Antibiotic Selection Pressure and Macrolide Resistance in Nasopharyngeal A Cluster-Randomized Clinical Trial
Background:
It is widely thought that widespread antibiotic use selects for community antibiotic resistance, though this has been difficult to prove in the setting of a community-randomized clinical trial. In this study, we used a randomized clinical trial design to assess whether macrolide resistance was higher in communities treated with mass azithromycin for trachoma, compared to untreated control communities.
Methods and Findings:
In a cluster-randomized trial for trachoma control in Ethiopia, 12 communities were randomized to receive mass azithromycin treatment of children aged 1–10 years at months 0, 3, 6, and 9. Twelve control communities were randomized to receive no antibiotic treatments until the conclusion of the study. Nasopharyngeal swabs were collected from randomly selected children in the treated group at baseline and month 12, and in the control group at month 12. Antibiotic susceptibility testing was performed on Streptococcus pneumoniae isolated from the swabs using Etest strips. In the treated group, the mean prevalence of azithromycin resistance among all monitored children increased from 3.6% (95% confidence interval [CI] 0.8%–8.9%) at baseline, to 46.9% (37.5%–57.5%) at month 12 (p = 0.003). In control communities, azithromycin resistance was 9.2% (95% CI 6.7%–13.3%) at month 12, significantly lower than the treated group (p<0.0001). Penicillin resistance was identified in 0.8% (95% CI 0%–4.2%) of isolates in the control group at 1 year, and in no isolates in the children-treated group at baseline or 1 year.
Conclusions:
This cluster-randomized clinical trial demonstrated that compared to untreated control communities, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to intensive azithromycin treatment. Mass azithromycin distributions were given more frequently than currently recommended by the World Health Organization's trachoma program. Azithromycin use in this setting did not select for resistance to penicillins, which remain the drug of choice for pneumococcal infections.
Trial registration:
www.ClinicalTrials.gov NCT00322972
: Please see later in the article for the Editors' Summary
Vyšlo v časopise:
Antibiotic Selection Pressure and Macrolide Resistance in Nasopharyngeal A Cluster-Randomized Clinical Trial. PLoS Med 7(12): e32767. doi:10.1371/journal.pmed.1000377
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pmed.1000377
Souhrn
Background:
It is widely thought that widespread antibiotic use selects for community antibiotic resistance, though this has been difficult to prove in the setting of a community-randomized clinical trial. In this study, we used a randomized clinical trial design to assess whether macrolide resistance was higher in communities treated with mass azithromycin for trachoma, compared to untreated control communities.
Methods and Findings:
In a cluster-randomized trial for trachoma control in Ethiopia, 12 communities were randomized to receive mass azithromycin treatment of children aged 1–10 years at months 0, 3, 6, and 9. Twelve control communities were randomized to receive no antibiotic treatments until the conclusion of the study. Nasopharyngeal swabs were collected from randomly selected children in the treated group at baseline and month 12, and in the control group at month 12. Antibiotic susceptibility testing was performed on Streptococcus pneumoniae isolated from the swabs using Etest strips. In the treated group, the mean prevalence of azithromycin resistance among all monitored children increased from 3.6% (95% confidence interval [CI] 0.8%–8.9%) at baseline, to 46.9% (37.5%–57.5%) at month 12 (p = 0.003). In control communities, azithromycin resistance was 9.2% (95% CI 6.7%–13.3%) at month 12, significantly lower than the treated group (p<0.0001). Penicillin resistance was identified in 0.8% (95% CI 0%–4.2%) of isolates in the control group at 1 year, and in no isolates in the children-treated group at baseline or 1 year.
Conclusions:
This cluster-randomized clinical trial demonstrated that compared to untreated control communities, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to intensive azithromycin treatment. Mass azithromycin distributions were given more frequently than currently recommended by the World Health Organization's trachoma program. Azithromycin use in this setting did not select for resistance to penicillins, which remain the drug of choice for pneumococcal infections.
