Info

The Revised Authoritative Guide To Vaccine Legal Exemptions

Vaccines Have Serious Side Effects

Get Instant Access

GRASP VIy

* Percentage intermediate + resistant.

y Data from Gary V. Doern, PhD, unpublished observations.

* Percentage intermediate + resistant.

y Data from Gary V. Doern, PhD, unpublished observations.

seem to have stabilized and currently exist at an overall rate of approximately 30%. More than 85% of the time, macrolide resistance with Spneumoniae occurs in strains that are coresistant to b-lactams, tetracycline, or TMP-SMX [29-32]. As noted above, 60% to 70% of macrolide-resistant strains in the United States have mefA-mediated efflux as their resistance mechanism; the remaining 30% to 40% are of the mLSB phenotype as a result of harboring the ermB gene. This proportion has remained remarkably constant over the 15-year period that macrolide resistance has emerged with S pneumoniae in the United States [32]. In Canada, although absolute rates of macrolide resistance with Spneumoniae are 10% to 12% lower than in the United States, the relative proportion of efflux versus mLSB is essentially the same [33-40]. Interestingly, in other parts of the world, mLSB is encountered far more frequently than efflux. This is especially true in certain Western European countries such as Spain, France, and Italy as well as in Hong Kong, Singapore, and South Africa [41-43]. These differences may be the result of different profiles of antibiotic usage in different countries.

In the past, ermB-positive isolates of S pneumoniae that were also mefA-positive were recognized only infrequently. As recently as the mid-1990s, such strains were very uncommon in North America [18]. Today, however, in the United States, nearly half of ermB-positive isolates of S pneumoniae also harbor the mefA gene (G.V. Doern, unpublished observations, data on file). It is highly likely that these organisms emerged as a result of mefA-positive strains acquiring the ermB gene, rather than vice versa. Interestingly, pneumococci harboring both mefA and ermB are far less prevalent in other parts of the world than they are in North America [44].

Macrolide resistance, like b-lactam and multidrug resistance with S pneumoniae, occurs most frequently among isolates from pediatric patients and in certain geographic areas [29-32]. For instance, in the United States, highest rates of resistance are typically encountered in the southeastern region of the country [30,32]. Certain pneumococcal serotypes including 6B, 9V, 14, 19F, and 23F are most often found to be resistant [45-47]. Further, as with resistance to other antimicrobial classes among S pneumoniae, the expansion of macrolide resistance has been largely the result of spread of a limited number of clonal groups that have the selective advantage of being macrolide resistant [45].

Importantly, it is now evident that use of recently introduced pediatric pneumococcal vaccines, while generally being effective [48], does not reduce the prevalence of pediatric infections caused by the 19F serotypes (included in the vaccine) and may unwittingly promote the emergence of serotype 19A strains (not included in the vaccines) [49]. Both 19F and 19A strains of S pneumoniae are typically macrolide resistant [45,49].

Independent risk factors for infection due to macrolide-resistant strains of S pneumoniae include age younger than 5 years or older than 65 years, recent hospitalization, residence in a long-term care facility, day care attendance, and previous receipt of antimicrobial therapy [50]. Regarding the last issue, antibiotic exposures, previous macrolide use is clearly associated with a higher likelihood of subsequent infection in an individual patient being caused by a macrolide-resistant strain of S pneumoniae [51-53]. It is also clear, however, that agents in different antibiotic classes can drive resistance not only to themselves but also to other, unrelated agents [51,52,54]. This is not surprising in view of the frequency with which S pneumoniae is found to be stably multiply drug resistant, including coresistance to b-lactams, mac-rolides, TMP-SMX, and other antimicrobial agents.

