND: Multiple sensory neuropeptides are present in human airways and may contribute to diseases such as asthma. This study quantified and characterised substance P (SP), neurokinin A (NKA), and calcitonin gene related peptide (CGRP) immunoreactivity in bronchoalveolar lavage fluid in asthmatic and normal subjects. METHODS: Using specific radioimmunoassay (RIA), SP, NKA and CGRP were measured in bronchoalveolar lavage fluid from asthmatic subjects (n = 5), normal subjects (n = 5), atopic non-asthmatic subjects (n = 6), and asthmatic subjects four hours after allergen challenge (n = 12). Peptide immunoreactivity was characterised using high performance liquid chromatography (HPLC) and RIA. RESULTS: No SP or CGRP immunoreactivity was detected in any of the fractions from samples after extraction, HPLC, and RIA. Non-specific binding resulted in spurious SP immunoreactivity being detected in bronchoalveolar lavage fluid when no extraction process was employed. NKA was detected in significant amounts in asthmatic (median 550, range 425-625 pg/ml) and normal subjects (median 725, range 350-1425 pg/ml). The level of NKA was significantly higher in the asthmatic subjects after allergen challenge (median 750, range 350-1250 pg/ml) than in unchallenged asthmatic subjects (median 600, range 425-600 pg/ml, p < 0.01). CONCLUSIONS: Extraction and characterisation of peptides from bronchoalveolar lavage fluid must be performed to ensure that the measured immunoreactivity represents target peptide. NKA is present in bronchoalveolar lavage fluid in high concentrations and is the predominant tachykinin. The concentrations of NKA are similar in normal subjects and subjects with mild asthma.     

Clostridium difficile colitis: factors influencing treatment failure and relapse--a prospective evaluation

OBJECTIVE: The aim of this study was to identify patient related factors that may influence the treatment response and relapse following Clostridium difficile (C. difficile) colitis. METHODS: A total of 36 patients with C. difficile colitis were followed for 3 months. Age, sex, place of residence, severity of infection, treatment, underlying medical condition, and treatment were compared in patients who failed to respond to treatment in 14 days and in patients who relapsed after a successful treatment. Student's t test and Fisher's exact test were used to compare the groups. A p value of <0.05 was considered significant. RESULTS: A low serum albumin (p=0.016) and continuation of systemic antibiotic treatment were found to be associated with refractoriness to treatment. Continuation or restarting of antibiotics after successful treatment increases the risk of relapse (p=0.003). The age, sex place of residence, underlying medical condition, and type of precipitating antibiotics had no effect on the treatment response and relapse. The severity of colitis and the type of therapy (metronidazole vs vancomycin) did not influence the treatment response or relapse. CONCLUSION: Low serum albumin serves as a useful marker for patients who require prolonged treatment for C. difficile colitis. It is prudent to review the need for the continuation of systemic antibiotic treatment, as it adversely affects the treatment response and increases the risk of relapse.     

Clostridium difficile: an increasing nosocomial pathogen

The following case example shows the difficulty dentists face when their alcohol or drug dependence causes them to violate laws or the Dental Practice Act. In this case, the dentist is charged with driving while intoxicated (DWI) and is in possession of inappropriately prescribed medications.     

Survey of incidence of Clostridium difficile infection in Canadian hospitals and diagnostic approaches

A questionnaire relating to Clostridium difficile disease incidence and diagnostic practices was sent to 380 Canadian hospitals (all with > 50 beds). The national questionnaire response rate was 63%. In-house testing was performed in 17.6, 61.5, and 74.2% of the hospitals with < 300, 300 to 500, and > 500 beds, respectively. The average test positivity rates were 17.2, 15.3, and 13.2% for hospitals with < 300, 300 to 500, and > 500 beds, respectively. The average disease incidences were 23.5, 30.8, and 40.3 cases per 100,000 patient days in the hospitals with < 300, 300 to 500, and > 500 beds, respectively. In the 81 hospitals where in-house testing was performed, cytotoxin testing utilizing tissue culture was most common (44.4%), followed by enzyme-linked immunosorbent assay (38.3%), culture for toxigenic C. difficile (32.1%), and latex agglutination (13.6%). The clinical criteria for C. difficile testing were variable, with 85% of hospitals indicating that a test was done automatically if ordered by a doctor. Our results show that C. difficile-associated diarrhea is a major problem in hospitals with > or = 200 beds. Despite a lower disease incidence in smaller hospitals, there was a higher diagnostic test positivity rate. This may reflect the preference of smaller hospitals for culture and latex agglutination tests.     

