Strategies to Prevent and Control the Emergence and Spread of Antimicrobial-Resistant Microorganisms in Hospitals. A challenge to hospital leadership.

OBJECTIVE: To provide hospital leaders with strategic goals or actions likely to have a significant impact on antimicrobial resistance, outline outcome and process measures for evaluating progress toward each goal, describe potential barriers to success, and suggest countermeasures and novel improvement strategies. PARTICIPANTS: A multidisciplinary group of experts was drawn from the following areas: hospital epidemiology and infection control, infectious diseases (including graduate training programs), clinical practice (including nursing, surgery, internal medicine, and pediatrics), pharmacy, administration, quality improvement, appropriateness evaluation, behavior modification, practice guideline development, medical informatics, and outcomes research. Representatives from appropriate federal agencies, the Joint Commission on Accreditation of Healthcare Organizations, and the pharmaceutical industry also participated. EVIDENCE: Published literature, guidelines, expert opinion, and practical experience regarding efforts to improve antibiotic utilization and prevent and control the emergence and dissemination of antimicrobial-resistant microorganisms in hospitals. CONSENSUS PROCESS: Participants were divided into two quality improvement teams: one focusing on improving antimicrobial usage and the other on preventing and controlling transmission of resistant microorganisms. The teams modeled the process a hospital might use to develop and implement a strategic plan to combat antimicrobial resistance. CONCLUSIONS: Ten strategic goals and related process and outcome measures were agreed on. The five strategic goals to optimize antimicrobial use were as follows: optimizing antimicrobial prophylaxis for operative procedures; optimizing choice and duration of empiric therapy; improving antimicrobial prescribing by educational and administrative means; monitoring and providing feedback regarding antibiotic resistance; and defining and implementing health care delivery system guidelines for important types of antimicrobial use. The five strategic goals to detect, report, and prevent transmission of antimicrobial resistant organisms were as follows: to develop a system to recognize and report trends in antimicrobial resistance within the institution; develop a system to rapidly detect and report resistant microorganisms in individual patients and ensure a rapid response by caregivers; increase adherence to basic infection control policies and procedures; incorporate the detection, prevention, and control of antimicrobial resistance into institutional strategic goals and provide the required resources; and develop a plan for identifying, transferring, discharging, and readmitting patients colonized with specific antimicrobial-resistant pathogens.

Randomized, prospective comparison of cefoxitin and gentamicin-clindamycin in the treatment of acute colonic diverticulitis.

In a randomized, prospective study, single-drug antibiotic therapy with cefoxitin (CFX) was compared to combination therapy with gentamicin and clindamycin (G/C) as definitive treatment for acute colonic diverticulitis. Excluding individuals requiring immediate operation, 51 patients with a clinical diagnosis of diverticulitis, who were hospitalized at five different medical centers, were randomized to receive CFX (30 patients) or G/C (21 patients). Age, sex, and the severity of diverticulitis were similar in the two groups. The cure rates of 90% and 85.7% observed for CFX and G/C, respectively, did not differ significantly. Leukocytosis resolved in a shorter time period in patients treated with CFX than in those treated with G/C (2.5 +/- 0.4 vs 4.1 +/- 0.6 days, respectively) (P = 0.03, Student's t test, unpaired data). Two cases of possibly antibiotic-related toxicity occurred in the CFX group versus three cases in the G/C group. The average cost of a course of CFX therapy was $417 compared with $488 for G/C. In this study, cefoxitin demonstrated efficacy and tolerability similar to that of gentamicin-clindamycin in the treatment of acute colonic diverticulitis and may be preferred in view of its narrower antimicrobial spectrum and lower cost.

Therapeutic and epidemiologic recommendations to reduce the spread of type-I beta-lactamase resistance.

