Sheldon M. Markowitz

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

Do protective devices prevent needlestick injuries among health care workers

OBJECTIVES To determine the effectiveness and direct of two protective devices-a shielded 3 ml safety syringe (Safety-Lok; Becton Dickinson and Co., Becton Dickinson Division, Franklin Lakes, N.J.) and the components of a needleless IV system (InterLink; Baxter Healthcare Corp., Deerfield, Ill.)--in preventing needlestick injuries to health care workers. DESIGN Twelve-month prospective, controlled, before-and-after trial with a standardized questionnaire to monitor needlestick injury rates. SETTING Six hospital inpatient units, consisting of three medical units, two surgical units (all of which were similar in patient census, acuity, and frequency of needlesticks), and a surgical-trauma intensive care unit, at a 900-bed urban university medical center. PARTICIPANTS All nursing personnel, including registered nurses, licensed practical nurses, nursing aides, and students, as well as medical teams consisting of an attending physician, resident physician, interns, and medical students on the study units. INTERVENTION After a 6-month prospective surveillance period, the protective devices were randomly introduced to four of the chosen study units and to the surgical-trauma intensive care unit. RESULTS Forty-seven needlesticks were reported throughout the entire study period, 33 in the 6 months before and 14 in the 6 months after the introduction of the protective devices. Nursing staff members who were using hollow-bore needles and manipulating intravenous lines accounted for the greatest number of needlestick injuries in the pre-intervention period. The overall rate of needlestick injury was reduced by 61%, from 0.785 to 0.303 needlestick injuries per 1000 health care worker-days after the introduction of the protective devices (relative risk = 1.958; 95% confidence interval, 1.012 to 3.790; p = 0.046). Needlestick injury rates associated with intravenous line manipulation, procedures with 3 ml syringes, and sharps disposal were reduced by 50%; however, reductions in these subcategories were not statistically significant. No seroconversions to HIV-1 or hepatitis B virus seropositivity occurred among those with needlestick injuries. The direct cost for each needlestick prevented was

Isolation of a beta-lactamase-producing, aminoglycoside-resistant strain of Enterococcus faecium.

789. CONCLUSIONS Despite an overall reduction in needlestick injury rates, no statistically significant reductions could be directly attributed to the protective devices. These devices are associated with a significant increase in cost compared with conventional devices. Further studies must be concurrently controlled to establish the effectiveness of these devices.

Antimicrobial susceptibility and molecular epidemiology of beta-lactamase-producing, aminoglycoside-resistant isolates of Enterococcus faecalis.

Beta-Lactamase-producing, aminoglycoside-resistant strains of Enterococcus faecalis have been isolated from different geographic areas and are endemic at our institution. We report the isolation of a beta-lactamase-producing, aminoglycoside-resistant strain of E. faecium. The beta-lactamase was plasmid mediated and transferable with high frequency into a plasmid-free E. faecalis recipient strain. MICs suggested that the E. faecium strain also contained intrinsic (chromosomal) resistance to penicillins.

