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Clostridium Difficile and Older Adults: What Primary Care Providers Should Know
The Nurse Practitioner July 1998
BY KAREN DEVEREAUX MELILLO, PhD, RN, CS
ABSTRACT Clostridium difficile was first described in 1935 by Hall and O'Toole, who named this gram-positive, spore-forming, anaerobic bacillus "the difficult Clostridium" because it resisted early attempts at isolation and grew very slowly in culture.1 Intensive investigation in several laboratories led to the identification in 1978 of C. difficile as the cause of almost all cases of pseudomembranous colitis. No other bacteria are routinely diagnosed as causing diarrhea after the administration of antibiotics.2 With or without symptoms, infection with C. difficile can lead to life-threatening pseudomembranous colitis.1 Pseudomembranous colitis has been recognized for a century, yet it continues to be a problem in hospitals, partly because many health care providers are not sufficiently familiar with the disease.3 In older adults, C. difficile can lead to such rare but serious symptoms as toxic megacolon, high fever without obvious source, fever with a leukemoid reaction, relapsing infection over many months, and protein-losing enteropathy, which may worsen the nutritional state of vulnerable older patients.2 Pathogenesis, Incidence, and PrevalenceC. difficile is the principal agent of antibiotic-associated diarrhea and colitis. In general, C. difficile accounts for 15% to 25% of antibiotic-associated diarrheas.4 After colonization, toxins A (enterotoxin) and B (cytotoxin) produced by C. difficile induce diarrhea, inflammation, and colonic mucosal damage.1 C. difficile infects the colon and perhaps the distal ileum. Neither the organism nor its toxins are believed to enter the bloodstream, even in the presence of severe infection.2 C. difficile produces toxins A and B, which activate the release of cytokines from human monocytes.5 These inflammatory effects on leukocytes may be instrumental in inducing the marked colonic inflammation seen in pseudomembranous colitis.6 The overgrowth of toxigenic C. difficile can be induced by almost any oral or parenteral antibiotic therapy that disturbs the indigenous flora of the colon. Pseudomembranous colitis is associated primarily with broad-spectrum antibiotics, especially those with activity against anaerobic organisms, including clindamycin, ampicillin, and the cephalosporins. Even a short perioperative prophylactic course can cause the disease.7 Antibiotic therapy is the key to altering the colonic flora and allowing C. difficile to flourish. The colon is home to more than 500 species of bacteria, of which normal stool may contain as many as 1012/gram. How these microbes resist colonization by C. difficile is unclear.6 C. difficile is easily transmitted by the fecal-oral route, similarly to other gastrointestinal (GI) pathogens.1 C. difficile forms heat-resistant endospores (Figure 1), which survive the acid environment of the stomach and become converted to vegetative forms in the colon.8 The C. difficile pathogen can survive for prolonged periods in the environment because of the resilience of its spores.1,8 The major mechanisms of transmission among hospitalized patients are believed to be environmental contamination and personnel hand carriage. Environmental contamination is heaviest in the rooms of patients with C. difficile diarrhea. The most common sites of contamination are floors, toilets, bedpans, sinks, bedding, mops, scales, furniture, and buzzers, where 10% to 30% of cultures tend to be positive.6,8 In one study, C. difficile contamination was detected on multiuse electronic rectal thermometers. Replacing the electronic thermometers with disposable ones throughout the hospital reduced the incidence of C. difficile in the acute and chronic care areas.9 Health care personnel may carry the bacteria from room to room on their hands, under rings, or on stethoscopes. Fecal carriage by hospital staff is rare.6 One group of researchers suggested that routinely wearing gloves to avoid contact with all body fluids was associated with an outbreak of C. difficile-associated diarrhea. Environmental cultures had revealed unexpected contamination of blood pressure cuffs, which the authors believed related to infrequent changing of soiled gloves by health care workers.10 No available reports implicate chronic carriers as sources for nosocomial outbreaks. There is no evidence that water or food supplies play a significant role in C. difficile transmission or that other routes of transmission occur.8 EpidemiologyMore than 50% of healthy neonates but fewer than 1% of healthy adults are asymptomatic carriers of C. difficile. Approximately 25% of adults who have been recently treated with antibiotics, however, are colonized with the pathogen. The majority of hospital inpatients infected with C. difficile are asymptomatic.6 Because most hospitalized patients are given antibiotics, a large number of people are at risk for C. difficile-associated diarrhea.8 C. difficile is the most common cause of