Keywords
Key points
- •Clostridium difficile is a formidable problem in the twenty-first century.
- •Because of injudicious use of antibiotics, the emergence of the hypervirulent epidemic strain of this organism has been difficult to contain.
- •The NAP1/BI/027 strain causes more severe disease than other widely prevalent strains and affects patients who had not been traditionally thought to be at risk for C difficile infection.
- •Critically ill patients remain at high risk for this pathogen, and preventive measures, such as meticulous contact precautions, hand hygiene, environmental disinfection, and, most importantly, antibiotic stewardship, are the cornerstones of mitigation.
- •The positive preliminary data for the role of probiotics in the intensive care unit population are intriguing, although their risk/benefit ratio requires further confirmation.
Over the past decade, C difficile has gained importance as a deadly pathogen. Beginning in the late 1990s, multiple groups noted that the epidemiology and outcomes of C difficile infection (CDI) in hospitals were evolving. A report from Pepin in 2004 documented a shocking 5-fold increase in the incidence of CDI in Quebec, Canada, increasing from 36 to 156 cases per 100,000 population between 1992 and 2003.
1
This increase was accompanied by roughly a doubling of the proportion that exhibited severe and complicated disease. In the United States, similar developments were noted first in Pittsburgh, Pennsylvania, and then across the United States.2
Sobering reports on the nationwide trends in CDI hospitalizations signaled a rapid doubling of CDI cases in U.S. hospitals between the mid 1990s and mid-2000s, with a similar 2-fold rise in case fatality.3
, 4
An investigation by the Centers for Disease Control and Prevention identified a new strain of C difficile named NAP1/BI/027 (toxinotype III, North American pulsed-field gel electrophoresis type 1, polymerase chain reaction–ribotype 027 [NAP1/027]).
5
This strain, responsible for a substantial proportion of the new epidemic cases, has several features that explain its hypervirulent character: it is capable of producing approximately 20 times the amount of the toxins A and B than other clinically relevant strains, and its plentiful spores are more adherent and, therefore, more likely to linger in the gut, and are more suited to being transmitted through fomites.6
Genetically, a deletion in the regulatory portion of the toxin-producing allele is present in the new strain, prompting exuberant and unchecked toxin overproduction. A binary toxin gene has also been identified, although its role remains a mystery. An important clinical feature of NAP1/BI/027 is its high level of fluoroquinolone resistance in vitro. Since the strain became evident in the early 2000s, it has been reported in most of the states in the United States, and in many locations abroad.Several epidemiologic features of CDI now directly reflect this increased virulence. Namely, the disease it causes is more severe, exhibiting greater morbidity and mortality and resulting in a higher likelihood of the need for intensive care unit (ICU) care.
1
, 2
, 4
, 7
, 8
, 9
In addition, CDI now can afflict what were previously considered low-risk populations: the young, those without comorbidities, and persons without a history of exposure to antibiotics.10
The economic burden of CDI is not trivial, particularly among those who require hospitalization. Four studies examined the costs attributable to a CDI admission, and these estimates range from approximately $3000 to more than $15,000 per case in 2008.
11
This broad range of values is because of different methodologies used and research questions asked. Nonetheless, extrapolating these costs to the full complement of 2008 CDI hospitalizations hints at the staggering price tag that this infection carries. Namely, the range of total CDI acute hospitalization costs is between $1 and $4.8 billion.11
Although no study has specifically focused on CDI costs in the ICU, these critically ill patients are likely to incur an even higher cost from this complication. In a study of patients receiving 96 or more hours of mechanical ventilation or prolonged acute mechanical ventilation (PAMV), the authors noted an additional 6.1-day hospital length of stay and $10,355 in hospital costs among PAMV discharges with CDI.
