Philip E. Coudron

Hospital-wide Restriction of Clindamycin: Effect on the Incidence of Clostridium difficile-Associated Diarrhea and Cost

Clostridium difficile is an important cause of nosocomial infection and is the organism most often linked to antibiotic-associated diarrhea and pseudomembranous colitis [1-3]. As many as 25% of cases of nosocomial diarrhea may be caused by C. difficile, leading to increased hospital costs, morbidity, and mortality [2-5]. Acquisition of C. difficile may result in asymptomatic carriage or more clinically significant manifestations, including antibiotic-associated diarrhea, colitis, pseudomembranous colitis, and toxic megacolon [6-9]. The most frequently identified risk factor for the development of C. difficile-associated diarrhea is the antecedent use of antibiotics that alter the normal intrinsic colonic microflora. Antibiotics commonly associated with C. difficile-associated diarrhea include penicillins, cephalosporins, and clindamycin [2, 3, 10-12]. Previous attempts to control nosocomial outbreaks of C. difficile-associated diarrhea have included emphasis on handwashing, enforced barrier precautions, enhanced educational initiatives, and increased environmental cleaning [12-14]. Recently, several investigations showed a substantial decrease in the incidence of C. difficile-associated diarrhea after hospital formulary restriction of clindamycin [11, 15]. Aside from the issue of efficacy, hospital formulary control of antibiotics as a strategy to decrease the incidence of nosocomial infections raises several other questions. What effect does restriction have on the use of other antibiotics? Does restriction of certain classes of antibiotics lead to increased use of more expensive antimicrobial agents? Does formulary control save money? Does restriction affect the antimicrobial susceptibility of nosocomial isolates? Beginning in 1993, our hospital had an unusually high number of cases of nosocomial C. difficile-associated diarrhea, which continued despite the use of barrier precautions, educational programs, and enhanced terminal cleaning of patient rooms. When our investigation identified clindamycin use as a significant risk factor among hospitalized patients, we instituted hospital-wide restriction of clindamycin as an infection control measure. In this study, we investigated the effects of hospital formulary control on the incidence of C. difficile-associated diarrhea and the antimicrobial susceptibility of nosocomial isolates of C. difficile. We also examined the overall economic impact of such restrictions on antibiotic use. Methods The Hunter Holmes McGuire Veterans Affairs Medical Center is a 703-bed tertiary care hospital affiliated with the Medical College of Virginia in Richmond, Virginia. Infection control at the hospital is directed by the hospital epidemiologist (a physician) and administered by four infection control nurses. The monthly incidence of C. difficile-associated diarrhea for the past 10 years is known because of the routine review of C. difficile cytotoxin assay results or stool cultures positive for C. difficile from patients with symptomatic diarrhea. In November 1993, we initiated a prospective cohort study. All inpatients who had been hospitalized for at least 48 hours and had had stool samples sent to the microbiology laboratory for C. difficile cytotoxin assay were studied. Case-patients were defined as patients who had diarrhea (three or four loose [unformed] stools) within a 24-hour period, a history of antibiotic use within 8 weeks, and a positive result on a cytotoxin assay. Symptomatic patients with negative results on cytotoxin assay with or without a history of antibiotic use were designated as controls. Hospital charts, microbiological laboratory test results, and hospital pharmacy records were reviewed to obtain data on demographic variables; admitting service and diagnosis; documented infections; use of antibiotics before the onset of diarrhea; use of medications, including antacids, H2 blockers, and stool softeners; concurrent medical illnesses; invasive procedures and devices placed during hospitalization; presence of nasogastric or feeding tubes; ambulation status; room type (single or multi-bed); discharge status; and time from admission to onset of diarrhea. All stool samples were tested for cytotoxin production by using tissue cell culture assay [16]. Stool specimens with positive results on cytotoxin assay were cultured on CCFA (cycloserine, cefoxitin, fructose) blood agar [17] and incubated under anaerobic conditions for 48 hours. Isolates were presumptively identified as C. difficile by colony morphology, Gram stain, and biochemical identification with the RapID ANA II system (Innovative Diagnostic Systems, Norcross, Georgia). All isolates presumptively identified as C. difficile underwent C. difficile cytotoxin assay to verify toxin production. Isolates of C. difficile were maintained in chopped-meat broth and were typed by using pulsed-field gel electrophoresis after restriction endonuclease