As part of the PROTEKT US study we have analyzed a large dataset for S. pneumoniae isolates sampled from across the USA. This has resulted in the generation of valuable information regarding temporal and geographic changes in antibacterial resistance patterns over the 4-year period from 2000 to 2004.
The latest data collected between 2003 and 2004 (Year 4) confirm the results of previous reports indicating that the prevalence of pneumococcal penicillin resistance across the USA appears to be stable or is decreasing, whilst intermediate penicillin resistance is increasing slightly [13
]. There are a number of possible reasons why pneumococcal resistance to penicillin and some other antibacterials (e.g., trimethoprim-sulfamethoxazole) may have stabilized or begun to decrease in the USA [30
]. First, recent local [31
] and national [32
] campaigns to promote appropriate antibacterial prescribing may have exerted a downward pressure on resistance rates as this factor is one of the most important drivers of resistance in community-acquired infections [33
]. Another factor may be the introduction in 2000 of the pneumococcal conjugate vaccine (PCV7) for routine immunization of infants; resistance rates have traditionally been highest among the pediatric population and the use of PCV7 has been shown to decrease pneumococcal resistance not only among children but also in the population as a whole, via a herding effect [34
]. A third factor may be the introduction of fluoroquinolones as a treatment for respiratory tract infections in adults. As the use of these agents has increased, it is possible that use of other more traditional agents may have declined, thus reducing associated rates of resistance.
Although the overall levels of in vitro
penicillin-nonsusceptibility in S. pneumoniae
may be a cause for concern, the clinical importance of this phenomenon in the management of pneumococcal pneumonia has been questioned [35
]. There is no evidence of widespread clinical failures among respiratory infections caused by S. pneumoniae
strains classified as penicillin-resistant in vitro
. Moreover, in respiratory infections documented as being due to resistant pneumococci, the infecting S. pneumoniae
strain generally exhibits low-level in vitro
resistance (penicillin MIC 1–2 μg/mL); in these cases, the infection can usually be successfully treated using high doses of β-lactam antibiotics [38
]. Nevertheless, careful monitoring of penicillin resistance rates should continue, especially since reports of S. pneumoniae
strains with high-level penicillin resistance (MIC ≥ 8 μg/mL) have appeared recently [39
]. Furthermore, there is clear evidence that infections of the central nervous system caused by penicillin-resistant S. pneumoniae
strains can be associated with the failure of β-lactam therapy [38
]. Consideration of the prevalent rates of penicillin resistance among S. pneumoniae
is therefore important in the management of such infections.
In common with recent reports from the USA and other countries, macrolide resistance over the 4 years of PROTEKT US exceeded penicillin resistance in all US regions [13
]. The macrolide resistance rate reported here for Year 4 was similar to those found for Years 1–3 (approximately 30%), suggesting that levels may have plateaued [12
In this study, the proportion of isolates in Year 4 exhibiting resistance to both penicillin and erythromycin decreased compared with previous years; this downward trend was also observed over Years 1–3 of the PROTEKT US study [13
]. As noted in other recent surveillance studies [7
], data for Years 1–4 of PROTEKT US showed considerable regional variation in the rates of resistance to penicillin and erythromycin across the USA.
Macrolide resistance mediated by erm
(B) has typically been associated with high-level resistance (MIC90
values of ≥ 64 μg/mL), while mef
(A)-mediated resistance has historically been characterized by lower-level resistance (MIC90
values of 4–8 μg/mL) [15
]. The predominant mechanism of pneumococcal macrolide resistance in the USA is mediated by mef
]. However, the latest PROTEKT US data presented here confirm that the prevalence of the mef
(A) genotype is decreasing and that clones expressing both erm
(B) and mef
(A) genes are increasing in prevalence. Of additional importance, the mef
(A)-positive isolates were found to exhibit levels of macrolide resistance that were higher (MIC mode 16 μg/mL) than those reported in previous surveillance studies (4–8 μg/mL) [15
]. This may impact on the ability of the macrolides to eradicate such strains from the sites of infection in patients with community-acquired RTIs.
