Barbara E. Laughon

Oral norfloxacin for prevention of gram-negative bacterial infections in patients with acute leukemia and granulocytopenia. A randomized, double-blind, placebo-controlled trial

We evaluated the effect of norfloxacin, 400 mg given orally every 12 hours, on the prevention of bacterial infections in 68 adult patients who had acute leukemia throughout prolonged courses of granulocytopenia (median, 32 days). Gram-negative infections were documented in 13 of the 33 patients receiving placebo, but only in 4 of the 35 patients receiving norfloxacin; no effect on the frequency of gram-positive or fungal infections was noted. Norfloxacin administration resulted in the suppression of gastrointestinal tract colonization by aerobic bacteria without the development of norfloxacin resistance. Patients receiving norfloxacin developed first infectious fevers later than did those receiving placebo, had more rapid resolution of that fever after systemic antibiotic treatment, and spent less time febrile. Therefore, although no difference was seen in survival duration, we found that the prophylactic administration of oral norfloxacin led to decreases in overall morbidity and gram-negative infections, was well tolerated, and did not predispose to the development of multiply drug-resistant bacteria.

Efficacy of alcohol-based hand rinses under frequent-use conditions.

Fifty volunteers randomly assigned to one of five hand washing agents (10 subjects per agent)--a nonantiseptic liquid soap (control), an antiseptic hand rinse containing 60% isopropyl alcohol (IPA) with emollients (Alc A), an antiseptic hand rinse containing 70% IPA and 0.5% chlorhexidine gluconate with emollients (Alc B), an antiseptic containing 4% chlorhexidine gluconate and 4% IPA (CHG), and 70% IPA--washed their hands 15 times per day for 5 days under supervision by using a standardized technique and measured amounts of test agent. Microbiologic samples of hand flora were obtained at base line and after hand washes 1 and 15 on test days 1 and 5. After the initial hand wash there were significant reductions over base line in aerobic and anaerobic log CFU among those using Alc A, CHG, and IPA. By the end of the first day of hand washing (15 washes), there were 2-log or greater reductions in aerobic counts among subjects using all antiseptics, but no significant reductions in controls. By the end of day 5, all agents produced significant reductions in aerobic (P = 0.0002) and anaerobic (P = 0.002) counts over control soap. Subject assessment of effects of hand washing on the skin and overall satisfaction varied significantly by product (P = 0.04 and 0.05, respectively). We conclude that alcohol-based hand rinses are highly efficacious, and such products are recommended as a health care personnel hand wash, particularly when sink and running water are inaccessible.

Integrity of vinyl and latex procedure gloves.

In a series of experiments the integrity of vinyl and latex procedure gloves were tested under in-use conditions. Both types of gloves were tested by three methods: watertight (645 samples), bacterial penetration (50), and dye exclusion (90). Results of the watertight test demonstrated visible defects in 4.1% of vinyl and 2.7% in latex gloves. Twenty percent of latex gloves and 34 % of vinyl gloves which had passed the watertight test allowed penetration of Serratia marcescens when worn by volunteers. A series of manipulations designed to simulate approximately 15 minutes of clinical activity in an intensive care unit resulted in failure rates as high as 66%. Using the dye penetration test, there was a statistically significant difference between vinyl and latex procedure gloves with full manipulations, with failure rates of 53% and 3%, respectively. Both types of gloves provided some barrier protection. However, latex gloves performed better when stressed.

Quantity of soap as a variable in handwashing.

The purposes of this study were to assess the effect of two quantities (1 mL or 3 mL) of four different handwashing products on reductions in log colony-forming units (CFU) from the hands and to determine the amount of liquid soap used for handwashing by personnel in one hospital. First, 40 subjects were assigned by block randomization to one of four handwashing products (4% chlorhexidine gluconate in a detergent base, two alcohol hand rinses, and a liquid, nonantimicrobial soap) to be used in either 1 mL or 3 mL amounts per wash. Each subject washed his or her hands 15 times per day for five days. After one and five days of handwashing there were significant reductions over baseline in log CFU between handwashing products (P less than 0.001). Additionally, subjects using 3 mL of antiseptic soap had significantly greater reductions in log CFU than those using 1 mL (P less than 0.001). Among subjects using control liquid soap there was no such dose response. Second, a survey of 47 members of a hospital nursing staff from nine specialty areas and ten individuals in the general population was conducted to measure amounts of two liquid soaps used for handwashing. Amount of soap ranged from 0.4 to 9 mL per handwash. Personnel working in clinical areas where patients were at high risk for nosocomial infection used significantly more soap than did others (P less than 0.05). We conclude that quantity of soap used for handwashing is one variable influencing the microbial counts on hands, and that the quantity of soap used by health care personnel varies considerably.

