Arthur R. English

CP-45,899, a Beta-Lactamase Inhibitor That Extends the Antibacterial Spectrum of Beta-Lactams: Initial Bacteriological Characterization

CP-45,899 {3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 4,4-dioxide, [2S-(2α,5α)]} is an irreversible inhibitor of several bacterial penicillinases and cephalosporinases. In the presence of low concentrations of CP-45,899, ampicillin and other β-lactams readily inhibit the growth of a variety of resistant bacteria that contain β-lactamases. CP-45,899 used alone displays only weak antibacterial activity, with the notable exception of its potent effects on susceptible and resistant strains of Neisseria gonorrhoeae. CP-45,899 appears to be somewhat less potent but markedly more stable (in aqueous solution) than the recently described β-lactamase inhibitor clavulanic acid. The spectrum extensions provided by the two compounds are similar. A 1:1 mixture of CP-45,899 and ampicillin displays marked antimicrobial activity in mice experimentally infected with ampicillin-resistant Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, and Proteus vulgaris.

Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution.

Azithromycin (CP-62,993), a new acid-stable 15-membered-ring macrolide, was well absorbed following oral administration in mice, rats, dogs, and cynomolgus monkeys. This compound exhibited a uniformly long elimination half-life and was distributed exceptionally well into all tissues. This extravascular penetration of azithromycin was demonstrated by tissue/plasma area-under-the-curve ratios ranging from 13.6 to 137 compared with ratios for erythromycin of 3.1 to 11.6. The significance of these pharmacokinetic advantages of azithromycin over erythromycin was shown through efficacy in a series of animal infection models. Azithromycin was orally effective in treating middle ear infections induced in gerbils by transbulla challenges with amoxicillin-resistant Haemophilus influenzae or susceptible Streptococcus pneumoniae; erythromycin failed and cefaclor was only marginally active against the H. influenzae challenge. Azithromycin was equivalent to cefaclor and erythromycin against Streptococcus pneumoniae. In mouse models, the new macrolide was 10-fold more potent than erythromycin and four other antibiotics against an anaerobic infection produced by Fusobacterium necrophorum. Similarly, azithromycin was effective against established tissue infections induced by Salmonella enteritidis (liver and spleen) and Staphylococcus aureus (thigh muscle); erythromycin failed against both infections. The oral and subcutaneous activities of azithromycin, erythromycin, and cefaclor were similar against acute systemic infections produced by Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, or S. aureus, whereas azithromycin was more potent than erythromycin and cefaclor against the intracellular pathogen Listeria monocytogenes. The pharmacokinetic advantage of azithromycin over erythromycin in half-life was clearly demonstrated in prophylactic treatment of an acute mouse model of S. aureus infection. These properties of azithromycin strongly support the further evaluation of this new macrolide for use in community-acquired infections of skin or soft tissue and respiratory diseases.

CP-45,899 in combination with penicillin or ampicillin against penicillin-resistant Staphylococcus, Haemophilus influenzae, and Bacteroides.

CP-45,899 is a new, semisynthetic beta-lactamase inhibitor. When tested alone, CP-45,899 displayed only weak antibacterial activity, with the notable exception of its potent action against penicillin-susceptible and -resistant Neisseria gonorrhoeae. A combination of 3.12 microgram of CP-45,899 per ml with 3.12 microgram of ampicillin per ml, tested in broth cultures, inhibited ca. 90% of resistant Staphylococcus and Haemophilus influenzae strains; similar data were obtained in a variety of media. The same combination of CP-45,899 with ampicillin or penicillin G inhibited 90% of Bacteroides fragilis as interpreted from agar dilution minimal inhibitory concentrations. Inhibitory concentrations of CP-45,899-ampicillin were bactericidal against H. influenzae strains and were as bactericidal as nafcillin or cephalothin against S. aureus. Ampicillin-resistant S. aureus, H. influenzae, and B. fragilis strains did not develop resistance to CP-45,899-ampicillin when transferred as many as six passages in the presence of a sublethal concentration of the combination.

Structure–Activity Relationships in the Tetracycline Series

Publisher Summary The tetracyclines may be defined as a family of broad-spectrum antibiotics, which have a perhydronaphthacene skeleton in common. Although discovered later than chlortetracycline and oxytetracycline, tetracycline is considered the parent compound for nomenclature purposes. In addition to these three tetracyclines, other tetracyclines that have found extensive clinical use are demethylchlortetracycline, rolitetracycline, methacycline, and doxycycline. Some common trade names and the typical oral and daily dosage of the tetracyclines are summarized in the chapter. The chapter discusses only the earliest stages of the route of a tetracycline from discovery to clinical use. This early stage is concerned with biological screening for in vitro and in vivo antibacterial activity. It is only at this level that a large number of derivatives have been studied so as to permit a detailed discussion of structure-activity relationships.