hospital-acquired infectious diarrhea and the fifth most common nosocomial infection.3 C. difficile is the only bacterial pathogen that regularly causes sporadic cases of diarrhea in nursing homes. Risk FactorsTable 1 summarizes important risk factors. Several studies support the theory that normal intestinal flora suppress the growth of C. difficile. Conversely, disturbing the GI flora can predispose the intestine to the overgrowth or acquisition of C. difficile. The condition can result from antibiotics, GI surgery, enemas, nasogastric (NG) drainage, and enteral feedings. That overgrowth and the consequent production of potent toxins cause diarrhea and colitis.11 C. difficile diarrhea typically occurs only in adults of any age who have been taking antibiotics. Normal courses of penicillins and cephalosporins most often lead to C. difficile-associated diarrhea, but other antibiotics have been implicated as well.1 C. difficile in the absence of recent antibiotic use is rare, although in many patients symptoms develop weeks or even several months after antibiotics have been discontinued.12 Older age has been consistently identified as a risk factor for C. difficile disease. Two possible explanations are that older people with diarrhea might be more likely than younger ones to visit a health care provider and be tested for C. difficile and that older people are more likely to be treated for other infections with antibiotics and thereby placed at increased risk for C. difficile infection.2 In a study to identify risk factors that predispose hospitalized patients to diarrhea caused by C. difficile, one investigator identified a longer mean duration of antibiotic use (6.7 versus 4.1 days) as statistically significant. Of the other 22 factors evaluated for their risk of predisposing to C. difficile, only clindamycin and third-generation cephalosporins showed any association.13 One study was performed to define the role of multiple risk factors for cytotoxic C. difficile-associated diarrhea. An analysis of 33 such patients and two control groups revealed that exposure to second- or third-generation cephalosporins was the most important independent risk factor. Combination antimicrobial therapy (simultaneous exposure to two or more antimicrobials) was another major risk factor for the development of C. difficile-associated diarrhea. Cross infection between patients probably played a relatively small role in the propagation of the outbreak, although previous studies have suggested that person-to-person transmission by means of the hands of medical personnel may be the major route of transmission.14 Yet another study compared 37 cases with 37 controls. Epidemiologic variables with significantly different adjusted odds ratios were: age over 65 years; being in an intensive care unit; undergoing nonsurgical GI procedures such as the insertion of an NG, gastrostomy, or jejunostomy tube, upper or lower endoscopy, barium enema, or upper GI series; and more than 10 days on antibiotics. The researchers could not identify the precise nature of the relationship between the insertion of an NG tube in cases and that in controls. The tube may have been inserted because of underlying bowel stasis that could facilitate the colonization and growth of C. difficile, or the insertion itself may have facilitated the inoculation of the organism.15 Differential DiagnosisThe differential diagnosis for patients presenting with symptoms of watery stools is broad and beyond the scope of this article (Table 2). In the elderly, fecal impaction has long been recognized as a presenting symptom of diarrhea. The new onset of loose stools in patients on tube feedings may be attributable to hyperosmotic load. Less than 1% of patients treated with antibiotics develop pseudomembranous colitis.12 The life-threatening infection is confirmed when pseudomembranes are identified with colonoscopy, which ordinarily is not performed unless a rapid diagnosis is required because the condition is suspected.4,11 Endoscopy is likely to reveal the characteristic pseudomembranes, but inflamed, friable, granular, or hemorrhagic mucosa may be seen in mild cases.7 Pseudomembranous colitis can lead to dehydration, colonic perforation, and death.4 Diarrhea may be profuse, copious, watery, and bloody and accompanied by high fever (as high as 103° to 105° F in nursing-home patients), nausea, crampy lower abdominal distension, and pain.1,2 Even without associated diarrhea, older patients may have an unexplained high fever or a distended abdomen. The development of a paralytic ileus may cause a paradoxical decrease in diarrhea while the patient's overall condition continues to deteriorate.1 Leukemoid reactions with white blood cell counts of 25,000/mm3 to 50,000/mm3 can occur. Immediate referral to a gastroenterologist is indicated in the presence of acute surgical abdominal signs and symptoms with associated fever, hypotension, tachycardia, distended abdomen, abdominal pain, and decreased bowel tones. Rapid medical or surgical intervention is necessary to prevent intestinal perforation, septicemia, and death.