Activities of Nigerian chewing stick extracts against Bacteroides gingivalis and Bacteroides melaninogenicus.

The in vitro activities of extracts of Nigerian chewing sticks against Bacteroides gingivalis and B. melaninogenicus are presented. The greatest inhibitory action was produced by Serindeia werneckei, whereas Fagara zanthoxyloides produced no appreciable inhibitory effect. A generally good correlation was found between the killing curves and MICs. Only extracts of Anogeissus leiocarpus showed acute toxicity in mice.

Recent Advances in the Management of AIDS-related Opportunistic Infections

Dr. H. Clifford Lane (National Institute of Allergy and Infectious Diseases [NIAID], National Institutes of Health [NIH], Bethesda, Maryland): Serious opportunistic infections rarely develop until late in the course of human immunodeficiency virus (HIV) infection. The risk for developing an opportunistic infection is closely associated with the CD4 count. Most serious opportunistic infections do not occur until the CD4 count decreases to below 200 cells/L. In the United States, almost 80% of patients with HIV die because of opportunistic infections. We focus on recent advances in the management of these problems. Preclinical Evaluation of Candidate Therapeutic Agents Dr. Barbara E. Laughon (NIAID, NIH): New agents to treat AIDS-related opportunistic infections are needed because of the relatively high rate of toxic reactions to current drugs, the treatment failures in various settings, and the increased emergence of resistant strains. The development of new therapies is often hampered by a lack of information on the basic biology of most of these organisms. Many exhibit complex life cycles, and both in vitro and in vivo culture systems are either difficult or nonexistent. The standard animal model for Pneumocystis carinii pneumonia is the corticosteroid-treated rat. In addition, molecular screens are now being established using enzymes purified from animal-derived organisms or derived by recombinant technology. Among the potential new drugs for treating P. carinii pneumonia are two compounds from Merck and Company that may be useful for long-term prophylaxis because they are potent inhibitors of cyst-wall formation; a dihydrofolate reductase inhibitor with less toxicity than trimetrexate; a group of primaquine-like drugs of the 8-aminoquinolone class that have been developed by the Walter Reed Institute of Army Research; and an oral version of pentamidine, a DMP-lactate being considered by Lyphomed (Rosemont, Illinois). Drug discovery efforts directed toward the treatment of disease caused by Toxoplasma gondii have focused on the relatively easy-to-grow tachyzoite form of the organism. In addition, molecular screens targeting specific T. gondii enzymes search for compounds with selectivity for the metabolic processes of the parasite. Although reactivation of the tissue cyst is the principal mechanism of disease in patients with AIDS, convenient models of chronic infection are not available, and most in vivo drug screening uses the acute systemic infection of mice. Currently, no compounds other than atovaquone (see below) are showing promise in these models. Mycobacterial infections present problems for rapid drug screening because the organisms routinely take 2 to 4 weeks to produce colonies. One alternative, using the Bactec technology to detect radiolabeled CO2 release, has recently shortened this process to about a week. Unfortunately, until recently no molecular screens have been in place because little is known about the metabolism of these microbes. At present, all new drugs for mycobacterial infections were originally discovered and developed for other diseases. Among them are the newer macrolides clarithromycin and azithromycin; the rifampin derivatives rifapentine, rifabutin, and rifamycin; and the newer fluoroquinolones sparfloxacin, ofloxacin, levofloxacin, and WIN-57273. Possible agents for the treatment of cytomegalovirus (CMV) infection are generally evaluated in tissue culture systems, which limit the rate at which new compounds can be screened. Several new compounds for treating CMV diseases are entering the pipeline. Among them are a series of nucleotide analogs, a ganciclovir prodrug, and a new series of heterocyclic benzimidazoles developed at the University of Michigan in collaboration with Burroughs-Wellcome. We are only beginning to understand the biology of the agents responsible for most AIDS-related opportunistic infections. The development of new therapies requires continued improvement in the basic foundations of preclinical science, including predictive animal models, rapid culture systems, and improved molecular probes to clone, express, and identify new therapeutic targets. The Developmental Therapeutics Branch of the NIH Division of AIDS supports a comprehensive research program of grants and contracts focused on targeted drug discovery and animal model testing of new therapies to facilitate the transition from the laboratory to the clinic. Treatment of Pneumocystis carinii Pneumonia Dr. Judith Falloon (NIAID, NIH): Before effective antipneumocystis prophylaxis was routinely used, P. carinii pneumonia occurred at least once in approximately 80% of North American patients with