Perhaps a more important question pertains to drivers of resistance in a broader epidemiologic context, ie, what is happening at the level of populations? First of all, among all Spneumoniae across the United States, both as causes of infection and as respiratory tract commensals, nearly 30% are now macrolide resistant. To wit, the pool of pneumococci is presently nearly two-thirds full of strains that are macrolide resistant. Further, the two principal resistance determinants are encoded for by genes that are not endogenous to S pneumoniae, ie, the mefA or ermB genes. These genes were acquired in the first place from other organisms as a result of exogenous genetic events but today they exist stably inserted into the pneumococcus genome. Under these circumstances, it seems prudent to consider drivers of resistance from a broader population-based perspective rather than only in the context of factors associated with resistance in individual patient infections.

Substantial evidence points to the importance of overall antibiotic usage profiles as the main driver of the general problem of resistance when viewed from a population perspective [51,55-60]. Accepting this, it may also be that different antibiotics within a given family behave differently in promoting the emergence of resistance, perhaps owing to their different antibacterial and pharmacokinetic properties, properties such as potency and elimination half-life. Macrolides and S pneumoniae represent a case in point.

As noted above, azithromycin is the least active macrolide versus S pneumoniae. In addition, levels of azithromycin achievable both in plasma and in sites such as epithelial lining fluid following administration of standard dosage amounts are substantially lower than those achieved with erythromycin and clarithromycin [61-64]. Potency, or effect, is clearly a product of both activity and levels of drug to which a pathogen is exposed. In this regard, azithromycin is clearly the least potent of the macrolides versus S pneumo-niae. Add to this the fact that azithromycin has an elimination half-life of nearly 3 days and use of this agent results in a situation where the pneumo-coccus either at the site of infection in the respiratory tract or residing as a commensal on the epithelial surfaces of airways, is exposed to low levels of a relatively inactive drug for a prolonged period of time. What better way to select for resistance?

Numerous peer-reviewed publications [52,53,65-68] and several commentaries [69-71] have made the point that different macrolides are distinguishable from one another in terms of their likelihood of promoting the emergence of macrolide resistance with S pneumoniae and further, among the macrolides, azithromycin usage has been most responsible for the emergence of macrolide resistance. Unfortunately, irrespective of how an isolate of S pneumoniae got to be macrolide resistant in the first place, if that organism harbors the ermB gene and as a result, expresses the mLSB phenotype, it is resistant from a clinical perspective to all the macrolides. This is referred to as the class killer concept. If we continue to use specific agents in a given antimicrobial family with a propensity for driving resistance, we run the risk of losing that entire family of agents.

The clinical significance of macrolide resistance

From an epidemiologic perspective, Spneumoniae has clearly changed with respect to macrolide resistance. The question arises, what does macrolide resistance mean clinically? At least some patients infected with macrolide-resis-tant S pneumoniae appear to fail therapy when treated with a macrolide. A recent case control study from four different centers described 86 patients with pneumococcal bacteremia as a result of macrolide-resistant strains and in 19 cases, patients had received a macrolide before developing bacteremia [72]. Conversely, none of 136 carefully matched control patients infected with macrolide-susceptible strains of Spneumoniae were receiving a macrolide at the time they developed bacteremia. In other words, macrolide resistance appeared to be associated with failure in some patients. These observations are consistent with the findings of two other published studies [73,74] and were recently summarized in an editorial commentary [75].

Of note, failure occurs far more often when the infecting strain has high-level ermB-mediated macrolide resistance with MICs of > 64 mg/mL than with strains that have mid-level resistance due to efflux (MICs 1-16 mg/mL). In addition, failures have been recognized most often in patients receiving azithromycin therapy.

