Eating Wheat Fuels Staphylococcus, Clostridium, and Klebsiella Growth, Study Suggests

Eating Wheat Fuels Staphylococcus, Clostridium, and Klebsiella Growth, Study Suggests

Research indicates that the consumption of wheat contributes to the growth of pathogenic bacteria in our gut, adding to growing concern that wheat (which is often contaminated with Roundup herbicide) is one of the worst foods to consume for gut health. 

A concerning study published in FEMS Microbiology Ecology titled, “Diversity of the cultivable human gut microbiome involved in gluten metabolism: isolation of microorganisms with potential interest for coeliac disease,” reveals something remarkable about the capabilities (and liabilities) of human gut bacteria (microbiome) when exposed to foods such as wheat.

Some of the extremely hard to digest proteins in wheat colloquially known as “gluten” (there are actually over 23,000 identified in the wheat proteome and not just one problematic protein as widely believed) were found metabolizable through a 94 strains of bacterial species isolated from the human gut (via fecal sampling).

This discovery is all the more interesting when you consider that, according to Alessio Fasano, the Medical Director for The University of Maryland’s Center for Celiac Research, the human genome does not possess the ability to produce enzymes capable of sufficiently breaking down gluten.

As reported on TenderFoodie in interview:

“We do not have the enzymes to break it [gluten] down. It all depends upon how well our intestinal walls close after we ingest it and how our immune system reacts to it.”

The new study helps to fill the knowledge gap as to how humans are capable of dealing with wheat consumption at all, considering it did not play a role in the diets of non-Western peoples until very recently (perhaps only a few generations), and even in those who have consumed it for hundreds of generations, it is still on a biological scale of time a relatively new food in the human diet which was grain free for 99.999% of human evolution.

As we have analyzed in a previous essay, The Dark Side of Wheat, the consumption of wheat is a relatively recent dietary practice, stretching back only 10,000 years – a nanosecond in biological time. We simply have not had time to genetically adapt to its consumption (at least not without experiencing over 200 empirically confirmed adverse health effects!).

The new finding reported here shows that bacteria in our microbiome extend our ability to digest physiologically incompatible foods – or at least tolerate them to the degree that they don’t outright kill us. This may explain why there is such a wide variability in responses to gluten and why the health of our microbiome may play a — if not the — central role in determining our levels of susceptibility to its adverse effects.

Another provocative finding of the study is that some of the strains capable of breaking down the more immunotoxic peptides in wheat, including the 33 amino acid long peptide known as 33-mer, are highly pathogenic, such as Clostridium botulinum – the bacteria that is capable of producing botulism. As we discussed in a previous article on Monsanto’s Roundup herbicide (glyphosate) contributing to the overgrowth of this pathogenic strain of bacteria in animals exposed to GMO feed,

“[It]t only takes 75 billionths of a gram (75 ng) to kill a person weighing 75 kg (165 lbs). It has been estimated that only 1 kilogram (2.2 lbs) would be enough to kill the entire human population.”

There are several important implications to this finding. First, the consumption of wheat preferentially favors the growth of pathogenic bacteria in the gut. Second, given that much of the Western diet now contains Roundup herbicide contaminated food, including wheat – where Roundup is used as a pre-harvest dessicant, virtually guaranteeing it is contaminated with it despite being non-GMO – there is likely an amplifying effect of this pathogenic bacteria in those who consume both wheat and GMO food (i.e. synergistic toxicity). This may help to explain why the mass introduction of GMOs over the past decade has contributed to the explosion in diagnoses of gluten sensitivity.

Additionally, a recent article by Dr. Kelly Brogan, MD, discussed how the hunter-gatherer microbiome is conspicuously low in the Clostridium bacteria family, based on research into the modern hunter-gatherer Hadza gastrointestinal flora. This study indicates that for much of our evolution – the vast majority of it – Clostridium was not present in significant quantities in our bodies, likely because their diet did not encourage it.

From the perspective of our ancestral microbiome, modern humankind has become almost a new species due to our reliance on novel new ‘foods’ like wheat and agrochemical contaminated GMOs that have contributed to the development of a relationship with strains of bacteria that were alien to us, for some populations, even 100 years ago. The microbiome’s genome is 99% larger than our genome – containing 2 million protein coding genes versus only 23,000 for the human body alone. The shift towards pathological strains may have to do both with a radical change in the human diet to a grain-based — and particularly wheat-based diet – and, again, the ever-expanding consumption of Roundup herbicide laden foods.

So, what does this mean?  Where do we go from here?

This study adds to a growing body of research showing that wheat is toxic to everyone, and not only to those with celiac disease. By forcing our body to become inhabitants of strains of bacteria that we have never before needed to occupy our bodies, and which are capable of doing great harm, it can lead to a wide range of health problems, such as infections and intestinal disases, that conventional medical thinking never connects to the diet. While some of the strains that degrade gluten are non-pathogenic (e.g. 39% were from the mostly beneficial Lactobacillus family), taken as a whole, the discovery that a variety of Clostridium strains (as well as related potentially pathogenic strains from genuses such as Klebsiella and Staphylococcus) thrive in a wheat-based diet, and adding in the fact that GMO foods further contribute to their overgrowth, it seems that the pathway towards optimal health requires the elimination of both.

Antibiotics for All but Very Mild C difficile.

On October 29, the European Society of Clinical Microbiology and Infection (ESCMID) issued updated guidelines for Clostridium difficile infection (CDI), reviewing treatment options of antibiotics, toxin-binding resins and polymers, immunotherapy, probiotics, and fecal or bacterial intestinal transplantation. The new recommendations, published online October 5 in Clinical Microbiology and Infection, advise antibiotic treatment for all but very mild cases of CDI.

CDI, which is potentially fatal, is now the leading cause of healthcare-acquired infections in hospitals, having surpassed methicillin-resistant Staphylococcus aureus.

“[A]fter the recent development of new alternative drugs for the treatment of CDI (e.g. fidaxomicin) in US and Europe, there has been an increasing need for an update on the comparative effectiveness of the currently available antibiotic agents in the treatment of CDI, thereby providing evidence-based recommendations on this issue,” write Sylvia B. Debast, from the Centre for Infectious Diseases, Leiden University Medical Center The Netherlands, and colleagues from the ESCMID Committee.

The new guideline, which updates the 2009 ESCMID recommendations now used widely in clinical practice, summarizes currently available CDI treatment options and offers updated treatment recommendations on the basis of a literature search of randomized and nonrandomized trials.

The ESCMID and an international team of experts from 11 European countries developed recommendations for different patient subgroups, including initial nonsevere disease, severe CDI, first recurrence or risk for recurrent disease, multiple recurrences, and treatment of CDI when patients cannot receive oral antibiotics.

Antibiotic Recommended in Most Cases

Specific recommendations include the following:

·         For nonepidemic, nonsevere CDI clearly induced by antibiotic use, with no signs of severe colitis, it may be acceptable to stop the inducing antibiotic and observe the clinical response for 48 hours. However, patients must be monitored very closely and treated immediately for any signs of clinical deterioration.