Therapeutic Failures with Miconazole

beta-Lactamase-producing (BL+), aminoglycoside-resistant (AR) Enterococcus faecalis is endemic in our hospital, having caused widespread colonization and infection. Suitable therapy for infections caused by these organisms has been problematic. We compared the antimicrobial and bactericidal activities, by broth macrodilution and time-kill methods, of several antibiotics, alone and in combination, against BL+, AR isolates of E. faecalis and determined the transmissibility of antibiotic resistance markers. Ampicillin-sulbactam, imipenem, daptomycin, and ciprofloxacin were the most active antibiotics with MICs for 90% of isolates tested of 2, 1, 2, and 1 microgram/ml, respectively, against inocula of 10(3) and 10(5) CFU/ml. Little inoculum effect was noted with imipenem, vancomycin, daptomycin, or ciprofloxacin, while the addition of sulbactam to ampicillin partially inhibited the effect of the increased inoculum. Penicillin-sulbactam and ampicillin-sulbactam combinations in a 2:1 ratio were most frequently bactericidal (greater than or equal to 3-log10-unit decrease in bacterial titers at 24 h for 13 of 20 isolates), followed by daptomycin (8 of 20 isolates) and ciprofloxacin (2 of 20 isolates). Bactericidal activity was not demonstrated for imipenem or teicoplanin. beta-Lactamase production and aminoglycoside resistance were associated with a 60- to 65-MDa plasmid which was easily transferred to a plasmid-free E. faecalis recipient. The 840-bp beta-lactamase gene probe hybridized to purified plasmid DNA from BL+ donor isolates of E. faecalis and transconjugants but not from BL- isolates. Ampicillin-sulbactam and daptomycin (an investigational antibiotic) seem to be reasonable choices for the empiric therapy of presumed enterococcal infections in hospitals in which BL+, AR E. faecalis strains are isolated. Their use should ideally be supported by tests for bactericidal activity.

Comparison of ampicillin-sulbactam with vancomycin for treatment of experimental endocarditis due to a beta-lactamase-producing, highly gentamicin-resistant isolate of Enterococcus faecalis.

A retrospective review of therapeutic failures of miconazole in three patients is presented. Miconazole, a new imidazole derivative, is a broad-spectrum antifungal agent purportedly effective topically, orally, and parenterally against a number of species of fungi. Three patients with the following culturally proven deep fungal infections were treated with miconazole: (i) destructive arthritis (Sporothrix schenckii), (ii) meningoencephalitis (Cryptococcus neoformans), and (iii) disseminated aspergillosis (Aspergillus fumigatus). All the organisms were susceptible in vitro to 1.56 μg or less of miconazole per ml using a broth dilution technique. In each patient, miconazole administered intravenously in dosages of 30 mg/kg per day failed to control or eradicate infection. Miconazole serum levels ranged from <0.5 to 4.35 μg/ml as determined by radial diffusion bioassay. Cerebrospinal fluid levels were virtually undetectable. In one patient (C. neoformans), miconazole was given intraventricularly in doses of 15 mg without response. Therapeutic failures were attributed to suboptimal body fluid levels of miconazole. The reason(s) for such low levels of activity was not clear, but may have been poor penetrance into tissues, in vitro inactivation, and/or unusually rapid excretion. Untoward reactions from miconazole included fever, chills, nausea, vomiting, and phlebitis. Images

Endocarditis due to accidental penetrating foreign bodies

Increasing antibiotic resistance in the enterococci, including the capacity for beta-lactamase production and the development of high-level aminoglycoside resistance, has complicated the treatment of serious enterococcal infections, which often require synergistic antibiotic combinations for cure. We utilized the rabbit model of aortic valve endocarditis to investigate the effects of various antibiotics, alone and in combination, against a multiply antibiotic-resistant isolate of Enterococcus faecalis. Female New Zealand White rabbits were infected with either a beta-lactamase-producing, gentamicin-resistant isolate of E. faecalis or a non-beta-lactamase-producing, aminoglycoside-susceptible isolate, and the mean log10 CFU per gram of vegetation were determined. The most active agents were low-dose ampicillin-sulbactam (200 mg/kg of body weight per day), high-dose ampicillin-sulbactam (400 mg/kg of body weight per day), and vancomycin (150 mg/kg of body weight per day), which reduced the titers of bacteria by 2.27, 2.76, and 2.85 log10 (CFU/g, respectively, compared with controls. While ampicillin-sulbactam and vancomycin were equally efficacious in reducing titers of bacteria in vegetations, no animals were cured (defined as < 2 log10 CFU/g of vegetation) by either agent, whether treatment was continued for 3 or 7 days. The addition of gentamicin was not associated with increased killing in rabbits infected with the aminoglycoside-resistant isolate. Both high-dose ampicillin-sulbactam and vancomycin regimens demonstrated significant, continued reduction in bacterial titers with the longer periods of treatment (P < or = 0.05); 7-day treatment with high-dose ampicillin-sulbactam produced a greater reduction in bacterial titers in vegetation than 7-day treatment with vancomycin (P < or = 0.05). We conclude that ampicillin-sulbactam and vancomycin are equally effective in the treatment of experimental endocarditis due to beta-lactamase-producing, highly gentamicin-resistant E. faecalis. The optimum therapy for such infections in humans is not known.