This latter observation may to related to the fact that, as noted above, azithromcyin is substantially less potent than clarithromycin versus S pneu-moniae. Specifically, when considered in the context of bronchopulmonary infections, clarithromycin is 20 to 30 times more potent than azithromycin. This is the result of the enhanced in vitro activity of clarithromycin, being 2 to 4 times more active than azithromycin in the test tube, combined with this agent's more favorable pharmacokinetic profile in the lung, ie, 5 to 10 times higher drug concentrations present in epithelial lining fluid. It might be that clarithromycin's potency advantage explains why macrolide failures when they do occur in patients with pneumococcal bronchopulmonary infections occur far more often with azithromycin than clarithromycin. Further, this would be consistent with the observations from three animal model studies that indicated that only organisms with clarithromycin MICs of > 16 mg/mL are likely to fail therapy with this agent [76-78]. As seen in Fig. 2 and as noted above, only approximately 10% of pneumococcal isolates in the United States have MICs of > 16 mg/mL to clarithromycin and nearly all of these express high-level macrolide resistance as a result of ermB.

This apparent disconnect in at least some patients between macrolide resistance as it is defined in the laboratory and failure, especially when clari-thromycin is used, has been referred to as the "in vitro-in vivo paradox'' [79]. This is not, however, to imply that macrolide resistance with S pneumo-niae is unimportant. It is very important. It clearly accounts for failure in certain patients and mitigates against use of macrolides in the management of patients with infections likely to be caused by macrolide-resistant S pneu-moniae. Rather the point is simply that resistance does not always result in failure particularly when the most potent agent in the family, clarithromy-cin, is used.

Will ketolide resistance emerge with S pneumoniae?

As stated above, ketolide resistance with S pneumoniae is distinctly uncommon in North America. This may be because the one ketolide thus far introduced into clinical practice in North America, telithromycin, has only been available for about 2 years. It remains, however, that more than 4,000,000 perscriptions for telithromycin have already been written in North America. Further, this antimicrobial has been available in some countries in Europe for as long as 5 years. Total ex-US usage of telithromy-cin is estimated to have approached 22,000,000 perscriptions. Despite this extensive usage profile both in North America and worldwide, telithromycin resistance remains distinctly uncommon with S pneumoniae. In this regard, the following statement seems to be true. While ketolide resistance may ultimately become a problem with S pneumoniae, it has not happened yet and it is unlikely to emerge as quickly as has occurred with certain other agents in the past.

From a purely teleological perspective, to completely escape the effect of telithromycin, an isolate of S pneumoniae would have to substantially change both of the ribosomal binding sites used by this agent in expressing its antibacterial effect, the A2058 site in domain V and the A752 site in domain II. Obviously both of these sites are important to the pneumococcus in manufacturing protein, otherwise telithromycin would not retain activity in the face of changes to the A2058 residue in ermB-positive isolates, or for that matter, in the face of other 23S rRNA mutations. One wonders whether the pneumococcus could survive changes at both of the telithromycin ribo-somal binding sites so as to escape the effect of the drug and become resistant while still remaining viable. This speaks to the issue of the fitness costs of resistance.

Numerous different antimicrobial agents are characterized as having multiple different targets within bacteria, all of which are important simultaneously. Two obvious examples are b-lactams and fluoroquinolones. The ketolides are unique, however, in having two different binding sites both present on the same target. This property, taken in the context of the foregoing discussion, may be an important means for this antimicrobial class to avoid the problems of developing resistance with S pneumoniae in the future.

Summary

Macrolide resistance has emerged as a major problem with S pneumoniae in North America, particularly in the United States, with overall resistance rates approaching 30%. Most of this change occurred during the 1990s. Interestingly, during the past 5 to 6 years in North America, the rate of increase in the overall prevalence of macrolide resistance with S pneumoniae seems to have plateaued. Two mechanisms of macrolide resistance dominate: midrange resistance due to mefA-mediated efflux (MICs 1-32 mg/mL) and high-level ermB-mediated mLSB resistance (MICs > 64 mg/mL). Approximately two thirds of resistant strains have efflux as their resistance mechanism; the remainder express high-level mLSB resistance. The epidemiology of macrolide resistance is well understood, resistance being seen most often in select pneumococcal serotypes, in a defined number of clonal groups, and very often in the background of strains of S pneumoniae that are stably resistant to multiple different antibiotic classes.