·         Antibiotic treatment is recommended for all cases of CDI except for very mild CDI, which is actually triggered by antibiotic use. Suitable antibiotics include metronidazole, vancomycin, and fidaxomicin, a newer antibiotic that can be given by mouth.

·         For mild/moderate disease, metronidazole is recommended as oral antibiotic treatment of initial CDI (500 mg 3 times daily for 10 days).

·         Fidaxomicin may be used in all CDI patients for whom oral antibiotic treatment is appropriate. Specific indications for fidaxomicin may include first-line treatment in patients with first CDI recurrence or at risk for recurrent disease, in patients with multiple recurrences of CDI, and in patients with severe disease and nonsevere CDI.

These recommendations were based on 2 large phase 3 clinical studies that compared 400 mg/day oral fidaxomicin with 500 mg/day oral vancomycin, the standard of care. The rate of CDI recurrence was lower with fidaxomicin, but the cure rate was similar for both treatments.

·         For severe CDI, suitable oral antibiotic regimens are vancomycin 125 mg 4 times daily (may be increased to 500 mg 4 times daily) for 10 days, or fidaxomicin 200 mg twice daily for 10 days.

·         In life-threatening CDI, there is no evidence supporting the use of fidaxomicin.

·         In severe CDI or life-threatening disease, the use of oral metronidazole is strongly discouraged.

·         For multiple recurrent CDI, fecal transplantation is strongly recommended.

·         Total abdominal colectomy or diverting loop ileostomy combined with colonic lavage is recommended for CDI with colonic perforation and/or systemic inflammation and deteriorating clinical condition despite antibiotic treatment.

·         Additional measures for CDI management include discontinuing unnecessary antimicrobial therapy, adequate fluid and electrolyte replacement, avoiding antimotility medications, and reviewing proton pump inhibitor use.

Secret Botulism Paper Published.

The discovery of a new form of the deadly botulinum toxin gets published, but its sequence is kept under wraps until an antidote is developed.

In a publishing first, the sequence of a newly discovered protein is not divulged in papers announcing the finding. Researchers at the California Department of Public Health in Sacramento discovered the protein, a new type of the extremely dangerous botulinum toxin, lurking in the feces of a child who displayed the symptoms of botulism. They published their findings in two reports on the website of The Journal of Infectious Diseases, but absent from either paper was the DNA sequence of the protein, the eighth form of botulinum toxin recovered from the bacteriumClostridium botulinum. The move represents the first time that a DNA sequence has been omitted from such a paper. “Because no antitoxins as yet have been developed to counteract the novel C. Botulinum toxin,” wrote editors at The Journal of Infectious Diseases, “the authors had detailed consultations with representatives from numerous appropriate US government agencies.”

These agencies, which included the Centers for Disease Control and Prevention and the Department of Homeland Security, approved publication of the papers so long as the gene sequence that codes for the new protein was left out. According to New Scientist, the sequence will be published as soon as antibodies are identified that effectively combat the toxin, which appears to be part of a whole new branch on the protein’s family tree.

Diverse Sources of C. difficile Infection Identified on Whole-Genome Sequencing.


It has been thought that Clostridium difficile infection is transmitted predominantly within health care settings. However, endemic spread has hampered identification of precise sources of infection and the assessment of the efficacy of interventions.


From September 2007 through March 2011, we performed whole-genome sequencing on isolates obtained from all symptomatic patients with C. difficile infection identified in health care settings or in the community in Oxfordshire, United Kingdom. We compared single-nucleotide variants (SNVs) between the isolates, using C. difficileevolution rates estimated on the basis of the first and last samples obtained from each of 145 patients, with 0 to 2 SNVs expected between transmitted isolates obtained less than 124 days apart, on the basis of a 95% prediction interval. We then identified plausible epidemiologic links among genetically related cases from data on hospital admissions and community location.


Of 1250 C. difficile cases that were evaluated, 1223 (98%) were successfully sequenced. In a comparison of 957 samples obtained from April 2008 through March 2011 with those obtained from September 2007 onward, a total of 333 isolates (35%) had no more than 2 SNVs from at least 1 earlier case, and 428 isolates (45%) had more than 10 SNVs from all previous cases. Reductions in incidence over time were similar in the two groups, a finding that suggests an effect of interventions targeting the transition from exposure to disease. Of the 333 patients with no more than 2 SNVs (consistent with transmission), 126 patients (38%) had close hospital contact with another patient, and 120 patients (36%) had no hospital or community contact with another patient. Distinct subtypes of infection continued to be identified throughout the study, which suggests a considerable reservoir of C. difficile.


Over a 3-year period, 45% of C. difficile cases in Oxfordshire were genetically distinct from all previous cases. Genetically diverse sources, in addition to symptomatic patients, play a major part in C. difficiletransmission.

Source: NEJM


Novel Strategy for Preventing CDI.


Antigermination therapy prevented disease in mice challenged with massive inocula of C. difficile spores.

Spore germination is necessary for the development of symptomatic Clostridium difficile infection (CDI). Recent investigations have yielded novel nonantibiotic agents that inhibit spore germination mediated by taurocholate, a bile salt. To determine whether CamSA — a taurocholate analog that inhibits germination in vitro — might prevent CDIs, researchers conducted experiments using a mouse model.

Mice received an antibiotic “cocktail” in their drinking water for 3 days, and then a single dose of intraperitoneally administered clindamycin on day 4. The animals, in groups of five, each received 0 mg/kg, 5 mg/kg, 25 mg/kg, or 50 mg/kg of CamSA by oral gavage, followed on day 5 by gavage challenge with a massive dose of C. difficile spores and additional doses of CamSA 1 and 24 hours thereafter. The mice were then monitored for clinical evidence of CDI, and disease signs were scored. Some animals in each group were sacrificed and underwent postmortem examination of the gastrointestinal tract.

All animals that received 0 mg/kg of CamSA developed severe CDI within 48 hours of spore inoculation. In contrast, those that received 50 mg/kg showed no clinical or histopathologic evidence of CDI. Animals that received either 5 mg/kg or 25 mg/kg had a delayed onset of CDI and a reduction in disease severity. The excretion of cells and spores in feces also correlated with CamSA dose: Vegetative cells predominated in animals in the untreated (0-mg/kg) and 5-mg/kg groups, whereas spores predominated in those in the 25-mg/kg and 50-mg/kg groups.

Although CamSA (3 doses at 50 mg/kg) was protective in mice challenged with spores, it was ineffective in preventing CDI in animals challenged with vegetative cells.

Comment: These findings in a murine model deserve special attention. The novel, nonantibiotic strategy studied could be a “game changer” as we consider potential approaches for CDI management. As the authors note, patients determined to be at risk for CDI could receive CamSA before initiating antibiotics, then additional doses as needed until the intestinal microbiota has recovered.

Source: Journal Watch Infectious Diseases


Antibiotic Stewardship Program Reduces C. difficile Infection Rates.