RAPID READ Clinical ManifestationsBecause symptoms can occur early in antibiotic therapy or may be delayed for up to 6 weeks after completion of the regimen,1 clinicians should ask patients how soon diarrhea began after antibiotics were started or ended. Ask about any GI procedures that have been performed. Ask the patient to describe bowel movement characteristics such as frequency, color, odor, and consistency.11 Most patients with C. difficile average 6 to 12 stools per day; some have as many as 30. Their diarrhea is usually watery, smells foul, and looks bloody, green, or yellowish brown. The patient may have a low-grade fever.2,11 Asymptomatic Carriage In one report, only 2% to 3% of normal adult volunteers had positive stool cultures for C. difficile.8 The risks of carriage have not been established. Intuitively, individuals who harbor this organism should be at higher risk for becoming symptomatic after exposure to antimicrobials and should contribute to environmental contamination. Carriage should be viewed simply as a marker for subsequent increased morbidity.2 C. Difficile-Associated Diarrhea C. difficile infection commonly presents as diarrhea that is mild to moderate and is sometimes accompanied by lower abdominal cramping. Symptoms usually begin either during or shortly after antibiotic therapy is initiated but occasionally are delayed for several weeks. In most cases, systemic symptoms are absent and the physical examination is normal apart from a slight tenderness in the lower abdomen.1 C. difficile toxins are present in the stool. The results of sigmoidoscopy, if performed, are frequently normal in patients with mild disease and are therefore of little diagnostic value. Diarrhea often subsides when the antibiotic is stopped, in which case no specific treatment for C. difficile infection is necessary.6 Laboratory Tests In the vast majority of clinical laboratories, infected patients and carriers--patients without symptoms but with a positive test for C. difficile--are identified by stool tests for toxins produced by the bacterium. Since the early 1980s, tissue culture cytotoxin assays have been widely available for this purpose. In recent years, latex agglutination tests and enzyme-linked immunosorbent assays that detect C. difficile toxins A, B, or both are increasingly being used. C. difficile is not identified with stool culture.4 Growth of the organism on agar plates takes up to 48 hours. Additional testing that can take 4 to 7 days is required to show that the recovered isolates produced toxins.2 One research group cautions that the stool must be tested within 12 hours of collection because toxin B is labile. Since there is no apparent clinical correlation between stool levels of toxin B and the severity of the disease, the results are reported simply as positive or negative.16 For accuracy, three fresh stool specimens are usually cultured.11 While the stool cytotoxin test is the gold standard because of its high sensitivity (94% to 100%) and specificity (99%),6 it is expensive and requires incubating samples overnight. Several rapid immunoassays for the detection of C. difficile antigens or toxins are commercially available. Several enzyme immunoassays have been introduced that rapidly detect toxin A or B in stool samples with good sensitivity and specificity.2,17 Treatment ProtocolsOptions for treatment depend on the severity of disease.2 Table 3 identifies the clinical interventions that are appropriate for each level. Table 4 lists goals of therapy for older adults. Oral Rehydration Lost fluids and electrolytes should be replaced.7 Oral rehydration therapy is the foundation of treatment for all patients with diarrhea; its use can minimize the morbidity and mortality associated with gastroenteritis. Immediate treatment is imperative because by the time the first diarrheal stool has been passed, the intravascular volume may already be reduced to an extent that compromises blood flow to vital organs. Patients with C. difficile diarrhea typically require 1 to 2 liters of fluids to replace diarrheal losses and intraluminal fluid as soon as symptoms have been identified and an additional 1 to 2 liters/day to replace ongoing losses.2 Commercial oral rehydration therapy solutions include packets with premeasured glucose and salts (Oral Rehydration Salts [Jianas Bros.]) or premixed solutions (Pedialyte [Ross Laboratories], Ricelyte [Mead Johnson]). Sports drinks such as Gatorade may contain too little salt and too much sugar to be appropriate for oral rehydration therapy in this context.2 Medications: Antibiotics C. difficile is always