The macrolides vary in terms of their potency for S pneumoniae, with clarithromcyin being the most potent, azithromycin being the least potent. These differences are not apparent when conventional in vitro susceptibility tests are performed because current CLSI interpretive criteria used to define susceptibility categories with S pneumoniae fail to delineate the potency distinctions. These differences, however, may be important in terms of the likelihood of use of a specific agent promoting the emergence of resistance in the first place, and in terms of the likelihood of a given macrolide being effective in the management of a respiratory tract infection caused by an isolate of S pneumoniae defined as being nonsusceptible in the laboratory.

The ketolide antimicrobial, telithromycin, was introduced into clinical practice in North America, 2 years ago. Because of its molecular structure, telithromycin retains sufficient activity against macrolide-resistant strains of S pneumoniae to be effective clinically even in the face of high-level ermB-mediated resistance. While rare, telithromycin-resistant strains have been recognized worldwide; currently in North America, telithromycin resistance with S pneumoniae remains vanishingly uncommon.

Dedication

This review is dedicated with love and admiration to my mother, Shirley Mae Doern, who passed away during its preparation. I have been the lifelong beneficiary of her counsel, her encouragement, her love, and her example. I will miss her deeply. Gareth V. Doern.

References

[1] Nightingale CH. Macrolides: new questions, new insights. Infect Med 1998;15(Suppl A):8-9.

[2] Balfour JAB, Figgitt DP. Telithromycin. Drugs 2001;61(6):815-29.

[3] Doern GV, Heilmann KP, Huynh HK, et al. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United States during 1999-2000, including a comparison of resistance rates since 1994-1995. Antimicrob Agents Chemother 2001;45(6):1721-9.

[4] Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing; fifteenth informational supplement: approved standard M100-S15. Wayne, PA: CLSI; 2005.

[5] Leclercq R, Courvalin P. Resistance to macrolides and related antibiotics in Streptococcus pneumoniae. Antimicrob Agents Chemother 2002;46(9):2727-34.

[6] Roberts MC, Sutcliffe J, Courvalin P, et al. Nomenclature for macrolide and macrolide-lin-cosamide-streptogramin B resistance determinants. Antimicrob Agents Chemother 1999; 43(12):2823-30.

[7] Farrell DJ, Morrissey I, Bakker S, et al. In vitro activities of telithromycin, linezolid, and quinupristin-dalfopristin against Streptococcus pneumoniae with macrolide resistance due to ribosomal mutations. Antimicrob Agents Chemother 2004;48(8):3169-71.

[8] Farrell DJ, Douthwaite S, Morrissey I, et al. Macrolide resistance by ribosomal mutation in clinical isolates of Streptococcus pneumoniae from the PROTEKT 1999-2000 study. Antimicrob Agents Chemother 2003;47(6):1777-83.

[9] Canu A, Malbruny B, Coquemont M, et al. Diversity of ribosomal mutations conferring resistance to macrolides, clindamycin, streptogramin, and telithromycin in Streptococcus pneumoniae. Antimicrob Agents Chemother 2002;46(1):125-31.

[10] Tait-Kamradt A, Davies T, Appelbaum PC, et al. Two new mechanisms of macrolide resistance in clinical strains of Streptococcus pneumoniae from Eastern Europe and North America. Antimicrob Agents Chemother 2000;44(12):3395-401.

[11] Davies TA, Bush K, Sahm D, et al. Predominance of 23S rRNA mutants among non-erm, non-mef macrolide-resistant clinical isolates of Streptococcus pneumoniae collected in the United States in 1999-2000. Antimicrob Agents Chemother 2005;49(7):3031-3.

[12] Reinert RR, Wild A, Appelbaum P, et al. Ribosomal mutations conferring resistance to mac-rolides in Streptococcus pneumoniae clinical strains isolated in Germany. Antimicrob Agents Chemother 2003;47(7):2319-22.

