Bacterial Growth Kinetics of &lt;i&gt;Escherichia coli&lt;/i&gt; and Mycobacteria in the Presence of Brodimoprim and Metioprim Alone and in Combination with Sulfamerazine and Dapsone (VI)

Seydel, Joachim K.; Wempe, E; Rosenfeld, M

doi:10.1159/000238206

Cited by 13 publications

(3 citation statements)

References 6 publications

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“…On the basis of the pioneering studies of Garret et al [13][14][15] and their application by Seydel et al [16][17][18] experimental methods and mathematical models have been developed to study the kinetics of bacterial growth or inhibition of growth and to quantify the decrease in growth rate caused by the antibacterial agent as a function of the drug concentrations.…”

Section: Introductionmentioning

confidence: 99%

Kinetics and Quantification of Antibacterial Effects of Beta-Lactams, Macrolides, and Quinolones against Gram-Positive and Gram-Negative RTI Pathogens

2005

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Traditionally, the in vitro activity of antibacterial agents is characterized by their minimal inhibitory concentrations. However, these endpoints are, by nature, discrete and do not provide information on time-dependent killing of the bacteria during the incubation period. Nevertheless, the pharmacodynamic characteristics of antibacterial agents are almost always defined by correlating a static endpoint describing the antibacterial activity of an agent with the pharmacokinetics, describing the time-dependent fluctuation of drug concentrations. This approach is basically a contradiction in itself. Therefore, it would be more logical to correlate pharmacokinetics to in vitro parameters describing the time- and concentration-dependent antibacterial action of an agent. Thus, experimental methods and mathematical models quantifying the decrease in growth rate of a bacterial population due to the action of an antibacterial agent as a function of time and drug concentration have been applied to quantitate their pharmacodynamics. The effect of nine antibacterial agents representing drug classes of penicillins, cephalosporins, penems, macrolides, and fluoroquinolones were mathematically analyzed by using three different but related models. The kill rate, maximal kill, the 50%-effective concentration (EC50), the Hill coefficient, and concentrations and times needed to obtain a 1,000-fold decrease of the initial number of viable counts were calculated. Both the phenotypic description of the time-kill curves and these five parameters mirror the bacteriostatic or bactericidal activity of all nine agents studied as a function of time and concentration. Therefore, it would be more logical to correlate a parameter quantifying the kinetics of antibacterial in vitro activity with the pharmacokinetics of the drug, thus, replacing static endpoints like minimal inhibitory concentrations.

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Section: Introductionmentioning

confidence: 99%

Kinetics and Quantification of Antibacterial Effects of Beta-Lactams, Macrolides, and Quinolones against Gram-Positive and Gram-Negative RTI Pathogens

2005

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“…lufu , the latter being the organism of choice as a model for folate metabolism in M . leprae (Kulkarni and Seydel, 1983;Seydel et al, 1983). In these experiments, maximum inhibition of hypoxanthine incorporation was only 50-60% (table 11) for agents other than dapsone.…”

Section: Discussionmentioning

confidence: 80%

Measurement of hypoxanthine incorporation in purified suspensions of Mycobacterium leprae: a suitable method to screen for anti-leprosy agents in vitro

Wheeler

1988

Journal of Medical Microbiology

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Summary. The rate of incorporation of hypoxanthine was measured in suspensions of Mycobacteriurn leprae, with and without added anti-leprosy agents. Dapsone, clofazamine and brodimoprim, as well as other benzylpyrimidines, inhibited hypoxanthine incorporation, and their minimum inhibitory concentrations for incorporation with intact M . leprae were near the minimum inhibitory concentrations at which the agents have antibacterial effects. At sub-inhibitory concentrations for hypoxanthine incorporation, some combinations of benzylpyrimidines and dapsone were inhibitory, suggesting that synergic effects of anti-leprosy agents might also be detected by the inhibition of hypoxanthine incorporation. Thus, demonstration of inhibition of hypoxanthine incorporation in M . leprae could be a rapid method for screening anti-leprosy agents and especially for preliminary testing of new, potential anti-leprosy agents. The rate of hypoxanthine incorporation was generally lower in suspensions of M . leprae with lower viability, but it was not proportional to viability so the technique would not be suitable for accurate determination of viability.

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“…A rational approach to generating potentially useful dihydrofolate reductase inhibitors for use in leprosy has been spearheaded by Professor Seyde1. 29 Seydel has been interested in a number of dihydrofolate reductase inhibitors, especially brodimoprim for its potential use in leprosy because of:…”

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confidence: 99%

The use of rodent models in assessing antimicrobial activity againstMycobacterium leprae

Rh¹

1986

Leprosy Review

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Prior to the landmark discovery in 1960 of ' The Experimental disease that fo llows the injection of human leprosy bacilli into fo otpads of mice,' 1 the only means of searching for drugs active against human disease was to conduct clinical trials. Because clinical improvement of lepromatous patients is both very slow and variable, because the number of AFB (BI) in the skin fa lls extraordinarily slowly despite adequate therapy, and because the viability of solid-staining bacilli (MI) was not appreciated, early short-term clinical trials were difficult to conduct and the results even harder to interpret. Of the earlier studies on dapsone only the study of Lowe2 fo llowed a stable population until bacteriological negativity, finding 32 of 39 (83%) negative at 5 years, 31 of 35 (89%) negative at 6 years, and 34 of 35 (97%) smear-negative at 7 years.The earliest studies on the effect of antimicrobial agents on My cobacterium leprae-infected mice utilized primarily drugs known to be effective against M. tuberculosis. These first studies utilized constant treatment from the time of mouse fo otpad infection, generally with 5 x 103 M. lepraejfootpad, either by incorporation of drug into mouse chow or daily (actually usually five times weekly) intraperitoneal injections. By these means Shepard3 fo und dapsone, clofazimine, isoniazid, para-aminosalicylic acid, streptomycin, and cycloserine active and ethambutal and pyrizinamide inactive. By similar means Gaugas4 in 1967 fo und the same drugs active, and notably, as well, rifampicin and cephaloridine. This method of drug testing, termed the 'continuous method', does not distinguish between purely bacteriostatic and bactericidal activity. Since it has been well established in bacterial endocarditis and a number of other infectious diseases where protective local or systemic host defence mechanisms are inadequate (osteomylitis, meningitis, and Gram negative bacteremia in the neutropenic patient) that bactericidal therapy is crucial to a salutary outcome and that the key to effective short-course chemotherapy for pulmonary tuberculosis is the inclusion of two or more bactericidal agents,5 actual bactericidal activity against M. leprae is likely to be similarly important in the therapy oflepromatous 0305-75 1 8/86/057137S + 12 $0 1 .00

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Bacterial Growth Kinetics of <i>Escherichia coli</i> and Mycobacteria in the Presence of Brodimoprim and Metioprim Alone and in Combination with Sulfamerazine and Dapsone (VI)

Cited by 13 publications

References 6 publications

Kinetics and Quantification of Antibacterial Effects of Beta-Lactams, Macrolides, and Quinolones against Gram-Positive and Gram-Negative RTI Pathogens

Kinetics and Quantification of Antibacterial Effects of Beta-Lactams, Macrolides, and Quinolones against Gram-Positive and Gram-Negative RTI Pathogens

Measurement of hypoxanthine incorporation in purified suspensions of Mycobacterium leprae: a suitable method to screen for anti-leprosy agents in vitro

The use of rodent models in assessing antimicrobial activity againstMycobacterium leprae

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