Restricted cephalosporin, fluoroquinolone, and clindamycin use was associated with reduced antibiotic consumption and a decline in the incidence trend of Clostridium difficile infection.

Use of cephalosporins, fluoroquinolones, and clindamycin has repeatedly been associated with increased risk for Clostridium difficile infection (CDI). However, little is known about how CDI rates are affected by antibiotic stewardship programs aimed at decreasing the administration of such “high-risk” antibiotics.

Researchers recently described their experience with a restriction policy for second- and third-generation cephalosporins, fluoroquinolones, and clindamycin at a hospital in Northern Ireland that became effective in January 2008, after a major CDI outbreak in other, affiliated institutions. The policy was devised based on a time-series analysis involving one of these affiliated institutions for the period February 2002 through March 2007, which suggested that treatment of 14 patients with second-generation cephalosporins or 8 with third-generation cephalosporins — versus 94 with amoxicillin/clavulanic acid or 78 with macrolides — would result in one CDI case (Antimicrob Agents Chemother 2009; 53:2082).

Cephalosporins, quinolones, and clindamycin were prescribed significantly less frequently during the study period following implementation of the restriction policy (January 2008–June 2010) than during the 4-year preimplementation period; the use of other antibiotics remained unchanged. The intervention resulted in an overall reduction in antibiotic use and a reversal of the increasing trend for antibiotic consumption. These changes were associated with a significant decline in the incidence trend for CDI (rate decrease, 0.047/1000 bed-days per month). Variations in CDI incidence were affected by the Charlson patient comorbidity index, with a lag of 1 month.

Comment: This report on a successful antibiotic stewardship intervention is a nice example of the cause–effect relationship between antibiotic use and the occurrence of potentially serious nosocomial infections. The authors note that an antimicrobial-management team’s close surveillance of prescribing was key to successful implementation of the restriction policy.

Sourc: Journal Watch Infectious Disease.


Bacterial infections in end-stage liver disease: current challenges and future directions.


Bacterial infections continue to be a leading cause of mortality andacute-on-chronic liver failure in end-stage liver disease (ESLD). The consequences of infection include prolonged hospitalisation, acute kidney injury (AKI), death, de-listing from liver transplant and susceptibility to further infections. The diagnosis of infections in cirrhosis is fraught due to the background of a partial systemic inflammatory response syndrome (SIRS) state and negative cultures in 30-50% of patients. Furthermore, the lack of multi-center studies limits the generalisability of currently available results. The modulation of infections by the underlying immune state, gut barrier function and super-imposed medications such as beta-blockers, proton pump inhibitors and antibiotics is required. A rational approach to the diagnosis and prevention of AKI associated with infection, withjudicious use of crystalloids and albumin, is also needed. Changes in bacteriology including emergence of multi-resistant organisms and Clostridium difficile have also recently changed the approach for prophylaxis and therapy of infections. Effective strategies for the prevention, diagnosis, and management of infections in ESLD form a large unmet need. A systematic approach to study the epidemiology, bacteriology, resistance patterns, and procedure and medication utilisation specific to ESLD is needed to improve outcomes.

Bacterial infections in patients with end-stage liver disease affect candidacy for liver transplantation. Up to one-third of all hospitalised patients with cirrhosis are infected.1–5 With sepsis, mortality increases to more than 50% and is associated with significant costs.6 A recent systematic review demonstrated a fourfold increased risk of death in infected cirrhotic patients compared with their non-infected counterparts.7 More importantly, intensive care unit (ICU) mortality of patients with cirrhosis has remained unchanged over 50 years, unlike disease states such as cardiac failure where mortality has decreased.8 Therefore the prevention, diagnosis and management of infections in patients with end-stage liver disease form a large unmet need. This commentary briefly reviews infections in patients with cirrhosis, and outlines specific areas that need to be addressed in such patients hospitalised with infections.

Scope of the problem

The magnitude of the problem of infections in cirrhosis is not quantifiable for many reasons. Infections are often difficult to recognise in patients with cirrhosis because 30–50% of infections, such as spontaneous bacterial peritonitis (SBP), can remain culture negative.9 Conventional risk-scoring strategies, such as the systemic inflammatory response syndrome (SIRS) criteria, cannot reliably differentiate sepsis (SIRS plus infection) from non-infectious SIRS.10 This is important because a partial SIRS-like state is present in most patients with decompensated end-stage liver disease and therefore in itself cannot be used to differentiate between infected and uninfected patients. There are also difficulties diagnosing the presence of infections, especially in hospitalised cirrhotic patients.5 Strategies such as measuring C-reactive protein and procalcitonin may be helpful in selected patients, but a specific differentiator is still needed.11 ,12 Time-appropriate strategies are needed to suspect infections and send cultures early so as to initiate appropriate antimicrobial therapy. Also a heightened suspicion of potentially resistant organisms is required in order to change therapy as needed.2 In addition, most current studies are single centre, and there are limited data on the emergence of multiresistant strains and healthcare-associated (which develop <48 h after admission in patients with previous exposure to healthcare services in the preceding 90 or 180 days) and nosocomial (which develop >48 h after admission) infections.

Some idea of the magnitude of the problem may be obtained from the US nationwide inpatient sample (NIS), which analyses data from 20% of acute care hospitals and includes 8 million discharge records from 38 states. The NIS identified 65 072 patients in 2006 with a discharge diagnosis of cirrhosis. The total costs incurred were approximately US$14 billion per year. Of the hospitalised patients, 26 300 had presumed infection and required ICU support, as identified by mechanical ventilation and invasive cardiovascular monitoring. The in-house mortality of the hospitalised cirrhotic patients was 53%, or 13 800 deaths a year nationwide. The mean length of hospitalisation was 13.8 days. The total costs associated with ICU admissions in cirrhotic patients with presumed infection were US$3 billion, with mean costs of US$116 200 per admission and average daily costs of US$16 589 in non-survivors.

Another study from the NIS showed that Clostridium difficile infection in patients with cirrhosis was associated with a significantly higher mortality, length of stay and total costs compared with patients admitted with cirrhosis without C difficile and patients with C difficile without cirrhosis. This is striking because the mean age of the patients with C difficile without cirrhosis was significantly higher than that of patients with C difficile and cirrhosis.13 In the Korean National database, patients with cirrhosis and bacteraemia were significantly more likely to die than those without cirrhosis.14 Bacteraemia in cirrhotic patients was more likely to be due to intra-abdominal infections and Klebsiella pneumoniae, and less likely to be due to coagulase-negative Staphylococcus. Multivariate analysis confirmed cirrhosis as an independent risk factor for mortality (HR 2.11, 95% CI 1.43 to 3.13).14