[13] Pihlajamaki M, Kataja J, Seppala H, et al. Ribosomal mutations in Streptococcus pneumoniae clinical isolates. Antimicrob Agents Chemother 2002;46(3):654-8.

[14] Wolter N, Smith AM, Farrell DJ, et al. Novel mechanism of resistance to oxazolidinones, macrolides, and chloramphenicol in ribosomal protein L4 of the Pneumococcus. Antimicrob Agents Chemother 2005;49(8):3554-7.

[15] Jones RN, Farrell DJ, Morrissey I. Quinupristin-dalfopristin resistance in Streptococcus pneumoniae: novel L22 ribosomal protein mutation in two clinical isolates from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother 2003;47(8):2696-8.

[16] Waites K, Johnson C, Gray B, et al. Use of clindamycin disks to detect macrolide resistance mediated by ermB and mefE in Streptococcus pneumoniae isolates from adults and children. J Clin Microbiol 2000;38(5):1731-4.

[17] Shortridge V, Doern GV, Brueggemann AB, et al. Prevalence of macrolide resistance mechanisms in Streptococcus pneumoniae isolates from a multicenter antibiotic resistance surveillance study conducted in the United States in 1994-1995. Clin Infect Dis 1999;29:1186-8.

[18] Farrell DJ, Jenkins SG. Distribution across the USA of macrolide resistance and macrolide resistance mechanisms among Streptococcus pneumoniae isolates collected from patients with respiratory tract infections: PROTEKT US 2001-2002. J Antimicrob Chemother 2004;54(Suppl. S1):i17-22.

[19] Reinert RR, van der Linder M, Al-Lahham A. Molecular characterization of the first telithromycin-resistant Streptococcus pneumoniae isolate in Germany. Antimicrob Agents Chemother 2005;49(8):3520-2.

[20] Rantala M, Haanpera-Heikkinen M, Lindgren M, et al. Streptococcus pneumoniae isolates resistant to telithromycin. Antimicrob Agents Chemother 2006;50(5):1855-8.

[21] Faccone D, Andres P, Galas M, et al. Emergence of a Streptococcus pneumoniae clinical isolate highly resistant to telithromycin and fluoroquinolones. J Clin Microbiol 2005;43(11): 5800-3.

[22] Farrell DJ, Felmingham D. Activities of telithromycin against 13,874 Streptococcus pneumoniae isolates collected between 1999 and 2003. Antimicrob Agents Chemother 2004;48(5): 1882-4.

[23] Spika JS, Facklam RR, Plikaytis BD, et al, and the Pneumococcal Surveillance Working Group. Antimicrobial resistance of Streptococcus pneumoniae in the United States, 19791987. J Infect Dis 1991;163:1273-8.

[24] Jorgensen JH, Doern GV, Maher LA, et al. Antimicrobial resistance among respiratory isolates of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in the United States. Antimicrob Agents Chemother 1990;34(11):2075-80.

[25] Barry AL, Pfaller MA, Fuchs PC, et al. In vitro activities of 12 orally administered antimicrobial agents against four species of bacterial respiratory pathogens from US medical centers in 1992 and 1993. Antimicrob Agents Chemother 1994;38(10):2419-25.

[26] Doern GV, Brueggemann A, Holley HP Jr, et al. Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study. Antimicrob Agents Chemother 1996;40(5):1208-13.

[27] Doern GV, Brueggemann AB, Huynh H, et al. Antimicrobial resistance with Spneumoniae in the United States, 1997-98. Emerg Infect Dis 1999;5(6):757-65.

[28] Sahm DF, Karlowsky JA, Kelly LJ, et al. Need for annual surveillance of antimicrobial resistance in Streptococcus pneumoniae in the United States: 2-year longitudinal analysis. Antimicrob Agents Chemother 2001;45(4):1037-42.

