The amphotericin B lipid complex (ABLC), which is composed of amphotericin B and the phospholipids dimyristoyl phosphatidylcholine and dimyristoyl phophatidylglycerol, was evaluated for its acute toxicity in mice and for its efficacy in mice infected with a variety of fungal pathogens. ABLC was markedly less toxic to mice when it was administered intravenously; it had a 50% lethal dose of >40 mg/kg compared with a 50% lethal dose of 3 mg/kg for Fungizone, the desoxycholate form of amphotericin B. ABLC was efficacious against systemic infections in mice caused by Candida albicans, Candida species other than C. albicans, Cryptococcus neoformans, and Histoplasma capsulatum. ABLC was also efficacious in immunocompromised animals infected with C. albicans, Aspergillusfumigatus, and H. capsulatum. Against some infections, the efficacy of ABLC was comparable to that of Fungizone, while against other infections Fungizone was two-to fourfold more effective than ABLC. Against several infections, Fungizone could not be given at therapeutic levels because of intravenous toxicity. ABLC, with its reduced toxicity, could be administered at drug levels capable of giving a therapeutic response. ABLC should be of value in the treatment of severe fungal infections in humans.

Auxotrophic and prototrophic control strain pairs of Candida albicans constructed by molecular biology methodologies were evaluated for pathogenicity in a systemic mouse model. Mutants that were auxotrophic for adenine, uracil, and heme each showed a lowered level of pathogenicity relative to control strains. It can be concluded from these experiments that decreased pathogenicity in each case is due to the auxotrophic mutation, because mutant and control strains were constructed so as to differ at a single locus. These observations suggest that new therapeutic agents for Candida infections might be designed based upon the inhibition of biosynthetic pathways that, in some cases, might be absent from the host.

Lysobactin, an antibiotic isolated from a strain of Lysobacter, is 2 to 4-fold more active than vancomycin against aerobic and anaerobic Gram-positive bacteria. Included in the spectrum of lysobactin are Staphylococci, Streptococci, corynebacteria, clostridia and various other Gram-positive anaerobic bacteria. The activity of lysobactin against aerobic and anaerobic Gram-negative bacteria is poor. Whengiven parenterally the compound was efficacious in systemic staphylococcal and streptococcal infections in mice. Similarly, when applied topically lysobactin was also curative in a staphylococcal woundinfection in mice. Somestudies on the modeof action of lysobactin are presented. Gram-positive bacteria have traditionally been susceptible to a wide variety of antimicrobial agents including the /Mactams, macrolides and tetracyclines. However, in recent years, multiply

Reproducible experimental surgical-wound infections in mice for use in the evaluation of topical antibacterial agents are described. The experimental wound was created on the backs of mice by means of a midline incision and was infected by means of cotton sutures monocontaminated with Staphylococcus aureus or Pseudomonas aeruginosa. The course of these wound infections was followed by quantitation of surface bacteria through use of a surface rinse technique. Surface wound counts of the infecting organisms thus obtained appeared to reflect the dynamics of the total wound count, as determined by homogenization of biopsied tissue. Treatment of infected wounds with a placebo cream had only a slight effect on surface wound counts and on mortality in the case of the S. aureus infection but enhanced markedly the lethality of the P. aeruginosa infection.The search for new drugs effective as topical antibacterial agents requires the careful and systematic evaluation of drugs not only in vitro but also in vivo, i.e., in the control and management of experimental infections. Several model infections for evaluating topical antibacterial agents have been developed in laboratory animals (5-7, 9, 18, 19, 21) and in humans (3,14,15,20). Although many of the models have proved to be effective in assessing topical agents, most of them do not lend themselves easily to a mass screening of potential agents. This paper describes and characterizes a relatively simple surgical-wound model in mice in which potential topical antibacterial drugs can be evaluated easily and expeditiously against Staphylococcus aureus and Pseudomonas aeruginosa wound infections.MATERIALS AND METHODS Animals. Female CF-1 mice, 18 to 20 g, purchased from a commercial source (Carworth Farms, New City, N.Y.) were used in all experiments. Mice were maintained, 10 to a cage, on wire, in temperatureand humidity-controlled quarters and were allowed food and water ad libitum.Test organisms. S. aureus SC 2406 (phage type 53/77/84/85) and P. aeruginosa SC 8822, clinical isolates from the departmental culture collection, were used as test organisms. The two organisms were maintained on brain heart infusion (BHI) agar (BBL) slants stored at 4 C, with transfers to fresh slants made monthly. For each experiment, a fresh slant was inoculated from the appropriate stock culture and incubated at 37 C for 18 h. After incubation, the growth was removed from the slant by washing with 0.1 M phosphate buffer, pH 7.2, and the resulting suspension was adjusted to a concentration of 2.0 x 109 cells/ml by use of a Klett-Summerson colorimeter with a 540-nm filter and a previously prepared standard curve. The suspension was then appropriately diluted and used for the contamination of sutures or the direct seeding of the experimental wounds. Preparation of contaminated sutures. Commercial cotton thread (Coats and Clark's, mercerized, size 8) monocontaminated with S. aureus or P. aeruginosa was used as the suture material to initiate and potentiate the experimental infection. The thread ...

Tigemonam, a novel, orally administered monobactam, exhibited potent and specific activity in vitro against members of the family Enterobacteriaceae, Haemophilus influenzae, and Neisseria gonorrhoeae. Its activity was variable to poor against gram-positive bacteria, Acinetobacter spp., Pseudomonas aeruginosa, and anaerobes. Within its spectrum of activity, tigemonam was far superior to oral antibiotics currently available, including amoxicillin-clavulanic acid, cefaclor, and trimethoprim-sulfamethoxazole. In addition, tigemonam was superior to cefuroxime, which is under development as an oral pro-drug, and more active than cefixime against several genera of the Enterobacteriaceae. The activity of tigemonam against the enteric bacteria, Haemophilus species, and Neisseria species was, in general, comparable to that of the quinolone norfloxacin. The excellent activity of tigemonam against ,B-lactamase-producing bacteria reflected its marked stability to hydrolysis by isolated enzymes. The expanded spectrum of activity against gram-negative bacteria observed with tigemonam thus extends oral ,I-lactam coverage to include members of the Enterobacteriaceae that are intrinsically or enzymatically resistant to broad-spectrum penicillins and cephalosporins.The use of oral antibiotics in the therapy of infectious diseases is generally limited to mild, community-acquired infections. Although community-acquired pathogens have historically been susceptible to current oral agents, resistant and multiply resistant isolates are becoming increasingly prevalent. The clinical utility of the oral P-lactam antibiotics is being rapidly eroded by the increasing isolation of Plactamase-producing strains of Escherichia coli, Haemophilus influenzae, and Neisseria gonorrhoeae, due to the acquisition and transfer of plasmid-mediated determinants (6, 8). Plasmid-mediated trimethoprim and tetracycline resistance is relatively common and may occur concomitantly with 3-lactamase production (4,6