Antimicrobial use and interpreting carriage risk of antimicrobial-resistant pneumococcus
I thank Costelloe et al. for their paper in BMJ and systematic
review and meta-analysis of studies where the effect of antimicrobial use
on the emergence of resistance has been assessed for individual patients
in primary care.
Since the 1990s penicillin resistance of Streptococcus pneumoniae in
Iceland has been a growing problem, and such resistance is still
increasing, much faster than in most other European countries (1). Over
35% of all pneumococci are now penicillin and macrolide non-susceptible
(2). This can probably be explained by the decades of higher antimicrobial
usage in Iceland than in the other Nordic countries.
Studies of the individual relationship between antimicrobial use and
resistance in pneumococci have produced conflicting results, reflecting
differences in the study design, setting, and measures of association used
(3). In previously published studies from Iceland, 1993(4), 1998(5) and
2003(6) the carriage rate of resistant pneumococci has usually been
calculated with the total number of children carrying pneumococci as the
denominator. In all our three cross-sectional studies, the risk of
carrying penicillin-nonsusceptible (PNSP)(penicillin MIC >/=0.1 mg/l)
was 4-5 times greater during the first 7 weeks after each antimicrobial
course for children actually carrying pneumococci (1). Antimicrobial
treatment does though not appear to increase an individual's absolute risk
of carrying PNSP after treatment in some studies. However, it may
increases a patient's relative risk of carriage of PNSP (3). In French
prospective studies, antimicrobial treatment did not increase the risk of
an individual child carrying PNSP even though the proportion of PNSP
increased (i.e., only for those carrying pneumococci) (7,8). This was
mainly explained by a significant decrease in the number of individuals
carrying penicillin-susceptible pneumococci after having received
antimicrobials and thereby relatively higher PNSP rate (relative risk)
among those still carrying pneumococci.
Because of the above-mentioned observations, I recalculated the data
from all three studies for all children, i.e., not only those carrying
pneumococci (1). The results were nevertheless identical to those that had
been obtained before i.e., higher (absolute) risk of PNSP carriage for all
children recently after antimicrobial treatment. In our first study in
1993(4), 580 children of 919 had received antimicrobials over the previous
12 months, and 191 had received treatment 2-7 weeks before sampling, of
which 27 were carrying penicillin-nonsusceptible (PNSP), as opposed to
only 17 out of 389 children who had received antimicrobials 8-52 weeks
before study entry (p<_0.0001. corresponding="corresponding" figures="figures" from="from" the="the" _1998="_1998" study="study" _5="_5" show="show" that="that" of="of" _743="_743" children="children" _372="_372" had="had" received="received" antimicrobials="antimicrobials" in="in" previous="previous" _12="_12" months="months" thereof="thereof" _11="_11" _129="_129" receiving="receiving" _2-7="_2-7" weeks="weeks" carried="carried" pnsp="pnsp" as="as" opposed="opposed" to="to" only="only" _8="_8" out="out" _243="_243" _8-52="_8-52" before="before" sampling="sampling" carrying="carrying" p="p" for="for" _2003="_2003" _6="_6" _824="_824" _357="_357" preceding="preceding" months.="months." these="these" _16="_16" _104="_104" _18="_18" _253="_253" antimicrobial="antimicrobial" treatment="treatment" _1.="_1." figure="figure" shows="shows" carriage="carriage" penicillin-susceptible="penicillin-susceptible" psp="psp" and="and" all="all" i.e.="i.e." not="not" those="those" pneumococci="pneumococci" three="three" studies="studies" by="by" number="number" last="last" relatively="relatively" speaking="speaking" strains="strains" are="are" similar="similar" two="two" after="after" treatment.="treatment." results="results" therefore="therefore" congruent="congruent" with="with" french="french" prospective="prospective" _78.="_78."/> Current antimicrobial use seems therefore to encourages the uptake of
resistant pneumococci and subsequent colonisation or “selective
acquisition of (foreign) nonsusceptible strains” from the outer ecosystem
(from the community). In addition, PNSP not previously detected by our
methods may proliferate and become abundant and detectable after
antimicrobial treatment (unmasking of dormant and/or nonsusceptible
strains present in very low numbers from the mucosa)(1).
2) Arason VA, Sigurdsson JA. The problems of antibiotic overuse;
Acute Otitis Media among Children and Resistance Development in the
Community (editorial). Scand J Prim Health Care 2010;28:65-66.
