A New Antibiotic: Lessons and Perspectives

R. A. Stein


Int J Clin Pract. 2008;62(12):1836-1837. 

Infectious diseases are still directly responsible for at least 13 million deaths worldwide and over 25% of the annual mortality.[1,2] Annually, an estimated 1.7 million individuals in the United States acquire an infection while hospitalised, resulting in nearly 100,000 deaths.[3] A major challenge, if not the major challenge for the 21st century, is antimicrobial resistance.

Historically, antibiotic resistance emerged almost as soon as individual antibiotics became commercially available.[4] After penicillin was introduced in 1943, resistant strains started to be observed in 1946. While most gram-positive pathogens were initially sensitive in the 1940s, over 50% of the Staphylococcus aureus strains were no longer susceptible a few years later, and today the majority of bacterial agents are penicillin resistant,[4] including over 95% of the staphylococci and 30-50% of the pneumococci. Other antibiotics, such as methicillin, tetracycline and cephalosporines, for which resistant strains were described just years after they became commercially available,[4] showed similar patterns.

Between 50% and 60% of the nosocomial infections in the United States are caused by resistant pathogens, and antibacterial resistance has become a complex medical, social and public health issue. To illustrate a few examples, the percentage of vancomycin-resistant enterococci isolated from patients in the United States increased from 0.4% in 1989 to 25.9% in 1999;[5] a survey of over 50,000 Pseudomonas aeruginosa isolates collected between 1999 and 2002 revealed that 24.9% were multidrug resistant;[6] over 40% of S. pneumoniae penicillin strains around the world display multidrug resistance;[7] and Neisseria gonorrhaea resistance rates to fluoroquinolones exceed 50-70% in several countries.[8]

But the leading bacterial pathogen worldwide, intimately linked to the growth of antimicrobial resistance, is S. aureus, and methicillin-resistant S. aureus (MRSA) has become one of the most fervent medical and public health problems. After methicillin introduction in 1960, MRSA strains were reported as soon as 1961 and 1968 in the UK[9] and the United States,[10] respectively, and their prevalence has been steadily increasing since then - from 2.4% in 1974 to 5% in 1981, 29% in 1991 and 43% in 1997.[11] MRSA spreads rapidly, as demonstrated by a single clone that since 2000 was isolated in 38 US States, Canada and nine European Union countries.[12] It can compromise indwelling devices, as the treatment failure of 12 out of 14 orthopaedic implants[13] revealed. Furthermore, MRSA brings an estimated $1.5-4.2 billion in excess medical costs in the United States.[14]

How did we get to this point, and what can we do? With 11 million kg of antimicrobials prescribed annually in the United States for human use, or 4.1 kg for every 100 persons,[15] antibiotics have become the second most frequently prescribed medication in physicians' offices,[16] outranked only by drugs acting on the central nervous system. Yet, half of all antibiotics prescribed on an outpatient basis are estimated to be for colds, upper respiratory infections and bronchitis, conditions that normally do not benefit from this class of medications. Moreover, large amounts of antibiotics are used in dental care - UK dentists, for example, dispensed 3.5 million antibiotic prescriptions only in 1996,[17] corresponding to three weekly prescriptions per practitioner on average.

Judicious antibiotic prescribing represents, therefore, a fundamental strategy, and its implementation should become a priority particularly in intensive care settings, where antibiotic use exceeds 10 times that in other hospital wards.[18] Controlling antibiotic use becomes an even more urgent task if we consider that resistance affects not only the person(s) using the antibiotics but, also, other household members.[19] Additional approaches such as education of healthcare providers and families, development of new guidelines, rotation of antibiotics and combination therapies were proposed. Many of these strategies do not work independently[20] and their benefit, when examined in isolation, is often confounded and unclear. Instead, it is the multimodal intervention approach that provides the best results.[20]

Finally, an essential strategy is to consider the place for new therapeutics in the context of resistance control, even before they become commercially available, in an attempt to extend their useful lifetimes. A new therapeutic agent, ceftobiprole, is one of the most recent antibiotics to receive an approvable letter from the Food and Drug Administration. When the X-ray crystal structure of PBP2a - the protein intimately linked to S. aureus methicillin resistance - became available,[21] the active site was visualised as an extended, narrow groove, leading to the prediction that ß-lactams with longer and more hydrophobic acyl groups will establish stronger and energetically more favourable interactions.[22] A vinylpyrrolidinone moiety at position 3 of ceftobiprole promotes association with PBP2a, and anti-MRSA bactericidal activity at very low minimum inhibitory concentrations sets this antibiotic aside among ß-lactams. Clinical trials in patients with skin and skin structure infections[23,24] and community-acquired pneumonia,[25] together with results from in vitro studies and animal models, converge to reveal that ceftobiprole could become a valuable therapeutic option against a broad group of gram-positive, gram-negative and anaerobic pathogens.

While vancomycin has long been considered the MRSA drug of choice, up to 40% of the evaluatable patients with S. aureus pneumonia were reported to experience treatment failure.[26] Therefore, whenever we welcome new antimicrobials, we should reflect upon the broad public health perspective and remember the lessons that we learned from the past. The way we use newly approved therapeutic agents will greatly shape our future interaction with bacteria, an interaction that Joshua Lederberg envisioned as episodes of a suspense thriller entitled Our Wits Versus Their Genes.[27]

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