AIDS. The lung is the most important target organ for P. carinii, although disseminated disease has been recognized more frequently in patients with AIDS than in other patients. Standard therapy with oral or intravenous trimethoprim-sulfamethoxazole or intravenous pentamidine is highly effective but often poorly tolerated [1]. Because of recent drug development, the list of treatment options for P. carinii pneumonia is growing (Table 1). Atovaquone, previously called 566C80, was approved by the Food and Drug Administration (FDA) in December 1992 for patients with mild to moderately severe P. carinii pneumonia (a PaO2 of 60 mm Hg or greater or an alveolar-arterial gradient of 45 mm Hg or less) who cannot tolerate trimethoprim-sulfamethoxazole. In a preliminary uncontrolled trial, atovaquone was shown to be highly effective and safe [2]. A large, double-blind controlled trial comparing trimethoprim-sulfamethoxazole with atovaquone in 322 patients was recently completed [3]. Overall response rates were similar, and both drugs were effective; however, trimethoprim-sulfamethoxazole was associated with a lower failure rate and fewer deaths (7% and 0.6%, respectively) than atovaquone (20% and 7%, respectively). Atovaquone was better tolerated, however; treatment-limiting adverse effects occurred in 20% of patients treated with trimethoprim-sulfamethoxazole but in only 7% of patients treated with atovaquone. The efficacy of atovaquone was correlated with plasma concentrations, and those patients with higher concentrations (>15 g/mL) were substantially more likely to have been successfully treated. Table 1. Drugs Used for the Treatment of Acute Pneumocystis carinii Pneumonia* In its current tablet form, oral atovaquone is variably absorbed, and higher concentrations cannot be reliably achieved by increasing the daily dosage or altering the schedule of administration. A suspension formulation designed to be more consistently and completely absorbed is currently being evaluated and may be a notable improvement over the tablet. An intravenous preparation is also being assessed. Atovaquone is safe and tolerable, but it is less effective than trimethoprim-sulfamethoxazole. Atovaquone is thus well suited for patients with mild to moderately severe P. carinii pneumonia who can be treated as outpatients and who cannot tolerate trimethoprim-sulfamethoxazole. Although not licensed for treating P. carinii pneumonia, the oral combination of dapsone plus trimethoprim is widely used. Data from a 60-patient, double-blind trial suggested efficacy similar to that of trimethoprim-sulfamethoxazole with less toxicity [4]. The study was too small to prove the equivalence or superiority of dapsone-trimethoprim. It is also not clear how many trimethoprim-sulfamethoxazole-intolerant patients can tolerate dapsone-trimethoprim. Nevertheless, it is proving to be a useful, well-tolerated alternative that is suited to the outpatient treatment of those with mild to moderately severe P. carinii pneumonia. Based on data from small, uncontrolled trials, clindamycin with primaquine is a highly effective regimen, regardless of whether clindamycin is given orally or intravenously [5, 6]. Rash, diarrhea, or methemoglobinemia occurs in many patients, and this regimen should be avoided in patients with glucose-6-phosphate dehydrogenase deficiency. This combination is also useful for the outpatient treatment of mild P. carinii pneumonia in trimethoprim-sulfamethoxazole-intolerant patients. Other agents that have been studied in humans include trimetrexate, piritrexim, inhaled pentamidine, dapsone alone, and eflornithine [7-11]. Intravenous trimetrexate and oral piritrexim are antifolate agents so potent that they have been assessed as single agents for the treatment of P. carinii pneumonia, usually combined with folinic acid to diminish hematologic toxicity. In a double-blind, randomized trial of 303 patients assigned to receive trimetrexate-leucovorin or trimethoprim-sulfamethoxazole, failure rates because of lack of efficacy were 20% for the patients treated with trimethoprim-sulfamethoxazole and 38% for patients treated with trimetrexate. Relapses occurred more often in patients treated with trimetrexate (12%) than in those treated with trimethoprim-sulfamethoxazole (0%). Trimetrexate was better tolerated than was trimethoprim-sulfamethoxazole: Nine percent of patients assigned to receive trimetrexate had the drug discontinued compared with 28% of patients assigned to receive trimethoprim-sulfamethoxazole [12]. Trimetrexate has recently been licensed for the treatment of P. carinii pneumonia. It appears to have a role in the treatment of patients with severe P. carinii pneumonia who require parenteral therapy and who are either unresponsive to or intolerant of both parenteral pentamidine and trimethoprim-sulfamethoxazole. Aerosol pentamidine is appealing because it could maximize delivery to the major target organ while minimizing systemic absorption and toxicity. Results of several trials suggest, however, that this approach is associated with numerous treatment failures and early relapses and thus cannot be advocated outside of organized trials [8, 9]. In addition to the development of new agents, another major advance in the treatment of P. carinii