The North American Consortium for the Study of End-Stage Liver Disease (NACSELD) currently includes 12 centres throughout North America focused on determining outcomes after infections in patients with cirrhosis.15 Preliminary data from the NACSELD study noted that, in 176 patients from nine sites, the majority of infections were SBP and urinary tract infection (UTI), followed by spontaneous bacteraemia, skin, respiratory and C difficile infections. Gram-positive (36%) organisms were the most common, followed by Gram-negative (30%) organisms. The remainder were either fungal (4%) in origin or infections without an isolated organism. The death rate was highest for respiratory (44%), bacteraemia (38%) and C difficile (41%) infections, and lowest for urinary (21%) and skin (29%) infections or SBP (17%). The index infections were healthcare-associated (56%) or nosocomial (20%), and, importantly, 28% of patients developed a second infection during hospitalisation. The overall mortality was 25%, and patients who died had a higher Model for End-Stage Liver Disease (MELD) score at admission (25±8 vs 19±7, p<0.001) and were more likely to have hepatic encephalopathy (HE), hepatorenal syndrome (HRS), mechanical ventilation and ICU stay during hospitalisation (all p<0.0001). There was a higher incidence of second infections during hospitalisation in patients who died than in patients who survived (53% vs 20%, p=0.0001). Patients who developed a second infection were more likely to have a Gram-negative first infection, an ICU stay, lower albumin, greater length of hospitalisation and higher MELD score. Multivariate analysis showed that only second infection (p=0.0009) and MELD score (p<0.0001) were associated with death. Therefore there is a need to develop early diagnostic and prognostic markers, including biomarkers, for a better understanding of infections so as to improve outcomes.

Contribution of drugs such as antibiotics, proton pump inhibitors (PPIs) and ß blockers to infections and underlying immune status

Changes in gut bacteria in cirrhosis can lead to bacterial overgrowth with subsequent enhanced bacterial translocation from the gut to the systemic circulation and ascites, identified by bacterial DNA or by isolating bacteria in systemic biofluids. Bacterial translocation is the major pathogenetic factor for infections.5 ,16–18 Bacterial translocation can be silent or can result in florid infections.19 Even in the absence of infection, bacterial translocation can increase mortality.20 ,21 It is also a process that is facilitated by acid suppression22 ,23 and increased intestinal permeability in cirrhosis, specifically with advanced disease. Sepsis as a result of bacterial translocation and small-bowel bacterial overgrowth is a key component of the natural history of infections.20 However, one of the key modulators of outcomes of infections is the underlying immune status, which is negatively affected at multiple levels in cirrhosis. Specifically, the neutrophil burst, phagocytosis and opsonisation are impaired.21 Recent evidence has also indicated that antimicrobial peptides and NOD2 genetic variants are altered in patients with cirrhosis.24 ,25 A deeper understanding of the bacterial–immune interface either at the intestinal wall or within the ascitic fluid or mesenteric lymph nodes is important for developing biomarkers that would predict development of infection with an overall view to prevention.26

Single-centre studies have associated the use of PPIs with SBP and C difficile.13 ,27 This is an important observation, as PPIs are some of the most overprescribed drugs for cirrhosis.28 An appropriate indication for PPI use exists in fewer than half of the patients.29 PPIs predispose to bacterial overgrowth and adversely affect immune function.30 Another seemingly contradictory association is the effect of non-selective ß blockers (NSBBs) on the negative outcomes in cirrhosis. While a meta-analysis showed a reduced development of SBP in previous studies, a recent non-randomised study demonstrated a worse survival in the subset with refractory ascites.31 ,32 The effect of NSBBs on cirrhosis outcomes has led to the formulation of a ‘window hypothesis’, which suggests that NSBBs only improve outcomes in a narrow window of the cirrhosis natural history between those who have medium to large varices before the development of end-stage liver disease.33 Therefore the clinical role of NSBBs in cirrhosis needs to be elucidated further.

The role of non-absorbable antibiotics, such as rifaximin, in the modulation of infections in cirrhosis is also emerging. Whereas the pivotal HE trial did not show a significant difference in the rate of infections between groups, subsequent small studies reported a protective role of rifaximin against endotoxaemia and SBP.34–36 Outpatient prophylaxis using fluoroquinolones or sulfamethoxazole/trimethoprim in patients with previous SBP has been clearly shown to reduce subsequent episodes of SBP, but not survival.37 It is not completely clear whether these agents can improve outcomes in subgroups of patients with ascites fluid albumin <1.0 g/dl. SBP prophylaxis has been associated with the development of C difficile in a single-centre study.13 The study of SBP prophylaxis becomes more nuanced, especially when the emergence of multiresistant strains is considered.2 Further studies into the use of antibiotics are required to determine their role in reducing infections and mortality.

Thus several lines of evidence suggest the influence of outpatient medication on infection risk. Considering the small sample size and retrospective nature of most of these studies, further evaluation of drugs such as PPIs, non-absorbable antibiotics (such as rifaximin) and NSBBs is needed to determine their role in infections.

Prognosis and management in the ICU

Several precipitating factors are associated with deterioration in cirrhosis leading to multiple organ failure. These include infection, gastrointestinal bleeding, alcoholic hepatitis, superimposed viral hepatitis, drug-induced hepatotoxicity, and surgery. The response to infection in patients with cirrhosis is often exaggerated, leading to ICU admission because of sepsis, severe sepsis and septic shock.38 MELD score has been validated as a predictor of mortality in cirrhotic patients in the ICU and may have better prognostic capacity than the Child–Turcotte–Pugh score and the Simplified Acute Physiology Score II. The Acute Physiology and Chronic Health Evaluation III score is another predictor of early ICU mortality. The Sequential Organ Failure Assessment score correlates with mortality: failure of two organ systems is associated with a mortality of 55%, and failure of three or more organs with almost 100% mortality.39 Even when supportive measures are introduced, the underlying immune dysfunction state (immune paralysis following the first infection which contributes to secondary infections), poor nutrition, ongoing portal hypertension-related systemic haemodynamic changes, HE and gastrointestinal bleeding prevent recovery in these patients. Liver transplantation is ultimately an effective form of therapy for these patients, and worsening liver and renal function increase the MELD score, but ongoing infection and multiorgan system dysfunction make them generally poor candidates.

The ‘sepsis bundle’ has been accepted as the standard of care in patients with severe sepsis in the ICU.40 It is not clear whether these recommendations apply to patients with cirrhosis and severe sepsis. For example, arterial lines and central venous catheters are recommended for monitoring of mean arterial pressure and central venous pressure in severe sepsis. However, in critically ill cirrhotic patients, such vascular access may be associated with a significantly increased risk of bleeding. Red blood cell transfusions are recommended to increase central venous oxygen saturation. However, red blood cell transfusions in cirrhotic patients may be associated with an increased risk of variceal bleeding. Thus the role of the sepsis bundle in cirrhosis needs validation.