[29] Doern GV, Heilmann KP, Huynh HK, et al. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United States during 1999-2000, including a comparison of resistance rates since 1994-1995. Antimicrob Agents Chemother 2001; 45(6):1721-9.

[30] Thornsberry C, Sahm DF, Kelly LJ, et al. Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catar-rhalis in the United States: results from the TRUST Surveillance Program, 1999-2000. Clin Infect Dis 2002;34(Suppl 1):S4-16.

[31] Karlowsky JA, Thornsberry C, Jones ME, et al. Factors associated with relative rates of antimicrobial resistance among Streptococcus pneumoniae in the United States: results from the TRUST Surveillance Program. Clin Infect Dis 2003;36:963-70.

[32] Doern GV, Richter SS, Miller A, et al. Antimicrobial resistance among Streptococcus pneu-moniae in the United States: have we begun to turn the corner on resistance to certain antibiotic classes? Clin Infect Dis 2005;41:139-48.

[33] Simor AE, Louie M, Low DE. Canadian national survey of prevalence of antimicrobial resistance among clinical isolates of Streptococcus pneumoniae. The Canadian Bacterial Surveillance Network. Antimicrob Agents Chemother 1996;40(9):2190-3.

[34] Davidson RJ. Canadian Bacterial Surveillance Network, Low DE. A cross-Canada surveillance of antimicrobial resistance in respiratory tract pathogens. Can J Infect Dis 1999;10(2): 128-33.

[35] Zhanel GG, Karlowsky JA, Palatnick L, et al. The Canadian Respiratory Infection Study Group. Prevalence of antimicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: results of a Canadian National Surveillance Study. Antimicrob Agents Chemother 1999;43(10):2504-9.

[36] Low DE, de Azavedo J, Weiss K, et al. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in Canada during 2000. Antimicrob Agents Chemother 2002; 46(5):1295-301.

[37] Zhanel GG, Palatnick L, Nichol KA, et al. Antimicrobial resistance in respiratory tract Streptococcus pneumoniae isolates: results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002. Antimicrob Agents Chemother 2003;47(6):1867-74.

[38] Powis J, McGeer A, Green K, et al. In vitro antimicrobial susceptibilities of Streptococcus pneumoniae clinical isolates obtained in Canada in 2002. Antimicrob Agents Chemother 2004;48(9):3305-11.

[39] Wierzbowski AK, Swedlo D, Boyd D, et al. Molecular epidemiology and prevalence of macrolide efflux genes mef(A) and mef(E) in Streptococcus pneumoniae obtained in Canada from 1997 to 2002. Antimicrob Agents Chemother 2005;49(3):1257-61.

[40] Hoban DJ, Wierzbowski AK, Nichol K, et al. Macrolide-resistant Streptococcus pneumoniae in Canada during 1998-1999: Prevalence of mef(A) and erm(B) and susceptibilities to keto-lides. Antimicrob Agents Chemother 2001;45(7):2147-50.

[41] Farrel DJ, Morrissey I, Bakker S, et al. Molecular characterization of macrolide resistance mechanisms among Streptococcus pneumoniae and Streptococcus pyogenes isolated from the PROTEKT 1999-2000 study. J Antimicrob Chemother 2002;50(Suppl S1): 39-47.

[42] Felmingham D, Reinert RR, Hirakata Y, et al. Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and comparative in vitro activity of the ketolide, telithromycin. J Antimicrob Chemother 2002;50(Suppl S1):25-37.

[43] Reinert RR, Ringelstein A, van der Linden M, et al. Molecular epidemiology of macrolide-resistant Streptococcus pneumoniae isolates from Europe. J Clin Microbiol 2005;43(3): 1294-300.

[44] Farrell DJ, Morrissey I, Bakker S, et al. Molecular epidemiology of multiresistant Streptococcus pneumoniae with both erm(B)- and mefA)-mediated macrolide resistance. J Clin Microbiol 2004;42(2):764-8.