12
The design, however, did not allow for the calculation of the attributable economic burden.CDI epidemiology in the ICU
The prevalence of CDI among the general hospitalized population is reported to be much less than 2%. McDonald and colleagues
3
reported that nationally in the United States, the annual volume of hospitalizations with CDI increased from 82,000 to 178,000 between 1996 and 2003. Similar reports based on the Nationwide Inpatient Sample documented a prevalence of CDI between 7 and 10 cases per 1000 hospitalizations in 2006, depending on the geographic region, or less than 1% of all adult acute hospitalizations.4
In the ICU, however, the proportion of patients with CDI is far higher, approaching 5% in some populations. Thus, in a single-center retrospective cohort enrolled before year 2000, Lawrence and colleagues
13
noted that 76 of 1872 critically ill patients had evidence of CDI, with roughly one-half developing it while in the ICU. The authors’ group has examined the epidemiology and outcomes of CDI among patients on PAMV in the Nationwide Inpatient Sample, a database that is a 20% representative sample of all acute hospital discharges in the United States.12
They found that in 2005, among the 64,910 PAMV discharges, 3468 (5.3%) had a concomitant International Classification of Disease, 9th Edition, Clinical Modification (ICD-9-CM) diagnosis of CDI, and its prevalence increased with age.Risk factors for CDI in the ICU are largely similar to those found on a general ward. Bobo and colleagues,
14
in their timely review of CDI in the ICU, divided these risks into 3 categories: (1) perturbation of the intestinal flora/mucosa or immune system (eg, from exposures to antibiotics, proton pump inhibitors, chemotherapy), (2) environmental contamination, and (3) host factors. Although most of these factors are well-known, the U.S. Food and Drug Administration recently mandated a warning in the labels of gastric acid–suppressing medications to indicate an increase in the risk of contracting CDI.15
US Food and Drug Administration. FDA drug safety communication: clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). Available at: http://www.fda.gov/drugs/drugsafety/ucm290510.htm. Accessed October 3, 2012.
A unique and potentially modifiable exposure defined in the ICU in a single-center cohort study is C difficile colonization pressure (CCP).
13
CCP is defined as the sum of the daily CDI point prevalence that an individual patient is exposed to while in the unit. The incidence of CDI in this study was reported to be 3.2 per 1000 patient-days, and CCP exhibited a dose–response relationship with CDI onset, with the odds of developing CDI ranging from 0.88 for CCP greater than 0 case-days of exposure to 2.17 for CCP greater than 10 case-days. However the relationship between C difficile acquisition and CCP reached significance only beyond 10 case-days of exposure. And in fact, nearly one-third of all CDI cases did not experience CCP before the onset of their infection.13
Because these data represent only a single center, where infection control measures are an emphatic part of routine care, it is difficult to know whether CCP may be a more important risk factor for ICU-acquired CDI in a setting where infection control measures are implemented with less vigor.Marra and colleagues
16
conducted a 9-ICU single-center retrospective cohort study between 2002 and 2005 to examine the epidemiology and outcomes of CDI among patients in the ICU. Only adult patients with the first microbiologically proven CDI in the setting of diarrhea were enrolled. Among the 613 total CDI cases identified, 58 (9.5%) met the enrollment criteria. In this study, more than one-third of all incident CDI cases occurred among patients 60 years of age or older, and two-thirds were in the surgical population. More than 90% had received antibiotic before the onset of CDI, and the mean lead time to CDI development was 16.8 ± 18.5 days. Although all but one were treated with metronidazole as first-line therapy, 8.6% experienced treatment failure.16
Another single-center retrospective study of patients in the ICU with incident CDI reported a high proportion of elderly individuals: 53% of the 278 cases identified were 65 years of age or older.
17
The time to onset of CDI was far shorter in the older (6.4 ± 9.6 days) than in the younger (11.0 ± 19.5 days) group.18
Outcomes
A handful of studies have examined the outcomes associated with CDI in the ICU. General disagreement exists as to whether CDI is associated with an increase in mortality in this population. Thus, one single-center matched case-control study in critically ill patients calculated the death rate attributable to CDI at 6%.
17
Two other studies failed to detect an increase in mortality, however. Lawrence and colleagues13
found no difference in hospital mortality among patients in the ICU with or without incident CDI. Similarly, Zilberberg and colleagues12
reported essentially equal rates of unadjusted hospital death among patients on PAMV with and without CDI. In the adjusted analysis, interestingly, the discharges diagnosed with CDI seemed to have a lower risk of hospital death than those without CDI, although this was attributed to the likely presence of immortal time bias (ie, one has to remain alive to develop CDI).12
Several mortality predictors among patients with CDI in the ICU have been reported, the most important of which are the severity of illness and age. In the study by Marra and colleagues,
16
Sequential Organ Failure Assessment (SOFA) score and age showed a strong and independent association with hospital mortality. In another cohort focusing specifically on the elderly, high Acute Physiology and Chronic Health Evaluation II (APACHE II) score correlated strongly with hospital death.18
Additional factors that emerged were the absence of chronic respiratory disease, age of 75 years or older, and the presence of septic shock.18
Although whether CDI adds to the risk of hospital mortality in patients in the ICU remains unclear, no doubt exists that it adds to hospital resource use. In the general hospitalized population, estimates show that in 2008, CDI was responsible for 2.8 to 6.4 additional days in the hospital, at a cost of $3000 to more than $15,000 per case.
