Predicting the future Streptococcus pneumoniae resistance landscape Robertino Mera Streptococcus pneumoniae resistance to antibiotics is considered a public health problem, and yet the link between year-to-year increases in resistance and antimicrobial consumption has been difficult to prove. Mathematical models and epidemiological studies have shown that there is no linear relationship between consumption and resistance, and that increasing resistance is caused by the removal of susceptible strains from the population. Pneumococcal conjugate vaccine has also been shown to have an impact over resistance. A model that relates resistance with the cumulative consumption of antibiotics over time explains low resistance rates in countries such as Germany and plateaus in resistance in the US. Moreover, understanding this temporal relationship allows us to predict that if the cumulative consumption stabilizes so will the resistance rates. Addresses 5 Moore Drive, MAI-B209.2D, Research Triangle Park, North Carolina, 27709, USA Corresponding author: Mera, Robertino (Robertino.M.Mera@gsk.com) Current Opinion in Pharmacology 2005, 5:459–464 This review comes from a themed issue on Anti–infectives Edited by Alisdair MacGowan and David payne Available online 9th August 2005 1471-4892/$ – see front matter # 2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2005.04.014 Introduction: resistance rates and surveillance There is a wealth of surveillance data [1] showing that penicillin resistance for community-acquired respiratory infections caused by Streptococcus pneumoniae in the US has been increasing and reached levels of 21.2% (14.2% intermediate) in 2002. Similarly, the erythromycin resis- tance rate was 27.9% among the same group of patients in 2002. These values, although high, tend to obscure the fact that some US regions, such as the Gulf of Mexico states, have resistance rates about 30% higher than the average, and that pre-school children have rates of peni- cillin and erythromycin S. pneumoniae resistance of 31.8% and 40.9%, respectively [2]. A related and important issue is the spread of multiple resistant S. pneumoniae clones in the US. A surveillance study [3] showed that during a 10-year period (1992–2001) resistance to more than one antibiotic increased 4.3-fold, from 6.4% in 1992 to 27.8% in 2001. Similarly, 75% of all penicillin-resistant isolates are now erythromycin resistant. Antimicrobial therapy and resistance Although genetic and environmental mechanisms that result in pneumococcal resistance are complex, the single most important consideration is the selective pressure imposed by the use of antimicrobial agents [4]. Well- designed cohort studies [5] have repeatedly identified recent antibiotic use as the strongest risk factor for the carriage and spread of resistant pneumococci, and this relationship has been shown to exist at both the commu- nity [6] and country level [7]. Epidemiological evidence [8] suggests that recent anti- microbial use not only increases the risk that an individual will carry, and therefore potentially transmit, resistant pneumococci, but among infected individuals also increases the risk of developing invasive pneumococcal illness caused by resistant strains. Additional risk factors for carrying resistant pneumococci identified by observa- tional studies include population density [9], low income [10], young age (<5 yrs old) and attendance of day care centers [11]. Longitudinal studies of nasopharyngeal carriage before and after the initiation of antibiotic therapy suggest that initially susceptible strains rarely acquire de novo resis- tance [12]. The most common mechanism behind the association of antibiotic use and carriage of resistance seems to be the unmasking of a minority subpopulation of resistant strains, followed by the acquisition of new resistant strains after antimicrobial therapy [13]. Antibiotic treatment generally does not eradicate bacteria from the nasopharynx and the reduction in carriage is only temporary. Changes in the flora include the suppression of susceptible bacteria, which creates the opportunity for both unmasking and/or acquisition of resistant strains [14]. Two risk factors that promote resistance, and are parti- cular to S. pneumoniae, include the high asymptomatic carriage rate among children (30 to 50% in several cohorts [15]), and the fact that S. pneumoniae is readily transmitted between individuals, particularly in settings such as day care centers. The Centers for Disease Control www.sciencedirect.com Current Opinion in Pharmacology 2005, 5:459–464