[45] Richter SS, Heilmann KP, Coffman SL, et al. The molecular epidemiology of penicillin-resistant Streptococcus pneumoniae in the United States, 1994-2000. Clin Infect Dis 2002;34: 330-9.

[46] Munford RS, Murphy TV. Antimicrobial resistance in Streptococcus pneumoniae: can immunization prevent its spread. J Investig Med 1994;42:613-21.

[47] Joloba ML, Windau A, Bajaksouzian S, et al. Pneumococcal conjugate vaccine serotypes of Streptococcus pneumoniae isolates and the antimicrobial susceptibility of such isolates in children with otitis media. Clin Infect Dis 2001;333:1498-2004.

[48] Pelton SI, Daga R, Gaines BM, et al. Pneumococcal conjugate vaccines: proceedings from an interactive symposium at the 41st Interscience Conference on antimicrobial agents and chemotherapy. Vaccine 2003;21:1562-71.

[49] McEllistrem MC, Adams JM, Patel K, et al. Acute otitis media due to penicillin-nonsuscep-tible Streptococcus pneumoniae before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis 2005;40:1738-44.

[50] Lynch JP, Martinez FJ. Clinical relevance of macrolide-resistant Streptococcus pneumoniae for community-acquired pneumonia. Clin Infect Dis 2002;34(Suppl 1):S27-46.

[51] Doern GV. Antimicrobial use and the emergence of antimicrobial resistance with Streptococcus pneumoniae in the United States. Clin Infect Dis 2001;33(Suppl 3):S187-92.

[52] Vanderkooi OG, Low DE, Green K, et al. for the Toronto Invasive Bacterial Disease Network. Predicting antimicrobial resistance in invasive pneumococcal infections. Clin Infect Dis 2005;40:1288-97.

[53] Beekmann SE, Diekema DJ, Heilmann KP, et al. Macrolide use identified as risk factor for macrolide-resistant Streptococcus pneumoniae in a 17-center case-control study. Eur J Clin Microbiol Infect Dis 2006. Available at: http://www.springerlink.com/openurl.asp?genre=article&id=. Accessed April 13, 2006.

[54] Ghaffar F, Muniz LS, Katz K, et al. Effects of large dosages of amoxicillin/clavulanate or azithromycin on nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae, nonpneumococcal a-hemolytic streptococci, and Staphylococcus aureus in children with acute otitis media. Clin Infect Dis 2002;34:1301-9.

[55] Diekema DJ, Brueggemann AB, Doern GV. Antimicrobial-drug use and changes in resistance to Streptococcus pneumoniae. Emerg Infect Dis 2000;6(5):552-6.

[56] Bronzwaer SL, Cars O, Buchholz U, et al. A European study on the relationship between antimicrobial use and antimicrobial resistance. Emerg Infect Dis 2002;8(3):278-82.

[57] Garcia-Rey C, Aguilar L, Baquero F, et al. Importance of local variations in antibiotic consumption and geographical differences of erythromycin and penicillin resistance in Streptococcus pneumoniae. J Clin Microbiol 2002;40(1):159-64.

[58] Kristinsson KG. Effect of antimicrobial use and other risk factors on antimicrobial resistance in pneumococci. Microb Drug Resist 1997;3(2):117-23.

[59] Hyde TB, Gay K, Stephens DS, et al. Macrolide resistance among invasive Spneumoniae isolates. JAMA 2001;286(15):1857-62.

[60] Hennessy TW, Petersen KM, Bruden D, et al. Changes in antibiotic-prescribing practices and carriage of penicillin-resistant Streptococcus pneumoniae: a controlled intervention trial in rural Alaska. Clin Infect Dis 2002;34:1543-50.

[61] Conte JE Jr, Golden JA, Duncan S, et al. Intrapulmonary pharmacokinetics of clarithromycin and of erythromycin. Antimicrob Agents Chemother 1995;39(2):334-8.