3) Lipsitch M. Measuring and interpreting associations between
antibiotic use and penicillin resistance in Streptococcus pneumoniae. Clin
Infect Dis 2001;32(7):1044-54.
4) Arason VA, Kristinsson KG, Sigurdsson JA, Stefansdottir G, Molstad
S and Gudmundsson S. Do antimicrobials increase the carriage rate of
penicillin resistant pneumococci in children? Cross sectional prevalence
study. BMJ 1996;313(7054):387-91.
5) Arason VA, Gunnlaugsson A, Sigurdsson JA, Erlendsdottir H,
Gudmundsson S and Kristinsson KG. Clonal spread of resistant pneumococci
despite diminished antimicrobial use. Microb Drug Resist 2002a);8(3):187-
92.
6) Arason VA, Sigurdsson JA, Erlendsdottir H, Gudmundsson S and
Kristinsson KG. The role of antimicrobial use in the epidemiology of
resistant pneumococci:a 10 years follow up. Microb Drug Resist 2006;12;169
-76
7) Cohen R, Bingen E, Varon E, de La Rocque N, Brahimi N, Levy C,
Boucherat M, Langue J and Geslin P. Change in nasopharyngeal carriage of
Streptococcus pneumoniae resulting from antibiotic therapy for acute
otitis media in children. Pediatr Infect Dis J 1997;16(6):555-60.
8) Varon E, Levy C, De La Rocque F, Boucherat M, Deforche D,
Podglajen I, Navel M and Cohen R. Impact of antimicrobial therapy on
nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus
influenzae, and Branhamella catarrhalis in children with respiratory tract
infections. Clin Infect Dis 2000;31(2):477-81.
Carriage rate (95% confidence interval) of penicillin-susceptible (PSP) (green) (n=648) and penicillin-nonsusceptible pneumococci (PNSP) (red) (n=97) by all children receiving antimicrobials during the 12 months prior to study entry (n=1315) for the 1993, 1998 and 2003 studies, by the number of weeks from the last antimicrobial treatment.
Rapid Response:
Antimicrobial use and interpreting carriage risk of antimicrobial-resistant pneumococcus
I thank Costelloe et al. for their paper in BMJ and systematic
review and meta-analysis of studies where the effect of antimicrobial use
on the emergence of resistance has been assessed for individual patients
in primary care.
Since the 1990s penicillin resistance of Streptococcus pneumoniae in
Iceland has been a growing problem, and such resistance is still
increasing, much faster than in most other European countries (1). Over
35% of all pneumococci are now penicillin and macrolide non-susceptible
(2). This can probably be explained by the decades of higher antimicrobial
usage in Iceland than in the other Nordic countries.
Studies of the individual relationship between antimicrobial use and
resistance in pneumococci have produced conflicting results, reflecting
differences in the study design, setting, and measures of association used
(3). In previously published studies from Iceland, 1993(4), 1998(5) and
2003(6) the carriage rate of resistant pneumococci has usually been
calculated with the total number of children carrying pneumococci as the
denominator. In all our three cross-sectional studies, the risk of
carrying penicillin-nonsusceptible (PNSP)(penicillin MIC >/=0.1 mg/l)
was 4-5 times greater during the first 7 weeks after each antimicrobial
course for children actually carrying pneumococci (1). Antimicrobial
treatment does though not appear to increase an individual's absolute risk
of carrying PNSP after treatment in some studies. However, it may
increases a patient's relative risk of carriage of PNSP (3). In French
prospective studies, antimicrobial treatment did not increase the risk of
an individual child carrying PNSP even though the proportion of PNSP
increased (i.e., only for those carrying pneumococci) (7,8). This was
mainly explained by a significant decrease in the number of individuals
carrying penicillin-susceptible pneumococci after having received
antimicrobials and thereby relatively higher PNSP rate (relative risk)
among those still carrying pneumococci.
