View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REVIEW 10.1111/j.1469-0691.2008.02125.x Currently available antimicrobial agents and their potential for use as monotherapy L. R. Peterson Northwestern University’s Feinberg School of Medicine, Departments of Medicine and Pathology, Chicago, IL; Evanston Northwestern Healthcare, Department of Medicine, Division of Infectious Diseases and Department of Pathology and Laboratory Medicine, Division of Microbiology, Evanston, IL, USA ABSTRACT Infectious diseases remain a serious and now re-emerging threat to human life, contributing to over ten million deaths per year. Treatment of major infectious diseases with antibacterial agents creates an ongoing and escalating public health issue that currently leads to more problems than solutions. By processes of adaptation and survival, bacteria consistently develop mechanisms to overcome the effects of the newest and most potent antibacterial compounds. Simultaneously, progressively fewer antibacterial agents are being developed by pharmaceutical and biotechnology companies. Although this dilemma is an inherent trade-off and has no imminent resolution, the most prudent paradigm to pursue is the judicious use of antibacterial agents in the most limited way possible to attain the desired treatment results. One straightforward approach to antimicrobial stewardship is to use a single agent as opposed to combination therapy, so as to subject bacteria to lower total antibiotic exposure whenever feasible. This article reviews current trends in antibacterial drug development and describes a context for adherence to monotherapy with newer agents. Keywords Antibiotic resistance, antimicrobial stewardship, glycylcycline, monotherapy, tigecycline Clin Microbiol Infect 2008; 14 (Suppl. 6): 30–45 new antimicrobial agents is declining, while rates INTRODUCTION of morbidity and mortality, and the costs associ- A potential ‘post-antibiotic era’ is threatening ated with suboptimal treatment of infections present and future medical advances. According caused by resistant organisms, are rising [2]. The to the WHO, there is a global risk of creating an combination of the current worldwide increase in environment similar to that of the pre-antibiotic resistant bacteria and the downward trend in the era (i.e. before the middle of the 20th century), development of new antibiotics has serious health when deaths from infectious diseases were much and economic implications [3–5]. Resistant bacte- more prevalent than they are currently, and ria dramatically reduce the possibility of treating modern implant and transplant surgery was infectious diseases effectively, increasing the risk impossible because of the risk of infection. Emer- of complications and fatal outcomes. gence of antimicrobial resistance is a natural Indeed, the pipelines of the world’s 15 largest phenomenon that is caused largely by antimicro- pharmaceutical companies reflect a notable de- bial use (and misuse). There is a global pandemic cline in the number of new antimicrobial agents of resistant organisms that requires changes in under development and recently introduced. A how we address the problem [1]. In parallel with survey by Spellberg et al. found that nine new escalating resistance, the rate of development of antibacterial agents were introduced between 1998 and 2003, a drop from 16 such agents introduced between 1983 and 1987 (the first Corresponding author and reprint requests: L. R. Peterson, period for which the authors obtained data), with Evanston Northwestern Healthcare, Walgreen Building, SB525, 2650 Ridge Avenue, Evanston, IL 60201, USA a steady decline during the intervening years up E-mail: [email protected] to the present [5]. Tigecycline, the first of the Ó 2008 The Author Journal Compilation Ó 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 Peterson Monotherapy of serious infection 31 glycylcyclines, a new class of semisynthetic tetra- treatment failure attributable to the emergence cyclines, was introduced in 2005, giving a current of resistance, the development of superinfection total of ten new antibacterials in the last decade; or overall disease mortality did not differ signi- most, tigecycline included, represent extensions ficantly between b-lactam monotherapy and com- of an existing class of compounds. The authors bination regimens containing a b-lactam and an contrasted this with the current trend in the aminoglycoside. Although generalization is prob- number of new molecular entities (NMEs) in ably unwise, the concept of monotherapy could other drug classes being developed by the same become one practical pillar of antimicrobial stew- companies, citing public disclosures