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• W1557731385 abstract "This paper discusses the question of how we can evaluate and predict the emergence of resistance to antibiotics. Resistance to antibacterials is not a new phenomenon; it has always been with us. It is a part of a bacterium's defense system to survive in hostile environments. Yet, there is public health concern over the emergence of antimicrobial resistance in man [1EMEA Discussion Paper on Antimicrobial Resistance, EMEA 9880/99. Rev.www.eudra.org/humandocsDate: March 1999Google Scholar]. This concern is caused by the following important behavioral determinants. Overuse and inappropriate use of antibiotics in humans are recognized as principal factors involved in the selection pressure for the emergence of resistance. Furthermore, the potential transfer of antimicrobial resistance in animals [1EMEA Discussion Paper on Antimicrobial Resistance, EMEA 9880/99. Rev.www.eudra.org/humandocsDate: March 1999Google Scholar] to humans resulting from uncontrolled use of antibiotics for treatment, prophylaxis and growth promotion in animals contributes to this concern. What aspects of the regulatory issues pertinent for drug development and approval of indications and mode of use do relate to the issue of antimicrobial resistance? I will focus here on the regulatory issues related to resistance to human antibacterial medicinal products. Veterinary measures to control antimicrobial resistance have been described in a recent paper by the EMEA through its Committee for Veterinary Medicinal Products (CVMP) [2Committee for Veterinary Medicinal Products (CVMP). A Risk Management Strategic Plan for Controlling Antimicrobial Resistance Through the Authorization Of Veterinary Medicines. EMEA/CVMP/818199. January 2000.Google Scholar]. There are three CPMP guidance documents of relevance for the topic of this paper [3Note for Guidance on Evaluation of New Antibacterial Medicinal Products. CPMP/EWP/558/95.www.eudra.org/humandocsDate: 1997Google Scholar, 4Note for Guidance on the Pharmacodynamic Section of the SPC for Antibacterial Medicinal Products. CPMP/EWP/520/96.www.eudra.org/humandocsDate: 1997Google Scholar, 5Points to Consider on Pharmacokinetics and Pharmacodynamics in the Development of Antibacterial Medicinal Products. CPMP/EWP/2655/99.www.eudra.org/humandocsDate: 2000Google Scholar]. These guidance documents mention measures and criteria relevant for controlled targeted use of antibiotics. A number of these are mentioned here, categorized according to subjects such as indications, posology, etc. as follows. •General indications, e.g. respiratory tract infections or urinary tract infections, are not acceptable. Specific infections should be reflected in the indications representing more tightly the studied patient populations, e.g. community-acquired pneumonia, cystitis, etc.•The need for antibacterial therapy in indications in which a high proportion of patients may have a self-limiting condition and/or a nonbacterial infection, e.g. bronchitis or sinusitis, should be critically assessed. The bacterial etiology should be substantiated and the focus should be on patients requiring antibiotic treatment after thorough assessment of their clinical condition. In case empiric treatment is claimed or unavoidable it may be justified to consider placebo-controlled studies to establish the role of the drug.•Under the listing of claimed indications a statement such as the following should be included: ‘Consideration should be given to official guidance on the appropriate use of antibacterial agents’. •Optimal duration of treatment and frequency of dosing should be addressed. Studies should include the evaluation of the effect of treatment duration whenever possible. Often this can be anticipated for drugs having long half-life or persistence at the site of infection, e.g. very short courses (1–3 days) of ciprofloxacin in cystitis and of azithromycin in most indications (3–5 days).•Consideration of the specific pharmacokinetic/pharmacodynamic (PK/PD) properties of a new antibacterial may aid in the choice of potentially efficacious and least resistance-enhancing therapeutic dosage regimen for clinical trials. This includes analysis of the relationship between PK/PD parameters and efficacy and the risk of selecting drug-resistant microorganisms, e.g. (i) time of serum or plasma levels exceeding the MIC of relevant pathogens such as for β-lactams (e.g. as assessed in otitis media), erythromycin, or (ii) AUC/MIC ratio or Cmax/MIC ratio such as for aminoglycosides and fluoroquinolones. This can be based on in vitro and experimental models of infection, whenever available, and human data [6Craig WA Pharmacokinetic/pharmacodynamic parameters: rationale for antimicrobial dosing of mice and men.Clin Infect Dis. 1998; 26: 1-12Crossref PubMed Scopus (2401) Google Scholar, 7Thomas JK Forrest A Bhavnani SM et al.Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy.Antimicrob Agents Chemother. 1998; 42: 521-527PubMed Google Scholar]. Presently, most human data are derived from retrospective studies and are not available for all classes of antibacterials. Attempts to confirm PK/PD-based findings in prospective human/clinical studies should be encouraged. A recent study with levofloxacin has described pharmacokinetic parameters, mathematical PK/PD modeling and has analyzed their predictive value for clinical and bacteriological outcome [8Preston SL Drusano GL Berman AL et al.Pharmacodynamics of levofloxacin–A new paradigm for early clinical trials.JAMA. 1998; 279: 125-129Crossref PubMed Scopus (570) Google Scholar]. Both clinical and microbiological outcomes were most likely to be favorable if the Cmax/MIC ratio was ≥ 12.2 in patients with bacterial respiratory, urinary and skin infections. It is yet unclear to what extent such trials can decrease the number of patients necessary for evaluation or the number of studies necessary in phase II clinical trials. Furthermore, dosage should be determined with certainty (with overkill factor). The total spectrum of antibacterial activity must be considered, including the less susceptible pathogens and sites of infection that are not well-penetrated by the antibacterial. Controlled phase II trials also aim at objective exploration of the safety of a given dosage. The clinical benefit/risk assessment of the chosen dosage regimen for a certain indication should ultimately consider host factors (e.g. immunocompetence), severity of infection and safety aspects as compared with available standard treatment in confirmatory comparative clinical studies. •The potential of a new drug to induce resistance the mechanism (and in vitro and in vivo experimental conditions involved) and the incidence of acquired resistance in the clinical trial populations (throughout phases I–III or IV) should be well described. Data on the impact on the composition of the normal flora must be included, e.g. gut, skin.