Influence of Subtherapeutic Levels of Oxytetracycline on Salmonella typhimurium in Swine, Calves, and Chickens

Subtherapeutic levels of oxytetracycline in animal feeds have been evaluated to determine their influence on the relative quantity, prevalence, shedding, and antibiotic susceptibility of Salmonella typhimurium in swine, calves, and chickens, when compared with nonmedicated controls. The medicated groups were fed rations containing oxytetracycline commencing 5 days prior to oral inoculation with S. typhimurium and continuing through a 28-day post-inoculation period. Colonization of S. typhimurium occurred in all three animal species as evidenced by clinical signs of infection and/or colony counts in feces measured on seven separate occasions over the 28-day observation period. The accumulated data demonstrate that the subtherapeutic use of oxytetracycline did not bring about any increases in the quantity, prevalence, or shedding of S. typhimurium in swine, calves, and chickens. In fact, the medication generally brought about a decrease in the percentage of animals carrying S. typhimurium during the study period. In contrast to results in swine and calves, there was a significant occurrence of S. typhimurium resistance to oxytetracycline in chickens. Resistant colonies were isolated from chickens sporadically but never on more than two consecutive test periods. These isolates were also resistant to streptomycin, but not to the other six antibiotics tested. The population of resistant S. typhimurium isolated from medicated chickens was no larger than that of susceptible S. typhimurium isolated from the nonmedicated animals. It is concluded that no evidence has been obtained which would relate the continuous low-level feeding of oxytetracycline for a 4-week period to an increased incidence of disease in animals or as a hazard to humans.

Carbenicillin Indanyl Sodium, an Orally Active Derivative of Carbenicillin

Carbenicillin indanyl sodium, an orally active derivative of carbenicillin, is active against a broad spectrum of bacterial species. Although the ester has in vitro antimicrobial activity per se when evaluated in Brain Heart Infusion broth, the in vivo antibacterial activity seen in mice and rats reflects primarily the efficient hydrolysis of the ester to carbenicillin. With an acute systemic infection in mice as a test system, orally administered carbenicillin indanyl sodium protected mice against lethal infections produced by Escherichia coli, Salmonella choleraesuis, Pasteurella multocida, Proteus vulgaris, Staphylococcus aureus, and Streptococcus pyogenes. The dose that protected 50% of the animals against each of these infections was comparable to that of parenteral carbenicillin. Against experimental urinary-tract disease in rats produced by E. coli, P. vulgaris, and Pseudomonas aeruginosa, it was again observed that carbenicillin indanyl sodium provided activity comparable to that of parenterally administered carbenicillin.

Microbial Resistance to Penicillin as Related to Penicillinase or Penicillin Acylase Activity

Summary 1. The penicillin moiety, 6-aminopenicillanic acid, has antibacterial activity but is considerably less active than penicillin. 2. Resistance to penicillin in one group of bacteria could be explained logically by presence of penicillinase activity, i.e., conversion of penicillin to the inactive penicilloic acid. 3. Resistance to penicillin in a second group of bacteria could be explained logically by presence of penicillin acylase activity, i.e., conversion of penicillin to the relatively inactive 6-aminopenicillanic acid. 4. In a third group of bacteria resistant to penicillin, neither penicillinase nor penicillin acylase activity could be detected. Still another metabolic mechanism other than penicillinase or penicillin acylase activity must be present in selected bacteria.

Immunologic response of rabbits to 6-aminopenicillanic acid

Abstract Injection of rabbits with penicillin G, penicillin O, or penicillin V in Freunds adjuvant is followed by the appearance of antibody that agglutinates penicillin-sensitized rabbit erythrocytes. The immunologic specificity of the antibody is identical whether the serum studied is from an animal injected with penicillin G, penicillin O, or penicillin V. Administration of 6-APA to rabbits results in the formation of antibody with the same specificity as animals injected with penicillin G, penicillin O, or penicillin V. However, the amount of antibody produced in response to injection with 6-APA is much greater than with the complete penicillin molecule. On the basis of these results, it is postulated that 6-APA, or some derivative of it, is an important determinant group for the formation of penicillin antibody in the rabbit.

Influence of Subtherapeutic Levels of a Combination of Neomycin and Oxytetracycline on Salmonella typhimurium in Swine, Calves, and Chickens

Subtherapeutic levels of oxytetracycline plus neomycin in animal feeds did not bring about increases in the quantity, prevalence, or shedding of Salmonella typhimurium in swine, calves, or chickens. In fact, the medication generally reduced the proportion of animals carrying S. typhimurium. The medicated groups were fed rations containing oxytetracycline plus neomycin commencing 5 days prior to oral inoculation with S. typhimurium and continuing through a 28-day postinoculation period. Colonization of S. typhimurium occurred in all three animal species, as evidenced by clinical signs of infection and/or colony counts in feces. Only from swine and on only one occasion was a single resistant colony isolated. It is concluded that no evidence has been obtained which would implicate the continuous low-level feeding of oxytetracycline and neomycin for a 4-week period to a potential increased incidence of disease in animals or as a hazard to humans.

Pharmacokinetics of sultamicillin in mice, rats, and dogs.

The irreversible beta-lactamase inhibitor sulbactam has been combined chemically via ester linkages with ampicillin to form sultamicillin . Upon oral absorption, sultamicillin is completely hydrolyzed to equimolar proportions of sulbactam and ampicillin, thereby acting as an efficient mutual prodrug. In rats, sultamicillin delivered 2 to 2.5 times greater total bioavailability for ampicillin and sulbactam than when each was used individually. Actual plasma or serum concentrations (measured in micrograms per milliliter) of ampicillin and sulbactam produced by sultamicillin were generally equivalent in rats, mice, and beagle dogs. Further studies also indicated that the components of sultamicillin were widely distributed in the various tissues of rats. These findings suggest that sultamicillin might be an effective agent against a variety of infections produced by both beta-lactamase-resistant and beta-lactamase-susceptible microorganisms.