of 23 NMEs ardship, involving only one antimicrobial agent for depression and anxiety, eight for bladder whenever possible while still covering the hyperactivity, and seven for osteoporosis, in breadth of likely infecting pathogens. contrast to only five antibacterial NMEs. Simi- The goals of this article are to: (i) discuss the larly, the world’s seven largest biotechnology antibiotics currently available for initial therapy; companies reported having a total 52 NMEs in (ii) summarize the mechanisms of resistance to development for indications in the areas of antimicrobials; and (iii) describe the microbiolog- oncology, inflammation ⁄ immunomodulation and ical and clinical profile of tigecycline, the first in a metabolism ⁄ endocrinology, but only one for anti- new group of broad-spectrum agents, the gly- bacterial therapy [5]. The challenge of new anti- cylcyclines, which provides a new, practical microbial development is one of the issues opportunity for increased use of monotherapy in addressed by the recent Infectious Diseases Soci- the seriously ill patient. ety of America (IDSA) policy document on anti- biotic resistance [1]. AVAILABLE AGENTS AND As few new antibacterials are being developed, TREATMENT GUIDELINES the global need for a cooperative effort to ensure their appropriate use is increasing, with the Since the discovery and development of antimi- objective of reducing the emergence of resistance. crobial agents in the 20th century, many novel There is a need in the drug development process agents have become available, including penicil- for a comprehensive approach that works in lins, carbapenems, b-lactam–b-lactamase inhibitor concert with health, education, economic and combinations, extended-spectrum cephalospo- industrial policies. Containment of antibiotic rins, aminoglycosides, monobactams, oxazolidi- resistance will depend on coordinated interven- nones, fluoroquinolones, macrolides, and tions to optimize antibiotic consumption. The tetracyclines [7,8]. current rising trends in resistance to antimicrobial Many of these drugs have provided extended- agents suggest that the real problems are still spectrum anti-Gram-positive and anti-Gram-neg- ahead of us [2]. ative activity, but despite the availability of these In the interim, judicious use of existing anti- agents, resistance continues to disseminate among bacterials is paramount, but how to achieve this common pathogens (e.g. Staphylococcus aureus), practically is unclear. It is realistic to hypothesize while pathogens with new types of resistance that the fewer antibacterials used the better, with emerge and spread (e.g. CTX-M-producing Esc- less exposure to antimicrobials limiting the herichia coli and carbapenemase-producing Klebsi- opportunity for microbes to develop resistance ella pneumoniae strains). to these critical agents. Put another way, the fewer Because prevalence patterns of resistant organ- antibacterials used, the less the selection pressure isms vary widely and change continually, regio- on organisms that might develop resistance to nal, national and local resistance must be multiple agents when used together. However, considered in the selection of appropriate anti- the use of fewer antimicrobial agents is not bacterials to combat specific pathogens [3,4]. acceptable if it is accompanied by worse thera- Accordingly, the appropriate use of both older peutic outcomes. and newer agents is recommended through treat- Conceptually, the efficacy of monotherapy ment guidelines that address antibacterial use by must be proven, as was done by a meta-analysis geographical region and type of infection. Guide- of randomized, controlled studies in a report by lines for antibacterial use are most effective when Bliziotis et al. [6]. They showed that rates of they are evidence-based and focus on practical Ó 2008 The Author Journal Compilation Ó 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 32 Clinical Microbiology and Infection, Volume 14, Supplement 6, December 2008 recommendations that remain up to date through Table 2. Guideline summary for antibiotic selection rec- ongoing monitoring of published clinical studies. ommended for community-acquired intra-abdominal infections adapted from the Infectious Diseases Society of They should also focus on the level of risk for the America [9] individual patient, which typically is different for healthcare-associated and community-acquired Ampicillin–sulbactama Ticarcillin–clavulanic acid infections. Piperacillin–tazobactamb Ertapenem In the USA, the IDSA and the Surgical Infection Cefazolin or cefuroxime plus metronidazole Society (SIS) regularly update guidelines address- Ciprofloxacin and similar quinolones