The objectives of this United States Consensus Panel meeting were to evaluate the effectiveness of current surveillance systems for the detection of bacterial resistance as well as to formulate recommendations that can assist hospitals in determining actions that should be taken when a resistance problem is detected. These recommendations may be particularly helpful in controlling the emergence and spread of type-I beta-lactamase resistance. Numerous case reports of antimicrobial resistance among Enterobacter species, Pseudomonas aeruginosa, and other Gram-negative nosocomial pathogens known to produce type-I beta-lactamases have appeared in the literature since the introduction of the newer "third-generation" cephalosporins. The widespread use of these newer antimicrobial agents, often selected as standard therapy for serious hospital-acquired infections, has been associated with a corresponding increase in resistance to them. The failure of hospitalwide surveillance methods to describe the scope of this problem, especially among the most critically ill patients, may have resulted in a false sense of security among some infectious disease specialists and clinicians prescribing these antimicrobials as empiric therapy. High-level resistance in individual hospital units may be masked in hospitalwide antibiograms. A variety of conclusions and recommendations were formulated based on the collective experiences of the Consensus Panel members. Microbiology laboratories must make it a high priority to identify markers that will assist in rapidly identifying resistant organisms. Cooperative efforts are needed among users of commercial and automated microbiology test instruments to standardize results and to improve quality control, thereby making the data more directly comparable between laboratories.(ABSTRACT TRUNCATED AT 250 WORDS)

Meningitis due to protozoa and helminths.

This article reviews the microbiology, pathogenesis, epidemiology, clinical manifestations, diagnostic tests, and recent advances in the therapy of protozoan and helminthic infections of the central nervous system, with more emphasis given to protozoan than to helminthic infections.

A prospective study of the clinical utility of lymphocyte monitoring in the cardiac transplant recipient.

Monitoring peripheral lymphocytes for changes in antigen expression or subpopulations was performed by flow cytometry in an attempt to identify infection or rejection in cardiac transplantation recipients (CTRs). In this study, 32 cardiac transplantation recipients were followed prospectively, and the results of 274 lymphocyte analyses for transferrin receptor expression, an indicator of lymphocyte activation, and CD4/CD8 lymphocyte ratios were correlated with the patient's clinical status, e.g., infection (early or late), rejection (mild, moderate, or severe), or quiescence. The percentage of lymphocytes expressing the transferrin receptor (%TR+) increased significantly during all stages of infection (2.9%, P = 0.02), or stratified into early (2.7%, P = 0.03) or late stage infection (2.6%, P = 0.03). The increase in %TR+ lymphocytes was also noted during mild (2.8%, P = 0.01) and moderate (3.0%, P = 0.008) rejection. The specificity and positive predictive value of an increased %TR+ lymphocyte was 97% and 93%, respectively, during early infection; 92 and 71%, respectively, during mild rejection; and 85 and 80%, respectively, during moderate rejection. The CD4/CD8 lymphocyte ratio did not correlate with either infection or rejection (P greater than 0.05). In conclusion, an increase in the %TR+ lymphocytes indicates the presence of infection, especially acute infection, or, less likely, rejection in the cardiac transplant recipient, but its clinical utility may be as a screening test for the presence of infection, especially early infection in CTRs during the posttransplantation period. The CD4/CD8 lymphocyte ratio does not correlate with the presence of infection or rejection in the CTR.

Infections of prosthetic heart valves and cardiac pacemakers.

Prosthetic valve endocarditis may be considered present when two fo the following criteria are met: (1) two or more blood cultures are positive with the same organism in the absence of extracardiac infections, (2) evidence of bacterial endocarditis by histology or cultures is obtained from surgical or autopsy specimens, and/or (3) a clinical picture compatible with endocarditis (fever, new or changing regurgitant murmur, splenomegaly, hematuria, or evidence of peripheral emboli) is present. The overall incidence of PVE ranges from 0.98 to 4.4 per cent. Early and late PVE (that is endocarditis developing less than 60 and 60 or more days following valve implantation, respectively) accounts for 18 to 36 per cent and 64 to 82 per cent of infections, respectively. The overall mortality is 53 per cent and is higher in patients with early versus late PVE. Coagulase-negative staphylococci are responsible for a higher percentage of early (43 per cent) than late (28 per cent) infections. Streptococci are more common in late (27 per cent) than in early (3 per cent) PVE, while diphtheroids are most common in early PVE. The diagnosis of PVE may be difficult to establish, especially in patients with postoperative bacteremias who have other potential sources of extracardiac infections. Antimicrobial therapy is generally based on the susceptibility of the offending pathogen. With respect to the use of synergistic combinations, results are controversial, and most available data are derived from patients with native-valve endocarditis. Surgery remains an important aspect of treatment, and the mortality among patients who undergo early surgical intervention, particularly if their illness is complicated, is less than in those who are treated only with antibiotics. Indications for surgery include: (1) moderate-severe refractory congestive heart failure, (2) persistent bacteremia or fungemia, (3) multiple emboli, (4) myocardial abscesses, (5) relapsing PVE, and possibly (6) patients with clinical evidence of PVE and negative blood cultures and persistent fever despite 1 week or more of appropriate antibiotics. Pacemaker infections occur in less than 6 per cent of patients who undergo pacemaker insertion. These infections generally result from wound contamination at the time of surgery, and 75 per cent of infections are due to staphylococci. Staphylococcus aureus causes most infections occurring within 2 weeks after surgery, while S. epidermidis causes most later infections. The need to remove infected pacemakers is controversial.