•For new antibacterial medicinal products, the European epidemiology of strains with acquired resistance should be well documented and reflected in the information for prescribers (data sheet/SmPC).•Applicants may also be expected to provide a protocol for active postmarketing surveillance of resistance.•Similarly, innovative industry-sponsored surveillance programs linked to old antibacterial products should be encouraged.•Postmarketing surveillance data discussed in the Periodic Safety Update Report (PSUR) must also contain information on targeted epidemiology of resistance to the antibacterial, with special focus on relevant notorious pathogens. •For old antibacterials, information about the European epidemiology of strains with acquired resistance in the data sheet/SmPC also deserves similar attention. Difficulties are encountered in the collection of adequate data. The data are also often difficult to interpret because of the limited character of the samples and the different breakpoints for susceptibility used. These factors and the divergent practices within Europe may explain the observed difference from area to area in the incidences for strains with acquired resistance. Agreed breakpoints for older products may need to be revised. The latter may also necessitate revision of the old indications. Ideally, the data should be derived from a database founded on appropriate surveillance systems that adequately represent hospital environment and other institutional settings (e.g. geriatric care) as well as the general practitioners'environment. A European antimicrobial resistance surveillance system has been recently founded (European Antimicrobial Resistance Surveillance System (EARSS), RIVM, NL). EARSS is an international network of national surveillance systems that aims to aggregate comparable and reliable antimicrobial resistance data for public health purposes in Europe. All EU countries plus Switzerland are participating in this project, including approximately 500 European laboratories (see http://www.earss.rivm.nl). •A European regulatory policy is under development to deal with the latter issue pertaining to the old antibiotics.•European breakpoints need to be agreed. This will help not only consistent enlisting of microorganisms according to uniformly defined susceptibility breakpoints but also better interpretation of the data on acquired resistance [9Leegaard TM Caugant DA Frøholen LO et al.Apparent differences in antimicrobial susceptibility as a consequence of national guidelines.Clin Microbiol Infect. 2000; 6: 290-293Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. The recently established European Committee on Antibiotic Susceptibility Testing (EUCAST) under the auspices of the ESCMID is involved in establishing harmonized definitions for breakpoints. A consensus report is expected shortly.•An antibacterial drug with an improved antibacterial activity spectrum targeted against infections caused by microorganisms resistant to other antibiotics should be substantiated with distinct clinical trial data in the target infection. This may require more than equivalence trials, e.g. salvage therapy data and superiority trials can be envisaged. The use of such an agent for infections that can be treated with available standard antibiotics should be avoided to avoid jeopardizing the clinical therapeutic merits of the new drug due to the emergence of resistance. For the same reason prophylactic use of such agents should be avoided. Also, specific warnings against the use of antibiotics for certain undesirable conditions because of resistance concerns may be reflected in the SmPC. This therapeutic strategy can only be realized if its importance is recognized equally by the pharmaceutical industry, regulatory authorities and prescribers. •The regulatory approach relies on state of the art (evidence-based) and rational pharmacotherapy, and strategic considerations put into regulatory perspective. The outlined measures, SmPC information, criteria and desirable improvements will contribute to the management of resistance.•No restrictions are considered here which may result in compromising the health of the patient.•During the development phase of new antibiotics companies are encouraged to seek advice from and discuss their drug development program with the regulatory authorities whenever appropriate, e.g. with respect to desired indications, patient populations, trial design.•The innovative pharmaceutical industry should be encouraged to continue efforts to develop new efficacious antibacterials, especially against resistant pathogens.•Advertising and promotion of antibiotics need to be subject to appropriate standards.•In general, judicious prescription of antibacterials by prescribers remains primarily an educational concern. Similarly, patients should be well informed about the importance of adherence to recommended dosage regimens.•Hospitals and other institutional settings have custody over strategies to prevent and control the emergence and spread of antibiotic-resistant microorganisms in their environments.•Co-ordinated measures are desirable and evaluation of their impact in due time is advisable." @default.
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• W1557731385 title "How to evaluate and predict the ecologic impact of antibiotics: a regulatory view" @default.
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• W1557731385 doi "https://doi.org/10.1046/j.1469-0691.2001.00075.x" @default.
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