11
This individual price tag adds up to between $1 billion and nearly $5 billion spent on this complication.11
Among the critically ill, CDI is associated with a 24% increase in the risk of a longer hospitalization (95% CI, 7%–44%).13
In the specific population of patients undergoing PAMV, CDI was associated with a 6.1-day prolongation of length of stay and additional hospital costs of $10,355.12
CDI prevention
The principles of CDI prevention were synthesized by Cohen and colleagues
19
in the 2010 clinical practice guidelines for CDI. Pathogen transmission between patients and health care professionals is a major source of CDI infection, and therefore personal and environmental strategies are the cornerstone of combating C difficile proliferation. The recommendations are divided into 4 categories: (1) measures for health care workers, patients, and visitors, (2) environmental cleaning and disinfection, (3) antimicrobial use restrictions, and (4) use of probiotics. Each deserves a brief discussion.Measures for Health Care Workers, Patients, and Visitors
The fundamental idea of this suite of interventions is to keep the infection limited to where it already exists and not allow the spores to spread to other individuals. To accomplish this, isolating all infected patients for the duration of their diarrhea symptoms is recommended. Moreover, all health care workers, even in the absence of any contact with known CDI, must follow meticulous hand hygiene protocols. Although alcohol-based hand sanitizers are deemed acceptable for use in routine practice, in the setting of an outbreak, soap and water are recommended. Recent evidence supports this recommendation, and even possibly to broaden it to routine use of soap and water. Oughton and colleagues
20
examined the efficacy of 5 different hand hygiene methods in removing C difficile from healthy volunteers inoculated with its spores. The groups, comprising 10 volunteers each, were exposed to (1) warm water with soap, (2) cold water with soap, (3) warm water with antibacterial soap, (4) alcohol hand wipe, and (5) alcohol hand rub. The greatest effect size for removing C difficile spores was detected in the warm and cold water with soap groups, followed by warm water with antibacterial soap and, finally, alcohol hand wipes. Startlingly, the average number of colony-forming units did not change at all in the alcohol hand rub group.20
This study, albeit small, attests to the value of hand washing with soap and water as a tool to curtail the transmission of C difficile spores.Gloves are another way to abrogate C difficile transmission. Therefore, the application of gloves on entry into a room of a patient infected with C difficile is recommended. Data supporting this recommendation come partly from a cluster randomized trial of intensive education regarding the use of gloves in the setting of CDI.
21
On the 2 wards randomized to the glove intervention, the incidence of CDI decreased 5-fold. At the same time, on the 2 comparable control wards with no intensive education, the CDI incidence drifted slightly lower, although not significantly.21
Environmental Cleaning and Disinfection
The recommendations under this rubric in the guidelines include the following 3 points: (1) environmental sources of C difficile should be identified and removed, including replacement of electronic rectal thermometers with disposables; (2) chlorine-containing cleaning agents or other sporicidal agents should be used to address environmental contamination; and (3) routine environmental screening for C difficile is not recommended.
19
Therefore, each patient in isolation should have dedicated equipment, such as stethoscopes and blood pressure cuffs, to avoid transmission to other patients through these fomites. Evidence suggests that busy health care workers do not always change their gloves after contact with contaminated commodes. In one single-center study, this behavior resulted in a 10% rate of contamination with C difficile spores on blood pressure cuffs, similar to the proportion of contaminated commodes (11.5%), ultimately leading to the spread of CDI.22
Several studies have also documented reductions in CDI spread after replacement of thermometers with single-use disposable devices.23
, 24
Environmental contamination with C difficile is associated with disease incidence. Several strategies are available for environmental cleaning, with chlorine bleach solutions carrying the most practical benefit. A 1000 to 5000 parts per million (ppm) solution of bleach is recommeded.