A prospective study of Clostridium difficile infection and colonization in pediatric oncology patients

BACKGROUND: Tumescent liposuction has proven to be an extremely safe and effective method of liposuction. However, the infusion of tumescent anesthesia can take 1 hour or more to complete. OBJECTIVE: To document the types, dosages, and routes of administration of premedication utilized by four experienced tumescent liposuction surgeons. To determine if infusion rates for tumescent anesthesia are affected by types of premedication. METHODS: Four experienced liposuction surgeons were asked to review their most recent 100 tumescent liposuction patients with respect to types and dosages of premedication and routes of administration. Data were also provided on corresponding infusion pump settings and infusion rates. Volumes of tumescent anesthesia and corresponding volumes of fat aspirated were also collected on the same 400 patients. RESULTS: Infusion of tumescent anesthesia could be performed more rapidly in patients who were given greater amounts of premedication. Volumes of tumescent anesthesia infused were generally two or more times the volume of fat aspirated. Patients could be infused with less premedication if slow infiltration was employed. CONCLUSION: Infusion rates for tumescent anesthesia can be increased of greater amounts of premedication are given. However, this must be balanced against the safety of the premedication.     

Clostridium difficile infections. Current aspects

Clostridium difficile is a gram-positive anaerobe that forms subterminal spores. It is now one of major nosocomial pathogens, mainly in older patients, because of its ability to persist in the environment and to become established in the gastrointestinal tract once the natural microflora has been modified by antibiotic therapy. Toxigenic strains of C. difficile produce toxin A (enterotoxin) or toxin B (cytotoxin) or both with cause the cytotoxic effect "rounding". C. difficile can spread from patient to patient and, probably, the primary way by which the organism is spread is by health care workers. C. difficile causes intestinal diseases ranging by mild diarrhea (antibiotic associated diarrhea) to fatal pseudomembranous colitis (PMC). The current therapy is based on oral administration of metronidazole or vancomycin . In patients non responders or that continue to relapse can be used other forms of therapy: antibiotic (teicoplanine, bacitracine, rifamixine); anion exchange resin (colestipol, colestiramine); probiotic therapy (S. boulardii, lactobacilli and fecal enemas). New and improved studies will lead to new and better ways of treating patients and better understanding of this unusual pathogen and how it causes diseases.     

Antibacterial activity of teicoplanin against Clostridium difficile

The in vitro inhibitory action of teicoplanin, vancomycin, metronidazole and clindamycin against clinical isolates of Clostridium difficile was investigated. Minimum inhibitory concentrations (MICs) were determined using E test. Teicoplanin (MIC range 0.023-0.75 microgram/ml), vancomycin (MIC range 0.5-3 micrograms/ml) and metronidazole (MIC range 0.19-1 microgram/ml) were all very active against the isolates examined. No resistant strains of C. difficile to those three antimicrobial agents were observed, whereas resistance to clindamycin was found in 39.5% of the tested strains. Teicoplanin was about 4-times more potent than vancomycin. It appears to be a more promising antimicrobial for treatment of C. difficile enteric disease.     

Physical map of the Clostridium difficile chromosome

The present study was designed to investigate the effect of mercuric chloride administration on copper, zinc, and iron concentrations in the liver, kidney, lung, heart, spleen, and muscle of rats. The results showed that after dose and time exposure to mercuric chloride, the concentration of mercury in the six tissues was significantly elevated. Data showed that there were no interaction between mercury and tissue iron. There was a considerable elevation of the content of copper in the kidney and liver. The most significant changes in the copper concentration took place in the kidneys. About a twofold increase in the copper content of the kidney was noted after exposure to mercuric chloride (3 mg and 5 mg/kg). Only slight elevations in the copper content occurred in the liver especially in high dose and longer exposure time. In the remaining organs, the copper content was not changed significantly (p > 0.05). The most significant changes in the zinc concentration took place in liver, kidney, lung and heart (5 mg/kg). Marked changes in kidney zinc concentrations were observed at any of the specified doses. Zinc concentrations were significantly increased in kidney of rats sacrificed 9-48 h after s.c. injection of HgCl2 (5 mg/kg); in liver obtained from rats at 18, 24 or 48 h after injection; and in lung after 24 or 48 h of treatment. The heart and spleen zinc concentrations were elevated at 24 and 48 h after injection of HgCl2 (5 mg/kg), respectively. The results of this study implicate that effects on copper and zinc concentrations of the target tissues of mercury may play an important role in the pathogenesis of acute mercuric chloride intoxication.     