Microbiology and pharmacology of aztreonam.

Aztreonam, the first monobactam antibiotic, represents a significant evolutionary advance in antimicrobial therapy. Aztreonam is stable in the presence of the hydrolytic beta-lactamase enzymes; as such, it is effective against most Gram-negative aerobes, including Pseudomonas aeruginosa, Escherichia coli, Klebsiella, and Enterobacter. Due to its specific spectrum of activity, aztreonam does not disturb the normal Gram-positive and anaerobic intestinal flora. The safety profile of aztreonam is superior: unlike the aminoglycosides, aztreonam does not cause nephrotoxicity or ototoxicity, and no routine monitoring of serum levels is required with its use. The pharmacokinetics of aztreonam after intravenous infusion or intramuscular dosing are presented as well as the dosage adjustments for hemodialysis and chronic ambulatory peritoneal dialysis (CAPD).

Cephalosporin therapy in intraabdominal infections. A multicenter randomized, comparative study of cefotetan, moxalactam, and cefoxitin.

Three broad-spectrum cephalosporins (cefotetan, moxalactam, and cefoxitin) proved effective in this randomized, prospective trial for treatment of 303 surgical patients with moderately severe regional peritonitis.

Comparative study of cefotetan and cefoxitin in the treatment of intra-abdominal infections.

One hundred eighty-eight patients were enrolled in a multicenter, randomized clinical trial to compare the safety and effectiveness of 1 to 2 gm cefotetan every 12 hours with those of 1 to 2 gm cefoxitin every 6 hours in patients with intra-abdominal infections. Most of the infections were community acquired, were associated with gastrointestinal tract perforation, and were caused by both anaerobic and aerobic bacteria. The median duration of therapy was 6 days for each group. The clinical response rate for the 95 evaluable patients in the cefotetan group was 98%, and that for the 43 evaluable patients in the cefoxitin group was 95%. Bacteriologically, 97% of the 58 evaluable patients in the cefotetan group and 89% of the 27 evaluable patients in the cefoxitin group had a satisfactory or presumed satisfactory response; two patients in the cefotetan group and three in the cefoxitin group were considered bacteriologic failures. Cefotetan was as effective as cefoxitin in eradicating Bacteroides fragilis and other species of Bacteroides, Clostridium sp., and gram-negative bacilli. The incidence of treatment-related adverse reactions for cefotetan (27%) was not statistically different from that for cefoxitin (17%). No clinically significant differences were detected between the treatment groups in changes in the results of clinical laboratory tests performed before and after treatment; a decrease in hematocrit among the cefotetan group was statistically greater (p = 0.04) than that for the cefoxitin group, and a decrease in serum creatinine level for the cefoxitin group was greater than that for the cefotetan group (p = 0.02). Cefotetan may represent an effective, safe, and cost-saving alternative to cefoxitin for the prompt treatment of community-acquired intra-abdominal infections.

Single-dose antibiotic prophylaxis for biliary surgery. Cefazolin vs moxalactam.

Cefazolin was compared with moxalactam for single-dose prophylaxis against infection in a double-blind, prospective, randomized trial of 90 patients undergoing cholecystectomy. Risk factors for infection were present in 65 (72%) of the 90 patients and were evenly distributed. Antibiotic levels in plasma, bile, and tissue measured when the cystic duct was divided were similar for both drugs. Age greater than 65 years but not recent cholecystitis or type of antibiotic was predictive of recovery of bacteria from bile cultures. Wound infections occurred in two patients receiving cefazolin and one patient receiving moxalactam for an overall infection rate of 3%. No toxic reactions to antibiotics, including bleeding disorders, were observed. In conclusion, no significant difference in prophylactic efficacy was detected in this comparison of a first-generation with a third-generation cephalosporin. Because of its lower cost and narrower antimicrobial spectrum, however, cefazolin should remain the agent of choice.