highly susceptible to vancomycin and usually to metronidazole and, although it is infrequently used, to bacitracin.7 Intravenous antibiotic therapy is not particularly efficacious; oral antibiotics are preferred to assure effective concentrations in the bowel lumen. Improvement is generally seen in 3 to 5 days. The full course of therapy is usually 10 days.7 Metronidazole, which tends to be prescribed for mild illness or outpatient use,11 is the drug of choice unless the patient is critically ill.7 Vancomycin is reserved for patients who cannot tolerate metronidazole or who fail to respond to it.6 Metronidazole is much less expensive than vancomycin and generally is well-tolerated. It may be preferred over vancomycin to reduce vancomycin resistance among other organisms in hospitals.17 Some infectious-disease specialists recommend 500 mg of metronidazole q.i.d. for the average adult.7 Another suggested dosage is 250 to 500 mg three or four times a day for 10 to 14 days, with the lower end of the dosing recommended for older adults. Because 30% to 60% of this drug is metabolized in the liver, caution is recommended in patients with liver impairment. Severe renal failure is another indication for lowered dosage.18 Metronidazole is readily absorbed in the upper GI tract. Systemic adverse effects, notably nausea, GI upset, and a metallic taste, can occur. Caution patients not to drink alcohol during and for up to 3 days after antibiotic treatment to prevent a disulfiram-like reaction that may include GI adverse reactions, headache, and flushing.18 Because vancomycin is expensive, metronidazole is usually the recommended initial treatment unless patients have diarrhea with fever > 101° F, suspected or documented pseudomembranous colitis, or a relapsing infection.12 Some isolates of C. difficile are resistant to metronidazole. Rare cases of antibiotic-associated colitis may be caused by Staphylococcus aureus, which is not susceptible to metronidazole.7 Vancomycin should be given in a regimen of 500 mg to 2 grams/day in three or four divided doses. The lower, less expensive dose is preferred unless the patient is severely ill.7 Oral vancomycin 125 mg q.i.d. is effective in most patients; they may take 500 mg q.i.d. if severely ill.1 Intravenous vancomycin should not be used because its marked excretion into the GI lumen has not been demonstrated.6 Age-related changes in renal function and volume of distribution make accumulation and toxicity risk factors in older adults. Careful monitoring and dosing adjustment may be necessary.18 Systemic antidiarrheal drugs can precipitate the development of pseudomembranous colitis because they can hamper toxin elimination and cause toxic megacolon12,19 and are therefore prohibited. Antidiarrheals such as diphenoxylate, camphorated opium tincture (Paregoric), and loperamide are contraindicated for antibiotic-associated colitis. Antidiarrheals should be avoided for almost all nursing-home residents. A high index of suspicion should be maintained for other potential sources of diarrhea before symptomatic treatment is initiated.12 The treatment of suspected pseudomembranous colitis begins with discontinuing the antibiotic therapy that precipitated the disease, if possible.7 Primary care providers should avoid prescribing the classes of antibiotics thought to be most likely to predispose patients to C. difficile. To minimize the use of antibiotics, nurses, physicians, and family members should be educated about the risks associated with the prescription of antimicrobials. They should be taught to adopt safe, appropriate alternatives to antibiotics in selected patients. For example, minor elevations in temperature occur frequently in nursing-home residents. A simple approach to treating patients who do not appear ill is to provide extra hydration, prescribe one or two doses of acetaminophen, and follow up to see whether symptoms develop.12 Clinicians should carefully consider the appropriateness of cephalosporins (especially second- and third-generation), clindamycin, and antimicrobial combination therapy, especially in instances of nosocomial C. difficile-associated diarrhea outbreaks. Controlling transmission can be very difficult once this organism has become widespread.14 In general, the use of systemic antibiotics should be avoided whenever possible.2 Supportive Therapy Patients with minimal symptoms may benefit from bismuth subsalicylate, a locally acting antidiarrheal agent, which has antibacterial activity against C. difficile in vitro.2 Bismuth subsalicylate can be prescribed in a dosage of 30 ml every 2 hours for