Study of the thermoresistance of Clostridium difficile spores

Thermoresistance of C. difficile spores was investigated. C. difficile strains were isolated from different sources. As control, toxigenic VPI 10463 and nontoxigenic NIH BRIGGS 8050 C. difficile strains were used. The inhibition of growth majority of C. difficile after heating at 85 degrees C was shown. No correlation between thermoresistance of C. difficile spores, toxigenicity and source of the strains was observed.     

Purification and characterization of Clostridium difficile glutamate dehydrogenase

Recombinant Clostridium difficile glutamate dehydrogenase (L-glutamate:NAD oxidoreductase, EC 1.4.1.2) was purified 177-fold to electrophoretic homogeneity with a 62% recovery through a four-step procedure involving gel filtration and ion-exchange and dye affinity chromatography. The approximate molecular weights of the native enzyme by gel filtration and subunits by sodium dodecyl sulfate-polyacrylamide gel electrophoresis were consistent with a hexameric structure for the purified enzyme. The enzyme-catalyzed glutamate oxidation was an NAD-dependent sequential process in which NADP could not be substituted as coenzyme. Several dinucleotide analogs of NAD structurally altered in either the pyridine or the purine moiety were observed to function as coenzymes when substituted for NAD. Nicotinamide mononucleotide did not serve as a coenzyme for glutamate oxidation. Product inhibition by NADH was competitive with respect to NAD. In deadend inhibition studies, adenosine diphosphoribose was shown to be an effective coenzyme-competitive inhibitor.     

Review article: current treatment and optimal patient management in pancreatic cancer

Pancreatic cancer is the tenth most prevalent malignancy and the fifth most common cause of cancer death in the developed world. Less than 10% of patients survive for more than 1 year following diagnosis and the 5-year survival rate (0.4%) is the lowest of any cancer. The poor prognosis associated with this diagnosis led in the past to therapeutic nihilism on the part of clinicians who were all too aware of the limitations of their available therapeutic strategies. Breaking this therapeutic impasse requires a significant expansion in the knowledge of clinicians concerning the pathogenesis and behaviour of pancreatic cancer. Recent advances in the scientific understanding of the aetiology of pancreatic cancer has facilitated progress towards the development of promising and innovative approaches to the early detection and diagnosis of pancreatic cancer. While acknowledging that pancreatic cancer will continue to present significant challenges to both scientists and clinicians in the foreseeable future, it is becoming increasingly clear that recent advances in our scientific knowledge base holds the potential to significantly improve prognosis for patients. The challenge facing both scientists and clinicians is how best to translate such promising scientific advances into survival and quality of life benefits to patients.     

Review article: glycyrrhizin as a potential treatment for chronic hepatitis C

The morphologic response of neonatal mouse retina to the alkylating agent N-methyl-N-nitrosourea (MNU) was examined at different periods of retinal development. A dose of 60 mg/kg N-methyl-N-nitrosourea was injected intraperitoneally to neonatal C57BL mice at 0, 3, 5, 8, 11, 14, 17, and 20 days of age and to C3H mice at 0 days of age, and the retinas were examined sequentially. In the C57BL mice, MNU evoked a time-dependent occurrence of retinal dysplasia and retinal degeneration. With MNU treatment at day 0 and day 3 (the stage of retinal cell proliferation), retinal dysplasia characterized by the progressive disorganization of neuroblasts, which led to the formation of rosettes, was found in the outer neuroblastic/nuclear layer above the normal pigment epithelial cells during days 8-20, but decreased at day 50. The rosettes were surrounded by photoreceptor segments and Müller cell processes, and by photoreceptor nuclei. The MNU response was related to retinal differentiation; following MNU treatment at day 5 or 8 (the stage of retinal cell differentiation) the cells were much less sensitive (i.e. no retinal response was found). However, with MNU treatment at days 11, 14, 17, and 20 (after cellular differentiation), retinal degeneration characterized by selective photoreceptor apoptosis was seen. These results suggest that there is a critical period for the time of MNU administration in the development of mouse retinal lesions. In C3H (rd/rd) mice, MNU treatment at day 0 resulted in retinal degeneration with only slight rosette formation at the peripheral retina.     

Review article: the diagnosis and treatment of haematinic deficiency in gastrointestinal disease

Deficiency of any of the vitamins and minerals essential for normal erythropoiesis (haematinics), including iron, copper, cobalt, vitamins A, B12, B6, C, E, folic acid, riboflavin and nicotinic acid, may be associated with defective erythropoiesis and anaemia. Iron, vitamin B12 and folate are the haematinics for which deficiency states manifest most often clinically and are the focus of this review. The normal absorption of these haematinics and gastrointestinal causes of their deficiency are described. Investigations, including the use of homocysteine metabolite levels and new techniques such as serum transferrin receptor assays, and treatment of haematinic deficiency are discussed in detail.