digestion with SmaI [18]. Pulsed-field gel electrophoresis of all isolates was completed over 20 hours with ramped pulsed-field times (initial 1 second to final 20 seconds). Antimicrobial susceptibility testing was done on all isolates by using an anaerobic agar dilution method according to guidelines from the National Committee for Clinical Laboratory Standards. Isolates were tested for susceptibility to clindamycin, metronidazole, and vancomycin and were considered resistant if the minimal inhibitory concentration (MIC) was greater than 4.0 g/mL for clindamycin and vancomycin or greater than 1.0 g/mL for metronidazole. The Fisher exact test was used to test for differences in proportions. The means of continuous variables were compared by using the Student t-test. Risk factors among the patient groups were compared by using the Cochran-Mantel-Haenszel chisquare test. Two-sided P values less than 0.05 were considered statistically significant. Results The Outbreak In September 1993, our hospital had the most cases of C. difficile-associated diarrhea (18 cases; 19 cases per 1000 discharges) seen since the introduction of surveillance for this condition. A review of hospital records showed a gradual increase in the number of cases of C. difficile-associated diarrhea since 1991 (Figure 1). The hospital averaged 4.3 cases of C. difficile-associated diarrhea per month in 1991 (4.5 infections per 1000 discharges), 6.4 cases per month in 1992 (6.5 infections per 1000 discharges), and 10.6 cases per month in 1993 (10.8 infections per 1000 discharges). The number of patients seen in the hospital between 1991 and 1996 was relatively constant, with a difference of less than 9% in the number of inpatient discharges per year over the entire period. Figure 1. Cases of Clostridium difficile -associated diarrhea, reported by quarter. C. difficile In response to the increasing number of cases of C. difficile-associated diarrhea, several control measures were instituted. All hospital staff were educated about the importance of barrier precautions and the appropriate isolation of patients with C. difficile-associated diarrhea. All patients identified as having C. difficile-associated diarrhea were placed in private rooms, and the use of barrier precautions was strictly enforced. Emphasis was placed on proper handwashing and the appropriate use of gloves. In addition, attempts were made to decrease environmental contamination with C. difficile; these attempts included terminal cleaning of the rooms of patients with C. difficile-associated diarrhea on selected wards. Despite these measures, the number of new cases of C. difficile-associated diarrhea remained high. In the first 3 months of 1994, 11.3 cases per month occurred and 25% of all stool specimens sent to the microbiology laboratory for C. difficile toxin assay had positive results. In March 1994, 35% of all stool specimens sent for C. difficile toxin assay had positive results. Over a 5-month period from November 1993 to March 1994, the microbiology laboratory received 159 stool samples for C. difficile toxin assay. Twenty-one of the samples were reported as formed stool and therefore were not satisfactory for testing. Of the remaining 138 samples, 52 (38%) were positive and 86 (62%) were negative for C. difficile toxin. Twenty percent of patients (10 of 50) had a relapse of C. difficile-associated diarrhea during the 5-month period. Patients identified with C. difficile-associated diarrhea were found on all wards of the hospital. Most patients (73%) were on medical wards (17.5 infections per 1000 discharges), but patients with C. difficile-associated diarrhea were also found on surgical wards (1.6 infections per 1000 discharges); on neurology wards (5.2 infections per 1000 discharges); in intensive care units (10.5 infections per 1000 discharges); and in long-term care facilities, including a nursing home and a spinal cord injury unit (24.4 infections per 1000 discharges). All patients identified with C. difficile-associated diarrhea were initially treated with oral metronidazole; regimens varied from 250 mg given orally every 8 hours to 500 mg given orally every 6 hours. Risk Factors for Clostridium difficile-Associated Diarrhea We did a prospective cohort study of 138 consecutive patients admitted to the hospital between November 1993 and March 1994 to determine the risk factors associated with C. difficile-associated diarrhea in hospitalized patients with symptomatic diarrhea. Increased age, bedridden status, documented underlying infection, and increased antibiotic use were significantly associated with C. difficile-associated diarrhea. Patients with C. difficile-associated diarrhea were older than controls (71 years compared with 63 years; P < 0.001) and were more likely to be bedridden (86% compared with 54%; P < 0.001; odds ratio, 5.2). No statistically significant differences were seen for admitting diagnosis, admitting service, discharge status, or death within 1 year of the onset of diarrhea. Patients with C. difficile-a