The key areas of need in the management of cirrhotic patients in the ICU is the prevention of nosocomial and second infections, reduction of unnecessary instrumentation, judicious use of antibiotic and antifungal agents, and validation of prognostic scores that take into account the underlying liver disease severity. Additional areas that need to be addressed are whether albumin is the preferred volume expander, how coagulopathy should be corrected, the optimal vasopressor support, the methodology for determining adrenal insufficiency, and the situations in which steroids should be given and the doses that should be used.6 Finally, the role of artificial and bioartificial liver support devices needs to be determined in this population.41

Prevention and treatment of acute kidney injury (AKI) in infected patients with cirrhosis

A critical need is to prevent and adequately treat renal dysfunction in infected cirrhotic patients. This is because renal dysfunction with AKI has emerged as a major determinant of mortality in patients with cirrhosis.42 ,43 AKI, including HRS, is associated with a markedly shorter survival. In patients with decompensated cirrhosis admitted to hospital, increased creatinine concentration within 24 h of admission is associated with poorer survival. Even more profound is the requirement of renal replacement therapy, which is associated with 94% in-hospital mortality.44 While most cases of functional renal impairment respond to volume challenge, with return of renal function to baseline levels, approximately one-third of patients are not volume responsive; these include patients with HRS or acute tubular necrosis.45 Therefore the first line of management of AKI in hospitalised cirrhotic patients is volume expansion, the response to which can determine the prognosis and subsequent management—for example, the use of vasoconstrictors would be indicated for volume-unresponsive cases of AKI such as HRS. Acute or type 1 HRS is defined as renal failure, which is characterised by a doubling of the initial serum creatinine to a level of >2.5 mg/dl in <2 weeks, which has been reported in about 10% of cirrhotic inpatients. Chronic or type 2 HRS is characterised by moderate renal failure, with serum creatinine between 1.5 and 2.5 mg/dl.45 Whereas type 2 HRS is usually associated with refractory ascites and follows a steady declining course, type 1 HRS is usually precipitated by an acute event and is often part of multiorgan system failure.46 The most common precipitating factor of type 1 HRS is bacterial infection,47 ,48 and this may occur despite clearance of the bacterial infection. The inflammatory response to bacterial infections increases systemic arterial vasodilatation, with further reduction of the effective arterial blood volume and further renal vasoconstriction, leading to renal failure.

SBP was the first bacterial infection recognised to be associated with a high incidence of renal failure in cirrhosis. This occurs in approximately one-third of patients despite resolution of the infection,48 ,49 and is associated with an in-hospital mortality of 42–67%.49 ,50 However, it was soon recognised that any bacterial infection could precipitate renal failure in cirrhosis.51 Patients who develop renal failure with bacterial infection have a higher MELD score and lower mean arterial pressure.47 Biliary or gastrointestinal tract infections are more likely to be associated with the development of renal failure, followed by SBP and UTI, although other infections such as pneumonia or even skin infections are associated with the development of renal failure. Once renal failure develops, it can be transient, resolving with the clearance of the infection, or it can persist, or even progress despite the clearance of infection.51 Biliary or gastrointestinal infection-induced renal failure is most likely to progress, followed by SBP- and UTI-related renal failure.47 Once renal failure sets in, the probability of survival at 3 months is only 31%, and decreases with higher MELD scores.52

Prevention of renal failure in the setting of infections remains a challenge. With SBP, patients given albumin have a lower incidence of renal failure, associated with improved survival.53 Underlying liver and renal function determine the risk of developing renal dysfunction associated with SBP. In one study, using the definition of high risk as plasma urea ≥60 mg/dl and serum bilirubin ≥4 mg/dl, almost 30% of patients who presented with SBP could be regarded as low risk for the development of renal failure and therefore were not given albumin. Renal failure only developed in 4.7% of the low-risk group, which had a 3.1% mortality. In contrast, 40% of the patients with SBP in the high-risk group (70% of the entire cohort) already had renal failure at the time of SBP diagnosis, while an additional 26% developed renal failure before SBP resolution.54 Those in the high-risk group treated with albumin had a significantly improved 90-day survival (p=0.01). The number of patients needed to treat in the high-risk group to avoid one death was 5.5. Similar findings were also reported by Sigal et al55 and Terg et al. 56 Thus the need for universal administration of albumin for the treatment of SBP needs to be re-evaluated. The need for albumin to prevent the development of renal failure in other bacterial infections also needs to be examined.

A small study assessed the effects of 2 mg/day terlipressin (a systemic vasoconstrictor) in addition to ceftriaxone (1 g every 12 h) on systemic haemodynamics and clinical outcome in patients with SBP.57 This regimen improved the hyperdynamic circulation compared with ceftriaxone alone. There was a significant increase in SBP reversal and a reduction in mortality with terlipressin at 48 h. Therefore the use of a vasoconstrictor should be investigated as a potential alternative, or additive, to albumin in the prevention of renal impairment in SBP.

Renal dysfunction, especially HRS type 1, is treated with vasoconstrictors and albumin infusion. The choice of vasoconstrictor depends on local availability: midodrine in North America in combination with octreotide, and terlipressin for most other parts of the world.45 Given the poor survival of patients with cirrhosis, bacterial infections and established renal failure,47 there is now a trend towards treating renal impairment at an earlier stage than defined type 1 HRS. One challenge has been to define an early stage of renal dysfunction, as serum creatinine is an inaccurate measure of renal function.58 ,59

A new definition of AKI in cirrhosis has been proposed,60 which is an increase in serum creatinine of 0.3 mg/dl in <48 h (table 1).61 The exact prevalence of AKI according to this new definition is unknown, but is an important question because it appears that such small increases in serum creatinine in patients with cirrhosis may negatively affect survival.

View this table:

Table 1

Proposed definition of kidney disease in cirrhosis60

Several newer concepts are helping to shape treatment strategies. These include the understanding that both the acute deterioration in renal function and the background chronic renal dysfunction can be functional or structural in nature, and the recent recognition that the inflammatory response to bacterial infection may be partly responsible for the development of renal failure.

Measures for prevention, surveillance and identification of healthcare-associated and nosocomial infections and multiresistant bacteria and C difficile

The emergence of multiresistant species and the looming spectre of nosocomial and healthcare-associated infections are concerning. Nosocomial infections in the general population are estimated to affect 1.7 million persons a year, cost at least US$5 billion annually, and are the sixth leading cause of death in the USA.62–65 Although healthcare-associated and nosocomial infections are different, they both increase length of stay, cost and mortality, and occur more commonly in ‘sicker’ patients following procedures such as surgery or in those who need mechanical ventilation or vascular or urinary catheters.66 The organisms responsible are often resistant to the ‘first line’ antibiotics often given for similar community-acquired infections, making empiric antibiotic treatment decisions more challenging and expensive.2 ,67–69