In vitro comparison of antiplatelet effects of beta-lactam penicillins.

beta-Lactam antibiotics have been shown to cause platelet dysfunction and bleeding in some patients. However, relative antiplatelet activity of various beta-lactams has remained controversial. Results of clinical studies have been variable because of the presence of underlying disease in the study patients, in addition to inherent difficulties of in vivo experimentation such as individual variations of drug metabolism and drug kinetics. Thus, we designed in vitro experiments to study the direct effect of penicillin G, carbenicillin, ticarcillin, mezlocillin, piperacillin, nafcillin, and azlocillin on platelets. Platelets obtained from normal volunteers were exposed in vitro for 15 minutes to increasing concentrations of the test penicillins (10.0, 12.5, 15.0, and 20.0 mmol/L), and the platelet aggregation response determined after the additional of adenosine diphosphate (2.5 to 5.0 mumol/L), epinephrine (0.1 X 10(-3) mol/L), thrombin (0.01 to 0.02 U/ml), and collagen (11.62 micrograms/ml). All tested penicillins inhibited platelet aggregation in a saturable dose-dependent manner that was reversible by platelet washing. Biostatistical comparison of inhibition of platelet aggregation demonstrated nafcillin to cause significantly more inhibition, followed by azlocillin, mezlocillin, and piperacillin as a group. Penicillin G, carbenicillin, and ticarcillin were the least inhibitory. The mean percent inhibition (epinephrine) at 20 mmol/L concentration was nafcillin 86.4%, mezlocillin 83.2%, piperacillin 80.3%, azlocillin 76.4%, ticarcillin 73.2%, carbenicillin 66.4%, and penicillin G 58.4% (overall P less than 0.001). We conclude that all penicillins tested in vitro inhibit platelet aggregation in normal individuals, but to varying degrees. The inhibitory response, which is most likely a membrane-related phenomenon, is dose dependent and reversible.

In vitro and in vivo studies of the effect of aztreonam on platelet function and coagulation in normal volunteers.

The in vitro effects of aztreonam on platelet aggregation were compared with those of cefotaxime, moxalactam, piperacillin, and carbenicillin. In addition, the in vivo effects of intravenously administered aztreonam on blood coagulation and platelet function were examined in 10 normal male volunteers in a randomized crossover study. In vitro, at concentrations of greater than 6.25 mM (2.7 mg/ml), aztreonam inhibited ADP-induced platelet aggregation in a dose-dependent manner. The effect was less than that produced by equimolar concentrations of cefotaxime, moxalactam, piperacillin, or carbenicillin. At all concentrations tested, aztreonam and cefotaxime inhibited epinephrine-induced aggregation least. All antibiotics inhibited collagen-induced aggregation, but only at inordinately high concentrations (25 mM). In vivo studies in 10 male subjects, randomly infused intravenously with 2 g of aztreonam or saline placebo every 6 h for 21 consecutive doses in a single-blind crossover study, revealed no evidence of bleeding or visible adverse side effects. Although plasma coagulation and platelet adhesion remained within normal limits in all subjects throughout the study, inhibition of ADP-induced platelet aggregation significantly (P less than 0.0001) increased on days 3 and 6, but still was below 40%. With the exception of one subject who had a mean template bleeding time of 7.3 min (normal, 2 to 7 min at 95% confidence limits) on day 6 of aztreonam administration, all volunteers exhibited bleeding times within the normal range. No abnormalities in platelet morphology were observed. Mean peak serum aztreonam concentrations on days 1 and 6 were 90.1 +/- 16.7 and 95.9 +/- 13.7 micrograms/ml, respectively; accumulation did not occur. Thus, in normal volunteers, aztreonam produced no significant recognizable abnormalities of hemostasis after 6 days of maximal recommended doses.

Timentin in the treatment of symptomatic complicated urinary tract infections in adult patients.