up to eight doses and then 30 to 60 ml every 6 hours as needed for diarrhea over the following 3 to 4 days. For older adults, bismuth subsalicylate can be prescribed as a dosage of 60 ml every 2 hours as needed for up to four doses, then 30 ml every 6 hours as needed for 4 to 7 days.12 Because C. difficile is often self-limited, there is currently no rigorous proof that this regimen is more effective than oral rehydration alone.2 Bismuth subsalicylate can be given to elderly patients safely. It appears to reduce the symptoms of diarrhea. Primary care providers should attend to infection control protocols. They should also know how to address the presence of environmental contaminants (Table 5). Recurrent Disease and RelapseThe risk of a recurrent bout of diarrhea may be higher in older patients who are diagnosed with C. difficile-associated diarrhea or pseudomembranous colitis than in younger patients. Approximately 5% to 10%2 or 10% to 20%7 of adults (depending on one's source) who develop symptomatic C. difficile have a relapse. Recurrence tends to be a problem with the use of all antiC. difficile activity agents. Treatment failures, which are rare, are assumed if the patient fails to improve after a week of therapy. Relapse typically occurs a few weeks after an initially successful 10-day course of therapy.7 The first relapse usually is not too uncomfortable and responds to retreatment. Possible causes of relapse include failure to eradicate the organism from the colon and reinfection from the environment, both of which may be related to the formation of antibiotic-resistant C. difficile spores. Any relapse usually occurs within 1 to 3 weeks after the termination of initial therapy. Further antibiotic therapy is not required to precipitate a relapse. The diagnosis of recurrent diarrhea from C. difficile infection should be confirmed by a stool-toxin assay. Metronidazole or vancomycin treatment may not be necessary for mild symptomatic relapses, since they often resolve spontaneously. This conservative approach may make a subsequent relapse far less likely.6 A second course of metronidazole is advised for patients with more severe or persistent diarrhea or overt colitis. There is no clear rationale for using vancomycin for relapses after metronidazole therapy, since the development of antibiotic resistance usually is not the cause of a relapse.6 Unfortunately, further relapses are common once therapy has been discontinued; some patients have numerous attacks. While various approaches have been suggested for managing repeated relapses, including a slow tapering of vancomycin therapy, the use of rifampin (used with caution in patients with liver impairment), cholestyramine or colestipol (antilipemic agents), bacteriotherapy with fecal enemas, or oral administration of nontoxicogenic C. difficile, and treatment with the yeast Saccharomyces boulardii,1,8 recurrent diarrhea from C. difficile infection has not been thoroughly studied in controlled trials. Therefore, the best therapeutic approach is not known.6 Introducing competing nonpathogenic organisms into the intestinal flora either orally or by enema has been suggested as a better way than repeated administration of vancomycin and metronidazole to treat recurrent C. difficile.1 S. boulardii has been used extensively in Europe to prevent antibiotic-associated diarrhea. It interferes with the binding of toxin A to intestinal receptor sites, thereby mediating the action of the toxin on the intestine.1 Lactobacillus spp. has also been given orally to prevent or treat various types of diarrhea.1,7 L. casei GG is a strain that survives passage through the GI tract to colonize the bowel, temporarily inhibiting the growth of C. difficile.1 The efficacy of treating patients with recurrent infection with microbial replacement is not yet established.2 Prophylaxis of patients on antibiotics with biologic agents such as S. boulardii offers a more attractive approach that warrants further investigation.8 SummaryPerhaps the safest and most effective means for preventing C. difficile diarrhea would be the development of a vaccine. The majority of adults secrete IgA antibody to toxin A into the colonic lumen. This antitoxin may block the binding of toxin A to its intestinal receptor. Preliminary observations suggest that immunization against C. difficile toxins may ultimately prove to be a useful means of preventing infection.6 Primary care providers should be aware of the risk factors, clinical presentation, and course of C. difficile-associated diarrhea and of how to diagnose and treat pseudomembranous colitis.