Nosocomial infections in non-cirrhotic patients are usually broken down into four categories62 ,66–68 as shown in table 2. However, there has been little published on nosocomial infections in patients with cirrhosis. Fernandez et al studied multiresistant organisms and nosocomial infections occurring in a single centre over three time periods: 1998–2002 (n=572), 2005–2007 (n=507) and 2010–2011 (n=162).2 ,3 Infection was present in one-third of hospital admissions: 25–32% healthcare associated and 36–45% nosocomial. Community-acquired infections were most commonly SBP (35%) and cellulitis (19%), healthcare-associated infections were most commonly SBP (28%) and UTIs (24%), and nosocomial infections were dominated by UTIs (31%).2 C difficile was not studied. Overall, multidrug-resistant (MDR) organisms caused 4% of community-acquired, 14% of healthcare-associated and 35% of nosocomial infections (p<0.001).2 This high risk of MDR organisms decreased the efficacy of their ‘standard of care’ antibiotic regimens to 40% in nosocomial infections, and doubled mortality in patients infected with MDR organisms. In another European single-centre study, Merli and colleagues found that one-third of 150 hospitalised patients with cirrhosis experienced at least one infection; 78% were healthcare-associated or nosocomial infections.4 UTIs were most common, and 64% were caused by MDR organisms. MDR organisms were predominantly Gram-negative isolates in SBP, such as Escherichia coli and K pneumoniae with extended spectrum β lactamase activity. The change in bacteriology also reflects an emergence of Gram-positive pathogens. A disturbing trend is the increased isolation of methicillin-resistant Staphylococcus aureus.70 Enterococcus faecalis and Enterococcus faecium have been isolated in 10–24% of infections in the setting of cirrhosis and are associated with a mortality of 25%. Focusing on specific infections, it has been found that SBP is an important cause of both community-acquired and nosocomial infections in patients with cirrhosis.71 ,72 Whereas community-acquired SBP is more commonly caused by Gram-negative rods, nosocomial SBP has an increased prevalence of Gram-positive cocci. In addition, nosocomial acquisition increases the risk of resistance to cephalosporin and fluoroquinolone and significantly increases mortality. Although previous reports on nosocomial infections did not include C difficile infection, it was a common nosocomial infection found in the NACSELD study and had the highest risk of mortality (28%).15 This is similar to the previous C difficile National Database study in cirrhosis in which length of stay doubled, mortality markedly increased, and cost increased by US$43 665/infected admission.13

View this table:

Table 2

Categories of nosocomial infections in the non-cirrhotic population66

We propose, on the basis of our and other previous work in this area, that healthcare-associated and nosocomial infections in cirrhosis be broken down into six categories: spontaneous bloodstream infections unrelated to interventions or infections at other sites, UTIs, pulmonary infections, SBP, C difficile and intervention-related infections (table 3). Although up to one-third of all nosocomial infections should be preventable,73 ‘success in curbing their emergence remains elusive.’74 It should be emphasised that the data available on healthcare-associated and nosocomial infections in cirrhosis are largely limited to single centres, although smaller multicentre studies exist.1–4 ,13 ,71 ,72 ,75–80

View this table:

Table 3

Proposed categories of nosocomial infections in cirrhosis


Because of the high morbidity and mortality in patients with cirrhosis who become infected (many of whom may be denied liver transplantation because of multiple organ failure) and the paucity of data in this field, we propose the studies outlined in table 4. Only through systematic study of epidemiology, bacteriology, resistance patterns, and procedure and medication utilisation specific to patients with cirrhosis will we discover how to routinely accomplish this in the most cost-effective way.

View this table:

Table 4

Challenges and future directions of bacterial infection management in cirrhosis


  • Funding This was partly funded by the NIH grant NIDDK RO1DK087913 and partly from an educational grant from Grifols Pharmaceuticals.
  • Competing interests None.
  • Provenance and peer review Not commissioned; externally peer reviewed.


    1. Borzio M,
    2. Salerno F,
    3. Piantoni L,
    4. et al

. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001;33:418.

[CrossRef][Medline][Web of Science]

    1. Fernandez J,
    2. Acevedo J,
    3. Castro M,
    4. et al

. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 2012;55:155161.


    1. Fernandez J,
    2. Navasa M,
    3. Gomez J,
    4. et al

. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 2002;35:1408.

[CrossRef][Medline][Web of Science]

    1. Merli M,
    2. Lucidi C,
    3. Giannelli V,
    4. et al

. Cirrhotic patients are at risk for health care-associated bacterial infections. Clin Gastroenterol Hepatol 2010;8:97985.


    1. Tandon P,
    2. Garcia-Tsao G

. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis 2008;28:2642.

[CrossRef][Medline][Web of Science]

    1. Olson JC,
    2. Wendon JA,
    3. Kramer DJ,
    4. et al

. Intensive care of the patient with cirrhosis. Hepatology 2011;54:186472.


    1. Arvaniti V,
    2. D’Amico G,
    3. Fede G,
    4. et al

. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010;139:124656.e1–5.


    1. Kim W,
    2. Shah N,
    3. Kamath P

. Economic impact of critical care in patients with cirrhosis in the US. Hepatology 2010;52:910A.

    1. Runyon BA,
    2. Canawati HN,
    3. Akriviadis EA

. Optimization of ascitic fluid culture technique. Gastroenterology 1988;95:13515.


    1. Cazzaniga M,
    2. Dionigi E,
    3. Gobbo G,
    4. et al

. The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome. J Hepatol 2009;51:47582.


    1. Li CH,
    2. Yang RB,
    3. Pang JH,
    4. et al

. Procalcitonin as a biomarker for bacterial infections in patients with liver cirrhosis in the emergency department. Acad Emerg Med 2011;18:1216.


    1. Fernandez J,
    2. Gustot T

. Management of bacterial infections in cirrhosis. J Hepatol 2012;56(Suppl 1):S112.


    1. Bajaj JS,
    2. Ananthakrishnan AN,
    3. Hafeezullah M,
    4. et al

. Clostridium difficile is associated with poor outcomes in patients with cirrhosis: a national and tertiary center perspective. Am J Gastroenterol 2010;105:10613.


    1. Kang CI,
    2. Song JH,
    3. Chung DR,
    4. et al

. Liver cirrhosis as a risk factor for mortality in a national cohort of patients with bacteremia. J Infect 2011;63:33643.


    1. Bajaj J,
    2. O’Leary JG,
    3. Olson JC,
    4. et al

. In hospital mortality in cirrhosis is related to infections independent of MELD score: a prospective multi-center study from the North American Consortium for the study of end-stage liver disease (NACSELD). Hepatology 2011;54. Abstract, 300A.

    1. Garcia-Tsao G

. Spontaneous bacterial peritonitis: a historical perspective. J Hepatol 2004;41:5227.


    1. Cirera I,
    2. Bauer TM,
    3. Navasa M,
    4. et al

. Bacterial translocation of enteric organisms in patients with cirrhosis. J Hepatol 2001;34:327.

[Medline][Web of Science]

    1. Garcia-Tsao G

. Bacterial translocation: cause or consequence of decompensation in cirrhosis? J Hepatol 2001;34:1505.


    1. Navasa M,
    2. Rodes J

. Bacterial infections in cirrhosis. Liver Int 2004;24:27780.

[CrossRef][Medline][Web of Science]

    1. Thabut D,
    2. Massard J,
    3. Gangloff A,
    4. et al

. Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure. Hepatology 2007;46:187282.