Trial registration:
www.ClinicalTrials.gov NCT00322972
: Please see later in the article for the Editors' Summary
Zdroje
1. LipsitchM
SamoreMH
2002 Antimicrobial use and antimicrobial resistance: a population perspective. Emerg Infect Dis 8 347 354
2. GoossensH
FerechM
Vander SticheleR
ElseviersM
2005 Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 365 579 587
3. BronzwaerSL
CarsO
BuchholzU
MolstadS
GoettschW
2002 A European study on the relationship between antimicrobial use and antimicrobial resistance. Emerg Infect Dis 8 278 282
4. Van EldereJ
MeraRM
MillerLA
PoupardJA
Amrine-MadsenH
2007 Risk factors for development of multiple-class resistance to Streptococcus pneumoniae Strains in Belgium over a 10-year period: antimicrobial consumption, population density, and geographic location. Antimicrob Agents Chemother 51 3491 3497
5. MeraRM
MillerLA
WhiteA
2006 Antibacterial use and Streptococcus pneumoniae penicillin resistance: a temporal relationship model. Microb Drug Resist 12 158 163
6. ArasonVA
SigurdssonJA
ErlendsdottirH
GudmundssonS
KristinssonKG
2006 The role of antimicrobial use in the epidemiology of resistant pneumococci: a 10-year follow up. Microb Drug Resist 12 169 176
7. ChenDK
McGeerA
de AzavedoJC
LowDE
1999 Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Network. N Engl J Med 341 233 239
8. PihlajamakiM
KotilainenP
KaurilaT
KlaukkaT
PalvaE
2001 Macrolide-resistant Streptococcus pneumoniae and use of antimicrobial agents. Clin Infect Dis 33 483 488
9. GranizoJJ
AguilarL
CasalJ
Dal-ReR
BaqueroF
2000 Streptococcus pyogenes resistance to erythromycin in relation to macrolide consumption in Spain (1986-1997). J Antimicrob Chemother 46 959 964
10. BergmanM
HuikkoS
PihlajamakiM
LaippalaP
PalvaE
2004 Effect of macrolide consumption on erythromycin resistance in Streptococcus pyogenes in Finland in 1997-2001. Clin Infect Dis 38 1251 1256
11. ArasonVA
KristinssonKG
SigurdssonJA
StefansdottirG
MolstadS
1996 Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children? Cross sectional prevalence study. BMJ 313 387 391
12. VanderkooiOG
LowDE
GreenK
PowisJE
McGeerA
2005 Predicting antimicrobial resistance in invasive pneumococcal infections. Clin Infect Dis 40 1288 1297
13. MetlayJP
FishmanNO
JoffeMM
KallanMJ
ChittamsJL
2006 Macrolide resistance in adults with bacteremic pneumococcal pneumonia. Emerg Infect Dis 12 1223 1230
14. CarmeliY
SamoreMH
HuskinsC
1999 The association between antecedent vancomycin treatment and hospital-acquired vancomycin-resistant enterococci: a meta-analysis. Arch Intern Med 159 2461 2468
15. BolonMK
WrightSB
GoldHS
CarmeliY
2004 The magnitude of the association between fluoroquinolone use and quinolone-resistant Escherichia coli and Klebsiella pneumoniae may be lower than previously reported. Antimicrob Agents Chemother 48 1934 1940
16. WrightHR
TurnerA
TaylorHR
2008 Trachoma. Lancet 371 1945 1954
17. MeleseM
ChidambaramJD
AlemayehuW
LeeDC
YiEH
2004 Feasibility of eliminating ocular Chlamydia trachomatis with repeat mass antibiotic treatments. JAMA 292 721 725
18. MeleseM
AlemayehuW
LakewT
YiE
HouseJ
2008 Comparison of annual and biannual mass antibiotic administration for elimination of infectious trachoma. JAMA 299 778 784
19. LietmanT
PorcoT
DawsonC
BlowerS
1999 Global elimination of trachoma: how frequently should we administer mass chemotherapy? Nat Med 5 572 576
20. HongKC
SchachterJ
MoncadaJ
ZhouZ
HouseJ
2009 Lack of macrolide resistance in Chlamydia trachomatis after mass azithromycin distributions for trachoma. Emerg Infect Dis 15 1088 1090
21. SolomonAW
MohammedZ
MassaePA
ShaoJF
FosterA
2005 Impact of mass distribution of azithromycin on the antibiotic susceptibilities of ocular Chlamydia trachomatis. Antimicrob Agents Chemother 49 4804 4806
22. LeachAJ
Shelby-JamesTM
MayoM
GrattenM
LamingAC
1997 A prospective study of the impact of community-based azithromycin treatment of trachoma on carriage and resistance of Streptococcus pneumoniae. Clin Infect Dis 24 356 362
23. GaynorBD
ChidambaramJD
CevallosV
MiaoY
MillerK
2005 Topical ocular antibiotics induce bacterial resistance at extraocular sites. Br J Ophthalmol 89 1097 1099