A multicenter comparative study of the in vitro activity of fleroxacin and other antimicrobial agents.

A 15 year old boy had an eight month history of recurrent fever, malaise and poor appetite. Chest roentgenogram revealed a foreign object overlying the right ventricle. Multiple blood cultures grew Enterobacter cloacae. The patients condition improved and blood cultures became negative following gentamicin and carbenicillin therapy. E. cloacae was isolated from the foreign body (a finishing nail) at surgery. Antimicrobial therapy was continued for a total of 30 days, and the patient made an uneventful recovery.

In vitro Activity of Cefoxitin, Alone and in Combination with Aminoglycoside or Other β-Lactam Antibiotics against Common Gram-Negative Pathogens

The in vitro activity of fleroxacin was determined by broth microdilution against 2,079 recent bacterial isolates and compared to the activities of ciprofloxacin, ofloxacin, lomefloxacin, cefaclor, cefuroxime, cefixime, ceftriaxone, amoxicillin/clavulanate, trimethoprim/sulfamethoxazole (TMP-SMX), and, as appropriate, erythromycin and oxacillin. Most Enterobacteriaceae were inhibited by the quinolones at a concentration of < or = 1 microgram/ml; MIC90s of fleroxacin, ciprofloxacin, ofloxacin, and lomefloxacin were 0.25, 0.5, 1 and 1 micrograms/ml, respectively. Fleroxacin was 2-fold more active than ciprofloxacin against Providencia stuartii and Serratia marcescens. Aside from the quinolones, ceftriaxone and TMP-SMX were the most active antibiotics against the Enterobacteriaceae, with MIC90s of 8 and 16 micrograms/ml, respectively. Ciprofloxacin was more active against Pseudomonas aeruginosa than the other quinolones, while fleroxacin was more active against Stenotrophomonas maltophilia: 17.7, 11.2, 20.0, and 22.4% of P. aeruginosa were resistant to fleroxacin, ciprofloxacin, ofloxacin, and lomefloxacin, respectively. Moraxella catarrhalis and Haemophilus influenzae were uniformally susceptible to all antibiotics tested, as were the majority of oxacillin-susceptible staphylococci. The MIC90s of the quinolones and of the beta-lactam antibiotics for oxacillin-resistant staphylococci were 8- to 256-fold higher than for oxacillin-susceptible staphylococci. The beta-lactam antibiotics, TMP-SMX, and erythromycin were more active than the quinolones against streptococci; all antibiotics were poorly active against enterococci. Fleroxacin is active against a broad range of gram-negative bacilli and against oxacillin-susceptible staphylococci and should prove useful for such infections. However, its use cannot be recommended for infections due to oxacillin-resistant staphylococci, streptococci, or enterococci.

Evidence for clonal spread of a single strain of β-lactamase-producing Enterococcus (Streptococcus) faecalis to six hospitals in five states

We examined 160 strains of Enterobacteriaceae and Pseudomonas aeruginosa for susceptibility to cefoxitin, aminoglycosides, and other beta-lactam antibiotics, alone and in combination. The aminoglycosides were the most effective agents tested, but, except for some strains, cefoxitin inhibited all organisms at a 90% minimal inhibitory concentration of 25 micrograms or less per ml. We observed a relatively high incidence of antagonism or nonsynergy when cefoxitin was tested in combination with other agents against 33 gentamicin-susceptible gram-negative bacilli. No synergy was observed when various combinations with cefoxitin were tested against three strains of cephalothin-resistant, carbenicillin-resistant Enterobacteriaceae of varying gentamicin susceptibility.