Inhibitor-Based Methods for Detection of Plasmid-Mediated AmpC β-Lactamases in Klebsiella spp., Escherichia coli, and Proteus mirabilis

ABSTRACT Non-beta-lactam inhibitor-based methods were evaluated for detecting plasmid-mediated AmpC β-lactamases in Klebsiella spp., Escherichia coli, and Proteus mirabilis. Using CLSI methodology and disks containing cefotetan alone and in combination with 400 μg of boronic acid, 9 of 10 positive control strains and 54 of 55 AmpC-PCR-positive clinical isolates were detected. Importantly 71% and 40% of these clinical isolates were susceptible by routine testing to ceftriaxone and ceftazidime, respectively. Boronic acid disks also enhanced detection of expanded-spectrum β-lactamases in AmpC producers.

Occurrence of Extended-Spectrum and AmpC Beta-Lactamases in Bloodstream Isolates of Klebsiella pneumoniae: Isolates Harbor Plasmid-Mediated FOX-5 and ACT-1 AmpC Beta-Lactamases

ABSTRACT We tested 190 Klebsiella pneumoniae bloodstream isolates recovered from 189 patients in 30 U.S. hospitals in 23 states to determine the occurrence of extended-spectrum β-lactamase (ESBL) and AmpC β-lactamase producers. Based on growth inhibition by clavulanic acid by disk and MIC test methods, 18 (9.5%) of the isolates produced ESBLs. Although the disk diffusion method with standard breakpoints identified 28 cefoxitin-nonsusceptible isolates, only 5 (18%) of these were confirmed as AmpC producers. Of two AmpC confirmatory tests, the three-dimensional extract test was easier to perform than was the double-disk approximation test using a novel inhibitor, Syn2190. Three of the five AmpC producers carried the blaFOX-5 gene, while the other two isolates harbored the blaACT-1 gene. All AmpC genes were transferable. In vitro susceptibility testing with standard inocula showed that all five AmpC-producing strains were susceptible to cefepime, imipenem, and ertapenem but that with a high inoculum, more of these strains were susceptible to the carbapenems than to cefepime. All but 1 of 14 screen-positive AmpC nonproducers (and ESBL nonproducers) were susceptible to ceftriaxone and cefepime at the standard inoculum as were 6 of 6 isolates that were randomly selected and tested with a high inoculum. These results indicate that (i) a significant number of K. pneumoniae bloodstream isolates harbor ESBL or AmpC β-lactamases, (ii) confirmatory tests are necessary to identify true AmpC producers, and (iii) in vitro, carbapenems are active against AmpC-producing strains of K. pneumoniae.

H. pylori acutely inhibits gastric secretion by activating CGRP sensory neurons coupled to stimulation of somatostatin and inhibition of histamine secretion

Acute Helicobacter pylori infection produces hypochlorhydria. The decrease in acid facilitates survival of the bacterium and its colonization of the stomach. The present study was designed to identify the pathways in oxyntic mucosa by which acute H. pylori infection inhibits acid secretion. In rat fundic sheets in an Ussing chamber, perfusion of the luminal surface with H. pylori in spent broth (10(3)-10(8) cfu/ml) or spent broth alone (1:10(5) to 1:10(0) final dilution) caused a concentration-dependent increase in somatostatin (SST; maximal: 200 ± 20 and 194 ± 9% above basal; P < 0.001) and decrease in histamine secretion (maximal: 45 ± 5 and 48 ± 2% below basal; P < 0.001); the latter was abolished by SST antibody, implying that changes in histamine secretion reflected changes in SST secretion. Both responses were abolished by the axonal blocker tetrodotoxin (TTX), the sensory neurotoxin capsaicin, or the CGRP antagonist CGRP8-37, implying that the reciprocal changes in SST and histamine secretion were due to release of CGRP from sensory neurons. In isolated rabbit oxyntic glands, H. pylori inhibited basal and histamine-stimulated acid secretion in a concentration-dependent manner; the responses were not affected by TTX or SST antibody, implying that H. pylori can directly inhibit parietal cell function. In conclusion, acute administration of H. pylori is capable of inhibiting acid secretion directly as well as indirectly by activating intramural CGRP sensory neurons coupled to stimulation of SST and inhibition of histamine secretion. Activation of neural pathways provides one explanation as to how initial patchy colonization of the superficial gastric mucosa by H. pylori can acutely inhibit acid secretion.

Vibrio furnissii: an Unusual Cause of Bacteremia and Skin Lesions after Ingestion of Seafood

ABSTRACT Vibrio furnissii in the blood is rarely reported, which may explain why clinical features of bloodstream infections with this organism have not been described. We describe a patient who developed skin lesions and V. furnissii bacteremia and was successfully treated with fluoroquinolones. V. furnissii may be a serious pathogen in patients with underlying comorbidities who are exposed to seafood.

Listeria monocytogenes Keratitis

We treated a farmer who had Listeria monocytogenes bacterial keratitis. Therapy with topical antibiotics was unsuccessful; it was necessary to treat the patient with topical and systemic penicillin and gentamicin. To elucidate the pathogenesis of this infection, we developed a rabbit model. Using the patients strain of L. monocytogenes, we determined that the severity of the rabbit infection was dose-related. If we used an inoculum of more than 10(7) organisms, many of the features of the human Listeria keratitis were mimicked. We also found that treatment with either penicillin or gentamicin did not control the infection as well as using both antibiotics simultaneously, a combination which resulted in relatively rapid resolution of infection and no corneal scarring. The human and animal data indicate that L. monocytogenes can be a virulent corneal pathogen. Listeria corneal infections must be treated aggressively with both penicillin and gentamicin to prevent permanent visual loss.