19
Although the latter is more effective, the former may be more tolerable to people in and around the area. The risk/benefit balance depends on the immediacy of the CDI problem in the particular unit. Although the peroxide vaporization technique has been shown to reduce C difficile spores, the process does not seem practical for broad adoption. Furthermore, nonchlorine cleaners in subinhibitory concentrations seem to encourage greater sporulation of the NAP1/BI/027 strain.Whether environmental cleaning can reduce the incidence of CDI in a nonepidemic or in low endemicity circumstances remains unclear. Mayfield and colleagues,
25
in a before-and-after study of environmental bleach disinfection, showed a sharp decrease of more than 60% in the hazard of contracting CDI on a hematopoietic stem cell transplant ward that had been experiencing high rates of this infection. The same intervention on wards that had much lower baseline incidence of CDI failed to achieve further reductions.Antimicrobial Use Restrictions
Because the pathogenesis of CDI is closely linked to use of antimicrobial agents, it stands to reason that imprudent use of these agents leads to an increased risk of CDI. Therefore, reining in overuse of these agents is recommended to reduce the risk of C difficile acquisition, and data support this approach. The guidelines acknowledge this by recommending that use of all antimicrobial agents, and particularly cephalosporins and clindamycin, be reduced to the minimum number of agents and minimum duration feasible.
19
Although a Cochrane review from 2005 found conflicting results in this regard, several studies since its publication have confirmed that antimicrobial stewardship interventions are reasonable.26
For example, in the midst of the multihospital outbreak of CDI in Quebec caused by the emerging NAP1/BI/027 strain, one of the affected hospitals reported a successful curbing of the spread of this pathogen through a nonrestrictive antibiotic control program.27
In this instance, the antibiotic restriction effort followed on the heels of strengthened infection control measures, which failed to bring the epidemic under control. Specific antibiotic classes targeted were second- and third-generation cephalosporins, ciprofloxacin, clindamycin, and macrolides. In addition, the local guidelines suggested shortening the duration of antibiotic exposure for some specific infection types. The resulting decrease in antibiotic consumption overall, and specifically of the second- and third-generation cephalosporins, was accompanied by a significant reduction in the incidence of CDI.27
Consistent with this role of antibiotics, a recent meta-analysis reported concomitant use of non-CDI antibiotics to be the strongest risk factor for a CDI recurrence, with an odds ratio of 4.23 (95% CI, 2.10–8.55; P<.001).28
Use of Probiotics
The Society for Healthcare Epidemiology of America/Infectious Diseases Society of America guidelines do not recommend the use of probiotics at this time.
19
This conclusion is based on several clinical trials in various settings that failed to show any advantage of probiotics compared with controls regarding CDI incidence. Although a single trial reported a reduction in CDI among patients receiving antibiotics for other infections,29
unfortunately multiple design issues precluded these data from being generalizable to recommend this approach.A systematic review from the Cochrane Collaboration reached the same conclusion.
30
The investigators identified only 4 studies that met their inclusion criteria, of which only one showed a benefit in reducing CDI recurrence.31
A more recent multicenter randomized controlled trial among patients in the ICU aimed to establish the efficacy of probiotics in preventing ventilator-associated pneumonia (VAP).
32
Specifically, the aim of this double-blind placebo-controlled randomized controlled trial was to determine whether oropharyngeal and gastric administration of Lactobacillus rhamnosus GG can reduce the incidence of VAP in a population of patients on mechanical ventilation at high risk for this infection. Enteral probiotics administered to 68 patients were compared with inert inulin-based placebo administered twice daily in addition to routine care among 70 controls. Microbiologically confirmed VAP occurred in 40% in the placebo group, compared with 19.1% in the Lactobacillus group (P = .007). Beyond this impact on VAP, the investigators also noted a significant reduction in CDI frequency, from 18.6% in the placebo to 5.8% in the probiotic group (P = .02). However, until these positive findings are incorporated into the full body of evidence on the role of probiotics in CDI prevention, whether the potential for developing invasive disease from a probiotic organism outweighs the potential benefits of these agents remains unclear.33
Summary
C difficile is a formidable problem in the twenty-first century. Because of injudicious use of antibiotics, the emergence of the hypervirulent epidemic strain of this organism has been difficult to contain. The NAP1/BI/027 strain causes more-severe disease than other widely prevalent strains and affects patients who had not been traditionally thought to be at risk for CDI. Critically ill patients remain at high risk for this pathogen, and preventive measures, such as meticulous contact precautions, hand hygiene, environmental disinfection, and, most importantly, antibiotic stewardship, are the cornerstones of mitigation. The positive preliminary data for the role of probiotics in the ICU population are intriguing, although their risk/benefit ratio requires further confirmation.
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Article info
Footnotes
Disclosure: Dr Zilberberg has received consulting fees and research funding from ViroPharma, manufacturer of Vancocin; and Optimer, manufacturer of fidoxamicin. The content of this manuscript was presented in part at the Society of Critical Care Medicine 2012 annual meeting.
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© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