Molecular epidemiology studies undertaken as part of PROTEKT US have shown that, of the erm
(A) isolates analyzed, > 90 % are clonally related to the multidrug-resistant international Taiwan19F-14
clonal complex 271 [12
]. Since these strains show high-level macrolide and multidrug resistance, their spread across the USA represents a serious public health threat.
The introduction of the 7-valent pneumococcal vaccine (PCV7) in 2000 was intended to reduce the incidence of pneumococcal disease in children. Recent evidence suggests that this reduction has indeed occurred [19
], with decreases of 58% in 2001 and 66% in 2002 in the number of invasive pneumococcal infections in children. However, the vaccine does not provide coverage against all S. pneumoniae
serotypes. Most dual erm
(A) isolates have been characterized as either serotype 19A or 19F and, although serotype 19F is represented in the PCV7 vaccine, 19A is not. As a result, incidence of the nonvaccine serotype 19A multidrug-resistant clone is proportionally higher in the pediatric population than in the past. According to recent surveillance data covering pneumococcal isolates collected in the USA, the prevalence of vaccine serotype 19F has decreased since introduction of PCV7, while that of nonvaccine serotype 19A has concomitantly increased [34
]. Among erm
(A) isolates collected for the PROTEKT US study in 2000–2001, serotype 19F was predominant over 19A (87% vs 8%); however, by 2003–2004, these two serotypes were of roughly equal prevalence (52% [19F] vs 46% [19A]) among erm
(A) isolates [46
Since the introduction of newer macrolide antibiotics, there has been a steady increase in macrolide resistance from year to year among pneumococci, which has been correlated with their consumption [47
]. Macrolide antibacterials are commonly used for the empiric treatment of community-acquired RTIs; therefore, pneumococcal macrolide resistance is of increasing concern in the clinical setting [18
]. In recent years, a number of reports have been published linking occurrences of macrolide treatment failure (often resulting in hospitalization with breakthrough bacteremia) to infection by macrolide-resistant strains of S. pneumoniae
in patients with community-acquired RTIs. Clinical failures in patients treated with azithromycin and clarithromycin have been documented [48
], and the number of reports appears to be increasing. It is notable that clinical failures have been reported in patients infected with pneumococcal strains expressing mef
(A)-encoded macrolide resistance as well as in those with erm
(B)-mediated resistance [52
]. Expression of both erm
(B) and mef
(A) among S. pneumoniae
isolates is strongly associated with the emergence of multidrug resistance. Almost all of the isolates (99.8%) expressing this dual mechanism of macrolide resistance in Year 4 of the study exhibited such resistance. Multidrug resistance has also been linked to an increased risk of clinical failure [54
Telithromycin represents the first in a new class of antimicrobials – the ketolides. Telithromycin demonstrated potent in vitro
activity against S. pneumoniae
isolates, including erm
(A) macrolide-resistant strains. The in vitro
susceptibility of S. pneumoniae
to telithromycin was very high in each of the study years, irrespective of the macrolide resistance mechanism. Overall, > 99% of macrolide-resistant S. pneumoniae
isolates were susceptible to this agent. These data are in agreement with corresponding longitudinal data from the international PROTEKT Global study (1999–2003), which indicate that no significant change in telithromycin susceptibility has been observed since the launch of the drug in some European countries in 2000–2001 [55
]. Currently, telithromycin is licensed in the USA for treating community-acquired pneumonia in adults; however, the most recent Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults [57
] do not carry any recommendations regarding the clinical use of telithromycin. Recommendations will be finalized when further evaluation of the safety of telithromycin by the US Food and Drug Administration has been completed.
The findings in this study highlight the need for the judicious use of antimicrobials and the continued monitoring of pneumococcal resistance patterns – in particular, the spread of multiresistant clones. Physicians should take local or regional resistance patterns into consideration when choosing empiric antibacterial treatment for community-acquired RTIs.
In summary, antimicrobial resistance in S. pneumoniae appears to have stabilized in the USA. However, geographic variations remain, and the prevalence of isolates with the combined erm(B) and mef(A) genotype, associated with high-level macrolide resistance (MIC50 > 256 μg/mL) and multidrug resistance, continues to increase. Telithromycin retains potent in vitro activity against S. pneumoniae, including isolates with the combined erm(B)+mef(A) macrolide resistance genotype.