24. FryAM
JhaHC
LietmanTM
ChaudharyJS
BhattaRC
2002 Adverse and beneficial secondary effects of mass treatment with azithromycin to eliminate blindness due to trachoma in Nepal. Clin Infect Dis 35 395 402
25. HouseJI
AyeleB
PorcoTC
ZhouZ
HongKC
2009 Assessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster-randomised trial. Lancet 373 1111 1118
26. ZerihunN
1997 Trachoma in Jimma zone, south western Ethiopia. Trop Med Int Health 2 1115 1121
27. O'BrienKL
BronsdonMA
DaganR
YagupskyP
JancoJ
2001 Evaluation of a medium (STGG) for transport and optimal recovery of Streptococcus pneumoniae from nasopharyngeal secretions collected during field studies. J Clin Microbiol 39 1021 1024
28. FarrellDJ
MorrisseyI
BakkerS
FelminghamD
2002 Molecular characterization of macrolide resistance mechanisms among Streptococcus pneumoniae and Streptococcus pyogenes isolated from the PROTEKT 1999–2000 study. J Antimicrob Chemother 50 Suppl S1 39 47
29. FarrellDJ
MorrisseyI
BakkerS
MorrisL
BuckridgeS
2004 Molecular epidemiology of multiresistant Streptococcus pneumoniae with both erm(B)- and mef(A)-mediated macrolide resistance. J Clin Microbiol 42 764 768
30. LeclercqR
CourvalinP
1991 Bacterial resistance to macrolide, lincosamide, and streptogramin antibiotics by target modification. Antimicrob Agents Chemother 35 1267 1272
31. SutcliffeJ
Tait-KamradtA
WondrackL
1996 Streptococcus pneumoniae and Streptococcus pyogenes resistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system. Antimicrob Agents Chemother 40 1817 1824
32. SutcliffeJ
GrebeT
Tait-KamradtA
WondrackL
1996 Detection of erythromycin-resistant determinants by PCR. Antimicrob Agents Chemother 40 2562 2566
33. HaugS
LakewT
HabtemariamG
AlemayehuW
CevallosV
2010 The decline of pneumococcal resistance after cessation of mass antibiotic distributions for trachoma. Clin Infect Dis 51 571 574
34. SeppalaH
KlaukkaT
Vuopio-VarkilaJ
MuotialaA
HeleniusH
1997 The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. N Engl J Med 337 441 446
35. GuillemotD
VaronE
BernedeC
WeberP
HenrietL
2005 Reduction of antibiotic use in the community reduces the rate of colonization with penicillin G-nonsusceptible Streptococcus pneumoniae. Clin Infect Dis 41 930 938
36. Malhotra-KumarS
LammensC
CoenenS
Van HerckK
GoossensH
2007 Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study. Lancet 369 482 490
37. PorcoTC
GebreT
AyeleB
HouseJ
KeenanJ
2009 Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial. JAMA 302 962 968
38. GaynorBD
HolbrookKA
WhitcherJP
HolmSO
JhaHC
2003 Community treatment with azithromycin for trachoma is not associated with antibiotic resistance in Streptococcus pneumoniae at 1 year. Br J Ophthalmol 87 147 148
39. BattSL
CharalambousBM
SolomonAW
KnirschC
MassaePA
2003 Impact of azithromycin administration for trachoma control on the carriage of antibiotic-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother 47 2765 2769
40. SolomonAW
HollandMJ
AlexanderND
MassaePA
AguirreA
2004 Mass treatment with single-dose azithromycin for trachoma. N Engl J Med 351 1962 1971
41. WestSK
MunozB
MkochaH
GaydosC
QuinnT
2007 Trachoma and ocular Chlamydia trachomatis were not eliminated three years after two rounds of mass treatment in a trachoma hyperendemic village. Invest Ophthalmol Vis Sci 48 1492 1497
42. BiebesheimerJB
HouseJ
HongKC
LakewT
AlemayehuW
2009 Complete local elimination of infectious trachoma from severely affected communities after six biannual mass azithromycin distributions. Ophthalmology 116 2047 2050
43. FeikinDR
DowellSF
NwanyanwuOC
KlugmanKP
KazembePN
2000 Increased carriage of trimethoprim/sulfamethoxazole-resistant Streptococcus pneumoniae in Malawian children after treatment for malaria with sulfadoxine/pyrimethamine. J Infect Dis 181 1501 1505
44. HillPC
AkisanyaA
SankarehK
CheungYB
SaakaM
2006 Nasopharyngeal carriage of Streptococcus pneumoniae in Gambian villagers. Clin Infect Dis 43 673 679
45. ThyleforsB
DawsonCR
JonesBR
WestSK
TaylorHR
1987 A simple system for the assessment of trachoma and its complications. Bull World Health Organ 65 477 483
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