REFERENCES
1. Melcher SA, Moyer KA: Clostridium difficile-associated disease: A clinical challenge.
Clin Rev 1995;5(9):75-92.
2. Bennett RG: Clostridium difficile infection in the elderly. In: Powers DC, Morley JE,
Coe RM, eds. Aging, Immunity and Infection. New York: Springer Publishing Co., 1994:216-29.
3. Silva J: Clostridium difficile nosocomial infections--still lethal and persistent. Infect
Control Hosp Epidemiol 1991;15:368-70.
4. Yablon SA, Krotenberg R, Fruhmann K: Clostridium difficile-related disease:
Evaluation and prevalence among inpatients with diarrhea in two freestanding rehabilitation
hospitals. Arch Phys Med Rehabil 1993;74:9-13.
5. Tierney LM, McPhee SJ, Papadakis MA: Current Medical Diagnosis and Treatment, 35th ed.
Stamford, Conn.: Appleton & Lange; 1996:699.
6. Kelly CP, Pothoulakis C, LaMont JT: Clostridium difficile colitis. N Engl J Med
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7. Diarrhea: Look beyond an antibiotic cause. Emerg Med 1993;25(9):33-36.
8. Samore MH: Epidemiology of nosocomial Clostridium difficile infection. Compr Ther
1993;19:151-56.
9. Brooks SE, Veal RD, Kramer M, et al: Reduction in the incidence of Clostridium
difficile-associated diarrhea in an acute care hospital and a skilled nursing facility following
replacement of electronic thermometers with single-use disposables. Infect Control Hosp
Epidemiol 1992;13:98-103.
10. Manian FA, Meyer L, Jenne J: Clostridium difficile contamination of blood pressure
cuffs: A call for a closer look at gloving practices in the era of universal precautions. Infect
Control Hosp Epidemiol 1996;17:180-82.
11. Carpenter DR, Zielinski DA: How do you treat--and control--C. difficile infection?
Am J Nurs 1992;92(9):22-24.
12. Bennett RG: Diarrhea among residents of long-term-care facilities. Infect Control Hosp
Epidemiol 1993;14:397-404.
13. Zimmerman RK: Risk factors for Clostridium difficile cytotoxin-positive diarrhea
after control for horizontal transmission. Infect Control Hosp Epidemiol 1991;12:96-100.
14. Nelson DE, Auerbach SB, Baltch AL, et al: Epidemic Clostridium
difficile-associated diarrhea: Role of second- and third-generation cephalosporins. Infect
Control Hosp Epidemiol 1994;15:88-94.
15. Brown E, Talbot GH, Axelrod P, et al: Risk factors for Clostridium difficile
toxin-associated diarrhea. Infect Control Hosp Epidemiol 1990;11:283-90.
16. Detmer WM, McPhee SJ, Nicoll D, et al: Pocket Guide to Diagnostic Tests. Norwalk, Conn.:
Appleton & Lange; 1994:65, 174.
17. Gerding DN, Johnson S, Peterson LR, et al: Clostridium difficile-associated diarrhea
and colitis. Infect Control Hosp Epidemiol 1995;16:459-77.
18. Semla TP, Beizer JL, Higbee MD: Geriatric Dosage Handbook, 3rd ed. Hudson, Ohio:
Lexi-Comp, 1997.
19. King M: Antibiotics and colitis: toxic combination...Clostridium difficile colitis.
Nursing91 1991;21(1):79.
20. Fekety R, Shah AB: Diagnosis and treatment of Clostridium difficile colitis. JAMA
1993;269:72-75.
21. Suppaiah L: Pseudomembranous colitis induced by Clostridium difficile. Critical
Care Nurse 1988;8(5):65-72.
22. Olson MM, Shanholtzer CJ, Lee JT, et al: Ten years of prospective Clostridium
difficile-associated disease surveillance and treatment at the Minneapolis VA Medical
Center 1982-1991. Infection Control and Hospital Epidemiology 1993;15(6):371-81.
23. Walker KJ, Gilliland SS, Vance-Bryan K, et al: Clostridium difficile colonization in
residents of long-term-care facilities: Prevalence and risk factors. J Am Geriatr Soc
1993;41:940-46.
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