Animal models as predictors of the safety and efficacy of antibiotics

Zak, O.; O’Reilly, Terence

doi:10.1007/bf01964286

Cited by 20 publications

(12 citation statements)

References 24 publications

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“…Serious consideration was given to the discovery of effective agents that could be used to cure and prevent this disease, especially in AIDS patients. In the battery of investigations for the identification of new chemotherapeutic agents, in vivo tests with suitable animal models assume great importance as predictors of chemotherapeutic efficacy and safety (1,14,100,101). Until recently, proper in vivo studies to discover drugs active against MAC could not be done for want of a suitable animal model (11,28,29).…”

Section: Introductionmentioning

confidence: 99%

Beige mouse model for Mycobacterium avium complex disease

Gangadharam

1995

Antimicrob Agents Chemother

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Section: Introductionmentioning

confidence: 99%

Beige mouse model for Mycobacterium avium complex disease

Gangadharam

1995

Antimicrob Agents Chemother

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“…It has the advantages of being simple, with short duration and easily-evaluated endpoints (Zak and Sande, 1999). The key parameter to keep constant in this model is the number of bacteria used for infection, as this can have a major effect on the results (Zak and O'Reilly, 1990). Animals are infected by inoculating bacteria directly into the peritoneal cavity.…”

Section: Mouse Peritonitis Primary Infection Model To Evaluate Antibamentioning

confidence: 99%

Primary Rodent Infection Models for Testing Antibacterial Compound Efficacy In Vivo

Marra

Girard

2005

CP Pharmacology

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There are many reasons for employing animal models of infection. These include the ability to establish a range of infections caused by a variety of pathogens at different host sites, to understand how in vitro antibiotic sensitivity or resistance correlates to therapy failure in vivo, to control the virulence of the infecting organism as well as the timing and route of infection, and to study drug pharmacokinetics (Bergeron, 1978;Andes and Craig, 2002;Dagan, 2003;Jacobs, 2003). The challenge to the scientist is to utilize or develop an animal infection model that closely approximates human disease and that can reliably predict clinical efficacy. The goal is to compare the effectiveness of a novel drug with an established agent by demonstrating either increased survival due to protection from a lethal pathogen, or reduction of bacterial numbers at a specific site in the host. There is a complex relationship between the drug, the host, and the pathogen that can only be addressed in the context of a whole animal. As such, it is imperative that the scientist understands, or is able to gain information on, the virulence of the pathogen, the pharmacokinetics of the new chemical entity (NCE) and its possible metabolites, any potential toxicity associated with the test agent, and host defenses, in order to make these studies ethically justifiable as well as scientifically robust.Some investigators have found it useful to divide infection models into four classes: basic, or primary screening models; ex vivo models; mono-parametric models; and discriminative models (Bergeron, 1978;Zak and O'Reilly, 1991). The basic screening models are most useful for obtaining a rough approximation of the efficacy of a potential new drug, while optimizing the route of administration and dosing regimen and identifying associated toxicity (Zak and O'Reilly, 1991). These are generally single-step, simple infections, with a short duration and easily interpretable results, usually lethality. The dose of test compound that protects 50% of infected animals is the protective dose, or PD 50 . This value is useful for directly comparing the efficacy of agents against a pathogenic organism.This unit describes three primary infection models routinely used to evaluate antibacterial efficacy. All three share the features of being simple to perform, utilize outbred mice, are compound-sparing, reproducible, and have easily interpretable outcomes (Zak and O'Reilly, 1991). In two of the models, the efficacy of potential antibacterial compounds can be evaluated either by monitoring survival or by enumerating bacterial numbers at the site of infection.Probably the most commonly used infection model is the murine acute systemic infection model, which is also called murine peritonitis or septicemia (see Basic Protocol 1; Zak and Sande, 1999). This model is most useful for demonstrating the relationship between the in vitro potency and the in vivo activity of a compound (Zak and Sande, 1999), and is important for the early demonstration of potential anti-bacte...

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“…Clearly, the limitations of these experiments must also be considered in order to assess the toxicity of new anti-infective agents accurately. Differences in pharmacokinetic profiles, drug metabolism, the susceptibilities of nontarget bacterial flora, and anatomy between humans and animals can lead to incorrect predictions of antibiotic toxicity in humans on the basis of data obtained from toxicity studies with animals (see reference 48). Despite these limitations, toxicity testing in animals can give clear indications of possible short-term and long-term toxic effects and the maximum tolerable doses, and is thus a prerequisite to clinical trials.…”

Section: Animal Models In the Evaluation Of The Toxicity Of Antimicromentioning

confidence: 99%

“…For the demonstration of the efficacies of antimicrobial agents in vivo, in contrast to the demonstration of their toxicity in vivo, there are no detailed or definitive guidelines (19,42,48). Those published by the World Health Organization concerning the preclinical testing of antibacterial drugs (42) merely state that "the behavior of the substances in infected experimental animals can give some guidance to the future possible effects in man.…”

Section: Animal Models In the Evaluation Of The Efficacies Of Antimicmentioning

confidence: 99%

“…(21), it is hardly possible to meet all of them. Despite that, experimental studies with discriminative models have delineated effective therapeutic strategies now adopted clinically, for example, (i) the combination of rifampin with vancomycin or isoazolyl penicillin for the treatment of osteomyelitis (32,47,48), (ii) the combination of P-lactam and aminoglycoside antibiotics for the treatment of endocarditis (12,17,39), and (iii) adjunctive dexamethasone therapy for bacterial meningitis (18, 23-26, 37, 38). Tunkel and Scheld (40) have provided a comprehensive review of the contributions made by animal models to the therapy of meningitis and endocarditis in humans.…”

Section: Animal Models In the Evaluation Of The Efficacies Of Antimicmentioning

confidence: 99%

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