[62] Conte JE Jr, Golden J, Duncan S, et al. Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects. Antimicrob Agents Chemother 1996;40(7):1617-22.

[63] Patel KB, Xuan D, Tessier PR, et al. Comparison of bronchopulmonary pharmacokinetics of clarithromycin and azithromycin. Antimicrob Agents Chemother 1996;40(10):2375-9.

[64] Rodvold KA, Gotfried MH, Danziger LH, et al. Intrapulmonary steady-state concentrations of clarithromycin and azithromycin in healthy adult volunteers. Antimicrob Agents Chemother 1997;41(6):1399-402.

[65] Guggenbichler JP, Kastner H. The influence of macrolide antibiotics on the fecal and oral flora. Infect Med 1998;15:17-25.

[66] Gray GC, Witucki PJ, Gould MT, et al. Randomized, placebo-controlled clinical trial of oral azithromycin prophylaxis against respiratory infections in a high-risk, young adult population. Clin Infect Dis 2001;33:983-9.

[67] Leach AJ, Shelby-James TM, Mayo M, et al. A prospective study of the impact of community-acquired azithromycin treatment of trachoma on carriage and resistance of Streptococcus pneumoniae. Clin Infect Dis 1997;24:356-62.

[68] Ghaffar F, Muniz LS, Katz K, et al. Effects of amoxicillin/clavulanate or azithromycin on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae in children with acute otitis media. Clin Infect Dis 2000;31:875-80.

[69] Blondeau JM. Differential impact of macrolide compounds in the selection of macrolide nonsusceptible Streptococcus pneumoniae. Therapy 2005;2(6):813-8.

[70] Doern GV. Correspondence - reply to: Predicting the emergence of antimicrobial resistance. Clin Infect Dis 2002;34:1418-20.

[71] Ambrose PG. Antimicrobial susceptibility breakpoints; PK-PD and susceptibility breakpoints. Treat Respir Med 2005;4(Suppl 1):5-11.

[72] Lonks JR, Garau J, Gomez L, et al. Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant Streptococcus pneumoniae. Clin Infect Dis 2002; 35:556-64.

[73] Van Kerkhoven D, Peetermans WE, Verbist L, et al. Breakthrough pneumococcal bacterae-mia in patients treated with clarithromycin or oral ß-lactams. J Antimicrob Chemother 2003; 51:691-6.

[74] Kelley MA, Weber DJ, Gilligan P, et al. Breakthrough pneumococcal bacteremia treated with azithromycin and clarithromycin. Clin Infect Dis 2000;31:1008-11.

[75] Jacobs MR. In vivo veritas: in vitro macrolide resistance in systemic Streptococcus pneumo-niae infections does result in clinical failure. Clin Infect Dis 2002;35:565-9.

[76] Hoffman HL, Klepser ME, Ernst EJ, et al. Influence of macrolide susceptibility on efficacies of clarithromycin and azithromycin against Streptococcus pneumoniae in a murine lung infection model. Antimicrob Agents Chemother 2003;47(2):739-46.

[77] Maglio D, Capitano B, Banevicius MA, et al. Efficacy of clarithromycin against Streptococcus pneumoniae expressing mefA)-mediated resistance. Int J Antimicrob Agents 2004;23: 498-501.

[78] Noreddin AM, Roberts D, Nichol K, et al. Pharmacodynamic modeling of clarithromycin against macrolide-resistant [PCR-positive mef(A) or erm(B)] Streptococcus pneumoniae simulating clinically achievable serum and epithelial lining fluid free-drug concentrations. Anti-microb Agents Chemother 2002;46(12):4029-34.

[79] Nuermberger E, Bishai WR. The clinical significance of macrolide-resistant Streptococcus pneumoniae: it's all relative. Clin Infect Dis 2004;38:99-103.

Med Clin N Am 90 (2006) 1125-1140

Med Clin N Am 90 (2006) 1125-1140

Was this article helpful?

0 0

Post a comment