Treatment of Relapsing Clostridium difficile Diarrhea with Lactobacillus GG

Thirty-two patients with relapsing C. difficile diarrhea were treated with a lyophilized preparation of Lactobacillus GG; 23 were outpatients treated in Boston, Massachusetts, and nine were nursing-home patients in Baltimore, Maryland. After receiving Lactobacillus GG, all subjects improved symptomatically. Twenty-seven (84%) patients were cured by the single treatment, based on a minimum follow-up of 2 months. Five others relapsed within 10 days after initial Lactobacillus GG treatment; three were retreated and cured, and two were lost to follow-up and are considered failures. The use of Lactobacillus GG offers a safe and. relatively effective alternative to antibiotic therapy for relapsing C. difficile diarrhea.

Prevalence of acute enteric viral pathogens in acquired immunodeficiency syndrome patients with diarrhea

Abstract Diarrhea due to enteric pathogens is an important complication of advanced human immunodeficiency virus infection. Whereas numerous bacterial and parasitic agents have been implicated, the role of pathogenic enteric viruses is less clear. Stools from 153 human immunodeficiency virus seropositive men were tested by electrophoresis, enzyme-linked immunosorbent assay, and immune electron microscopy for the presence of rotaviruses (group A and non-group A), adenoviruses, and Norwalk agent. Virus was detected in 9% of the patients with acquired immunodeficiency syndrome, 3% of the patients with acquired immunodeficiency syndromerelated complex, and none of the seropositive men without these diagnoses. Virus detection was not more likely in stool from patients with diarrhea.

Alcohol-impregnated wipes as an alternative in hand hygiene.

The antimicrobial effectiveness of four hand-wash products for health care personnel included three liquid soaps that contained 4% chlorhexidine gluconate, 1% triclosan, or no antiseptic ingredient, respectively, and a 30% w/w ethyl alcohol-impregnated hand wipe. These products were evaluated for reduction in bacterial counts on hands after extended use of 15 handwashes per day for 5 consecutive days. The order of greatest to least log reduction among products at the end of the 5-day test period was chlorhexidine gluconate (2.01), triclosan (1.52), alcohol wipe (0.04), and control soap (0.03). Skin condition before and after handwash was assessed for each treatment group. Subjects reported less skin irritation with alcohol wipes than with the two antiseptic products. Repeated washing with alcohol wipes results in reductions in bacterial colony counts comparable with nonmedicated soap, sufficient to prevent transmission of pathogens by the hands in most situations that arise in nonacute health care settings. This evidence, in addition to increased user acceptability reported by the subjects who used alcohol wipes, suggests that alcohol wipes are an acceptable alternative to soap-and-water handwashing in nonacute health care settings.

Comparison of four antiseptic products containing chlorhexidine gluconate

The purpose of this study was to compare the antimicrobic efficacies of four formulations of chlorhexidine gluconate (CHG) for handwashing under frequent-use conditions. Fifty volunteers were assigned by block randomization to one of five products: one of two liquid detergents containing 4% CHG, a liquid detergent containing 2% CHG, a foam containing 4% CHG, and a nonantiseptic soap (control). Subjects washed their hands by a standardized technique 15 times per day for 5 days. After days 1 and 5 of handwashing, there was a significant reduction in log CFU for subjects using all four CHG-containing products compared with subjects using control soap and for subjects within each group after days 1 and 5 compared with the base-line CFU counts (all P less than 0.05). There were no significant differences between the four CHG products at any testing time. We conclude that all four formulations are satisfactory for clinical use.