[CrossRef][Medline][Web of Science]

    1. Manakkat Vijay GK,
    2. Taylor NJ,
    3. Shawcross DL

. The quest for the elusive factors that underpin neutrophil dysfunction in cirrhosis goes on. J Hepatol 2012;56:121213.


    1. Frances R,
    2. Zapater P,
    3. Gonzalez-Navajas JM,
    4. et al

. Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis. Hepatology 2008;47:97885.

[CrossRef][Medline][Web of Science]

    1. Jun DW,
    2. Kim KT,
    3. Lee OY,
    4. et al

. Association between small intestinal bacterial overgrowth and peripheral bacterial DNA in cirrhotic patients. Dig Dis Sci 2010;55:146571.


    1. Nischalke HD,
    2. Berger C,
    3. Aldenhoff K,
    4. et al

. Toll-like receptor (TLR) 2 promoter and intron 2 polymorphisms are associated with increased risk for spontaneous bacterial peritonitis in liver cirrhosis. J Hepatol 2011;55:101016.


    1. Teltschik Z,
    2. Wiest R,
    3. Beisner J,
    4. et al

. Intestinal bacterial translocation in rats with cirrhosis is related to compromised paneth cell antimicrobial host defense. Hepatology 2012;55:115463.


    1. Wiest R,
    2. Krag A,
    3. Gerbes A

. Spontaneous bacterial peritonitis: recent guidelines and beyond. Gut 2012;61:297310.

[FREE Full text]

    1. Bajaj JS,
    2. Zadvornova Y,
    3. Heuman DM,
    4. et al

. Association of proton pump inhibitor therapy with spontaneous bacterial peritonitis in cirrhotic patients with ascites. Am J Gastroenterol 2009;104:11304.

[CrossRef][Medline][Web of Science]

    1. Chavez-Tapia NC,
    2. Tellez-Avila FI,
    3. Garcia-Leiva J,
    4. et al

. Use and overuse of proton pump inhibitors in cirrhotic patients. Med Sci Monit 2008;14:CR46872.


    1. Goel GA,
    2. Deshpande A,
    3. Lopez R,
    4. et al

. Increased rate of spontaneous bacterial peritonitis among cirrhotic patients receiving pharmacologic acid suppression. Clin Gastroenterol Hepatol 2012;10:4227.


    1. Kedika RR,
    2. Souza RF,
    3. Spechler SJ

. Potential anti-inflammatory effects of proton pump inhibitors: a review and discussion of the clinical implications. Dig Dis Sci 2009;54:231217.


    1. Serste T,
    2. Melot C,
    3. Francoz C,
    4. et al

. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010;52:101722.


    1. Senzolo M,
    2. Cholongitas E,
    3. Burra P,
    4. et al

. Beta-blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int 2009;29:118993.


    1. Krag A,
    2. Wiest R,
    3. Albillos A,
    4. et al

. The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease. Gut 2012;61:9679.

[FREE Full text]

    1. Bass NM,
    2. Mullen KD,
    3. Sanyal A,
    4. et al

. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010;362:107181.


    1. Kalambokis GN,
    2. Tsianos EV

. Rifaximin reduces endotoxemia and improves liver function and disease severity in patients with decompensated cirrhosis. Hepatology 2012;55:6556.


    1. Vlachogiannakos J

. Long-term administration of rifaximin improves the prognosis of patients with alcohol-related decompensated cirrhosis: a case-control study (abstract). Hepatology 2010;52:328A.

    1. Rimola A,
    2. Garcia-Tsao G,
    3. Navasa M,
    4. et al

. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000;32:14253.

[Medline][Web of Science]

    1. Levesque E,
    2. Hoti E,
    3. Azoulay D,
    4. et al

. Prospective evaluation of the prognostic scores for cirrhotic patients admitted to an intensive care unit. J Hepatol 2011;56:95102.


    1. Lehner S,
    2. Stemmler HJ,
    3. Muck A,
    4. et al

. Prognostic parameters and risk stratification in intensive care patients with severe liver diseases. J Gastrointestin Liver Dis 2010;19:399404.


    1. Jain R,
    2. Kralovic SM,
    3. Evans ME,
    4. et al

. Veterans affairs initiative to prevent methicillin-resistant Staphylococcus aureus infections. N Engl J Med 2011;364:141930.

[CrossRef][Medline][Web of Science]

    1. Hassanein TI,
    2. Tofteng F,
    3. Brown RS Jr.,
    4. et al

. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology 2007;46:185362.

[CrossRef][Medline][Web of Science]

    1. Garcia-Tsao G,
    2. Parikh CR,
    3. Viola A

. Acute kidney injury in cirrhosis. Hepatology 2008;48:206477.

[CrossRef][Medline][Web of Science]

    1. Belcher JM,
    2. Garcia-Tsao G,
    3. Sanyal AJ,
    4. et al

. Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology. Published Online First: 27 March 2012. doi:10.1002/hep.25735

    1. Mackle IJ,
    2. Swann DG,
    3. Cook B

. One year outcome of intensive care patients with decompensated alcoholic liver disease. Br J Anaesth 2006;97:4968.

[Abstract/FREE Full text]

    1. Salerno F,
    2. Gerbes A,
    3. Gines P,
    4. et al

. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:131018.

[FREE Full text]

    1. Guevara M,
    2. Arroyo V

. Hepatorenal syndrome. Expert Opin Pharmacother 2011;12:140517.


    1. Fasolato S,
    2. Angeli P,
    3. Dallagnese L,
    4. et al

. Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features. Hepatology 2007;45:2239.

[CrossRef][Medline][Web of Science]

    1. Follo A,
    2. Llovet JM,
    3. Navasa M,
    4. et al

. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology 1994;20:1495501.

[Medline][Web of Science]

    1. Angeli P,
    2. Guarda S,
    3. Fasolato S,
    4. et al

. Switch therapy with ciprofloxacin vs. intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis: similar efficacy at lower cost. Aliment Pharmacol Ther 2006;23:7584.

[CrossRef][Medline][Web of Science]

    1. Tandon P,
    2. Garcia-Tsao G

. Renal dysfunction is the most important independent predictor of mortality in cirrhotic patients with spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol 2011;9:2605.


    1. Terra C,
    2. Guevara M,
    3. Torre A,
    4. et al

. Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score. Gastroenterology 2005;129:194453.


    1. Martin-Llahi M,
    2. Guevara M,
    3. Torre A,
    4. et al

. Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology 2011;140:48896.e4.


    1. Sort P,
    2. Navasa M,
    3. Arroyo V,
    4. et al

. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:4039.

[CrossRef][Medline][Web of Science]

    1. Poca M,
    2. Concepcion M,
    3. Casas M,
    4. et al

. Role of albumin treatment in patients with spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol 2012;10:30915.


    1. Sigal SH,
    2. Stanca CM,
    3. Fernandez J,
    4. et al

. Restricted use of albumin for spontaneous bacterial peritonitis. Gut 2007;56:5979.