The safety and effectiveness of Timentin were evaluated in 34 adult patients with symptomatic complicated urinary tract infections, principally due to multiply-drug-resistant bacteria. Although a wide variety of organisms, particularly gram-negative bacilli, were found, Escherichia coli was the most frequent, accounting for 14 of 45 (31 percent) pathogens isolated. Ten (22 percent) isolates were Pseudomonas aeruginosa; 11 (24 percent) were Proteus or Morganella species; three (7 percent) were Citrobacter; one (2 percent) was Klebsiella pneumoniae; two (4 percent) were Staphylococcus aureus; and two (4 percent) were enterococci. Ninety-three percent of all pathogens isolated produced a beta-lactamase. Eight (24 percent) infections were polymicrobial; seven (21 percent) were associated with bacteremia. Clinical improvement occurred in 30 of 34 (86 percent) patients. All bacteremias were cured. Although bacteriologic cure occurred in only 32 percent of patients, control of sepsis and temporary eradication of bacteria (bacteriologic improvement) occurred in 96 percent. Not surprisingly, the rates of relapses and reinfections were high. It was concluded that Timentin is a useful agent in the management of complicated urinary tract infection and offers clinicians an alternative to more toxic antibiotics, such as aminoglycosides.

Pneumonia treated with imipenem/cilastatin.

In an open, prospective, multicenter trial the efficacy and tolerance of imipenem/cilastatin for the treatment of bacterial pneumonia was investigated. Forty-three adults were studied: 29 with nosocomial and 14 with community-acquired infections. Significant underlying disease was present in 91 percent of patients. Nosocomial infection was frequently associated with endotracheal intubation (48 percent), prior antibiotic therapy (48 percent), and recent surgery (31 percent). Most frequent sputum isolates included Pseudomonas aeruginosa (10, all nosocomial), Hemophilus influenzae (10), Escherichia coli (eight), Staphylococcus aureus (seven), and Streptococcus pneumoniae (six). Treatment with imipenem/cilastatin was associated with clinical cure in 93 percent of patients. Two of three failures and one superinfection occurred in association with isolates of Pseudomonas aeruginosa resistant to imipenem. Overall, six of 10 strains of Pseudomonas aeruginosa isolated prior to therapy developed resistance to imipenem after an average of 10 days of therapy. Adverse effects occurred in nine patients (21 percent) and included one case of pseudomembranous colitis. Monotherapy with imipenem/cilastatin of serious lower respiratory tract infections was relatively safe and highly effective with the exception of disease associated with P. aeruginosa.

Gram-negative bacillary infections. Pathogenic and pathophysiologic correlates.

Gram-negative bacillary infections continue to be extremely important. Escherichia coli is the single most frequently encountered pathogen, followed by organisms belonging to the tribe Klebsiella-Enterobacter-Serratia and Proteus-Providencia. Pseudomonas aeruginosa, although it receives considerable (perhaps excessive) attention, is found relatively less frequently, occurring principally in the hospitalized patient who is immunocompromised. Many factors, both host and microbial, are responsible for invasiveness, virulence, and pathogenicity of gram-negative bacilli, but their relative roles, importance, and the pathophysiologic reactions they trigger are yet to be precisely defined. Certain aspects of many (but certainly not all) of the pathogenic correlates considered important in gram-negative bacillary infections, such as microbial flora, local barriers, surface and serum antibodies, complement, cell-mediated immunity, slime production, capsules, pili, endotoxin, cell wall components, extracellular products, and inoculum size are discussed herein. Points at which preventive or therapeutic strategies might be developed are offered. The benefits of antibiotics in managing susceptible gram-negative bacillary infections appear to be plateauing. If further advances are to be made in the therapy of these infections, new approaches to rapidly identifying the responsible etiologic agent and a better understanding of the factors responsible for invasiveness, virulence, and pathogenicity are needed.

Primaxin in the treatment of acute bacterial pneumonia in adults.

Imipenem (N-Formimidoyl thienamycin) (MK-0787) is a new beta-lactam carbapenem antibiotic. When it is combined with the renal dipeptidase inhibitor cilastatin (MK-0791) the combination is known as primaxin. In this study 28 adult patients (24 males and 4 females) with acute bacterial pneumonia were treated with primaxin. Twenty-one patients were evaluable and 20 (95%) were clinically cured of their pneumonia. Bacteriological cures were demonstrated in 84% of the cases. One patient with a susceptible Pseudomonas aeruginosa failed. Major complications or toxic reactions included antibiotic associated diarrhoea in one patient; hypotension in one patient; increased grand mal seizures in one patient and elevated liver function studies in one patient. Results of this study suggest that primaxin will be useful in the treatment of a variety of serious Gram-positive and Gram-negative pneumonias. The true incidence of possible toxic reactions with this drug is not known at this time and awaits further experience.