[FREE Full text]

    1. Terg R,
    2. Gadano A,
    3. Cartier M,
    4. et al

. Serum creatinine and bilirubin predict renal failure and mortality in patients with spontaneous bacterial peritonitis: a retrospective study. Liver Int 2009;29:41519.

[CrossRef][Medline][Web of Science]

    1. Chelarescu O,
    2. Chelarescu D,
    3. Stratan I,
    4. et al

. Terlipressin influence in spontaneous bacterial peritonitis (abstract). J Hepatol 2004;40:67.

    1. Caregaro L,
    2. Menon F,
    3. Angeli P,
    4. et al

. Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis. Arch Intern Med 1994;154:2015.

[CrossRef][Medline][Web of Science]

    1. Sherman DS,
    2. Fish DN,
    3. Teitelbaum I

. Assessing renal function in cirrhotic patients: problems and pitfalls. Am J Kidney Dis 2003;41:26978.

[CrossRef][Medline][Web of Science]

    1. Wong F,
    2. Nadim MK,
    3. Kellum JA,
    4. et al

. Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. Gut 2011;60:7029.

[Abstract/FREE Full text]

    1. Mehta RL,
    2. Kellum JA,
    3. Shah SV,
    4. et al

. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.


    1. Peleg AY,
    2. Hooper DC

. Hospital-acquired infections due to gram-negative bacteria. N Engl J Med 2010;362:180413.

[CrossRef][Medline][Web of Science]

    1. Klevens RM,
    2. Edwards JR,
    3. Richards CL Jr.,
    4. et al

. Estimating health care-associated infections and deaths in U.S. hospitals, 2002. Public Health Rep 2007;122:1606.

[Medline][Web of Science]

    1. Kung HC,
    2. Hoyert DL,
    3. Xu J,
    4. et al

. Deaths: final data for 2005. Natl Vital Stat Rep 2008;56:1120.


    1. Stone PW,
    2. Hedblom EC,
    3. Murphy DM,
    4. et al

. The economic impact of infection control: making the business case for increased infection control resources. Am J Infect Control 2005;33:5427.

[CrossRef][Medline][Web of Science]

    1. Kasper DL,
    2. Braunwald E,
    3. Fauci AS,
    4. et al

. eds. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill, 2005.

    1. Wisplinghoff H,
    2. Bischoff T,
    3. Tallent SM,
    4. et al

. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004;39:30917.

[Abstract/FREE Full text]

    1. Hidron AI,
    2. Edwards JR,
    3. Patel J,
    4. et al

; Participating National Healthcare Safety Network Facilities. NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol 2008;29:9961011.

[CrossRef][Medline][Web of Science]

    1. Kallen AJ,
    2. Mu Y,
    3. Bulens S,
    4. et al

. Health care-associated invasive MRSA infections, 2005-2008. JAMA 2010;304:6418.


    1. Piroth L,
    2. Pechinot A,
    3. Minello A,
    4. et al

. Bacterial epidemiology and antimicrobial resistance in ascitic fluid: a 2-year retrospective study. Scand J Infect Dis 2009;41:84751.


    1. Cheong HS,
    2. Kang CI,
    3. Lee JA,
    4. et al

. Clinical significance and outcome of nosocomial acquisition of spontaneous bacterial peritonitis in patients with liver cirrhosis. Clin Infect Dis 2009;48:12306.


    1. Campillo B,
    2. Richardet JP,
    3. Kheo T,
    4. et al

. Nosocomial spontaneous bacterial peritonitis and bacteremia in cirrhotic patients: impact of isolate type on prognosis and characteristics of infection. Clin Infect Dis 2002;35:110.

[Abstract/FREE Full text]

    1. Yokoe DS,
    2. Mermel LA,
    3. Anderson DJ,
    4. et al

. A compendium of strategies to prvent healthcare-asscoiated infecitons in acute care hospitals. Infect Control Hosp Epidemiol 2008;29(Suppl 1):S1221.


    1. Perencevich EN,
    2. Lautenbach E

. Infection prevention and comparative effectiveness research. JAMA 2011;305:14823.


    1. Christou L,
    2. Pappas G,
    3. Falagas ME

. Bacterial infection-related morbidity and mortality in cirrhosis. Am J Gastroenterol 2007;102:151017.


    1. Bernard B,
    2. Cadranel JF,
    3. Valla D,
    4. et al

. Prognostic significance of bacterial infection in bleeding cirrhotic patients: a prospective study. Gastroenterology 1995;108:182834.

[CrossRef][Medline][Web of Science]

    1. Deschenes M,
    2. Villeneuve JP

. Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis. Am J Gastroenterol 1999;94:21937.

[Medline][Web of Science]

    1. Campillo B,
    2. Dupeyron C,
    3. Richardet JP

. Epidemiology of hospital-acquired infections in cirrhotic patients: effect of carriage of methicillin-resistant Staphylococcus aureus and influence of previous antibiotic therapy and norfloxacin prophylaxis. Epidemiol Infect 2001;127:44350.


    1. Ortiz J,
    2. Vila MC,
    3. Soriano G,
    4. et al

. Infections caused by Escherichia coli resistant to norfloxacin in hospitalized cirrhotic patients. Hepatology 1999;29:10649.

[CrossRef][Medline][Web of Science]

    1. Campillo B,
    2. Dupeyron C,
    3. Richardet JP,
    4. et al

. Epidemiology of severe hospital-acquired infections in patients with liver cirrhosis: effect of long-term administration of norfloxacin. Clin Infect Dis 1998;26:106670.

[Abstract/FREE Full text]

Source: BMJ/Gut






Proton-Pump Inhibitors Raise Risk for C. difficile Infections.

In two meta-analyses, PPI use was associated with a 1.7-fold higher risk for Clostridium difficile infection.

In February 2012, the FDA issued a safety alert regarding an association between proton-pump inhibitors (PPIs) and Clostridium difficile infection. In new meta-analyses, two groups of researchers used slightly different criteria to select studies in which this association could be evaluated; all included studies (23 and 42, respectively) were observational (cohort or case-control). Each meta-analysis involved roughly 300,000 patients.

In both meta-analyses, risk for C. difficile infection was significantly higher in PPI users than in nonusers (risk ratio, about 1.7). Although results across individual studies were heterogeneous, nearly all trended toward higher risk. Most of the included studies were adjusted for confounding variables, including antibiotic use. Concomitant use of both PPIs and antibiotics — examined in one meta-analysis — was associated with greater risk for C. difficile infection than was use of PPIs alone or antibiotics alone. Risk for C. difficile infection was higher with histamine (H)2-receptor antagonists than with no acid-suppressive therapy, but lower with H2-receptor antagonists than with PPIs.

Comment: The opportunity for residual confounding in these studies is substantial, because sicker patients are more likely both to receive PPIs and to be vulnerable to C. difficile infection. Still, these worrisome findings should remind clinicians to initiate PPIs only for valid indications and to stop PPIs in patients who take them for unclear reasons.

Source:Journal Watch General Medicine