Because of the above-mentioned observations, I recalculated the data
from all three studies for all children, i.e., not only those carrying
pneumococci (1). The results were nevertheless identical to those that had
been obtained before i.e., higher (absolute) risk of PNSP carriage for all
children recently after antimicrobial treatment. In our first study in
1993(4), 580 children of 919 had received antimicrobials over the previous
12 months, and 191 had received treatment 2-7 weeks before sampling, of
which 27 were carrying penicillin-nonsusceptible (PNSP), as opposed to
only 17 out of 389 children who had received antimicrobials 8-52 weeks
before study entry (p<_0.0001. corresponding="corresponding" figures="figures" from="from" the="the" _1998="_1998" study="study" _5="_5" show="show" that="that" of="of" _743="_743" children="children" _372="_372" had="had" received="received" antimicrobials="antimicrobials" in="in" previous="previous" _12="_12" months="months" thereof="thereof" _11="_11" _129="_129" receiving="receiving" _2-7="_2-7" weeks="weeks" carried="carried" pnsp="pnsp" as="as" opposed="opposed" to="to" only="only" _8="_8" out="out" _243="_243" _8-52="_8-52" before="before" sampling="sampling" carrying="carrying" p="p" for="for" _2003="_2003" _6="_6" _824="_824" _357="_357" preceding="preceding" months.="months." these="these" _16="_16" _104="_104" _18="_18" _253="_253" antimicrobial="antimicrobial" treatment="treatment" _1.="_1." figure="figure" shows="shows" carriage="carriage" penicillin-susceptible="penicillin-susceptible" psp="psp" and="and" all="all" i.e.="i.e." not="not" those="those" pneumococci="pneumococci" three="three" studies="studies" by="by" number="number" last="last" relatively="relatively" speaking="speaking" strains="strains" are="are" similar="similar" two="two" after="after" treatment.="treatment." results="results" therefore="therefore" congruent="congruent" with="with" french="french" prospective="prospective" _78.="_78."/> Current antimicrobial use seems therefore to encourages the uptake of
resistant pneumococci and subsequent colonisation or “selective
acquisition of (foreign) nonsusceptible strains” from the outer ecosystem
(from the community). In addition, PNSP not previously detected by our
methods may proliferate and become abundant and detectable after
antimicrobial treatment (unmasking of dormant and/or nonsusceptible
strains present in very low numbers from the mucosa)(1).
References:
1) Arason VA. Use of Antimicrobials and Carriage of Penicillin-
Resistant Pneumococci in Children. Repeated cross-sectional studies
covering 10 years. PhD thesis University of Iceland 2006.
http://www.hirsla.lsh.is/lsh/bitstream/2336/11250/3/use_of_arason_ot_1.pdf
2) Arason VA, Sigurdsson JA. The problems of antibiotic overuse;
Acute Otitis Media among Children and Resistance Development in the
Community (editorial). Scand J Prim Health Care 2010;28:65-66.
3) Lipsitch M. Measuring and interpreting associations between
antibiotic use and penicillin resistance in Streptococcus pneumoniae. Clin
Infect Dis 2001;32(7):1044-54.
4) Arason VA, Kristinsson KG, Sigurdsson JA, Stefansdottir G, Molstad
S and Gudmundsson S. Do antimicrobials increase the carriage rate of
penicillin resistant pneumococci in children? Cross sectional prevalence
study. BMJ 1996;313(7054):387-91.
5) Arason VA, Gunnlaugsson A, Sigurdsson JA, Erlendsdottir H,
Gudmundsson S and Kristinsson KG. Clonal spread of resistant pneumococci
despite diminished antimicrobial use. Microb Drug Resist 2002a);8(3):187-
92.
6) Arason VA, Sigurdsson JA, Erlendsdottir H, Gudmundsson S and
Kristinsson KG. The role of antimicrobial use in the epidemiology of
resistant pneumococci:a 10 years follow up. Microb Drug Resist 2006;12;169
-76
7) Cohen R, Bingen E, Varon E, de La Rocque N, Brahimi N, Levy C,
Boucherat M, Langue J and Geslin P. Change in nasopharyngeal carriage of
Streptococcus pneumoniae resulting from antibiotic therapy for acute
otitis media in children. Pediatr Infect Dis J 1997;16(6):555-60.
8) Varon E, Levy C, De La Rocque F, Boucherat M, Deforche D,
Podglajen I, Navel M and Cohen R. Impact of antimicrobial therapy on
nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus
influenzae, and Branhamella catarrhalis in children with respiratory tract
infections. Clin Infect Dis 2000;31(2):477-81.
Carriage rate (95% confidence interval) of penicillin-susceptible (PSP) (green) (n=648) and penicillin-nonsusceptible pneumococci (PNSP) (red) (n=97) by all children receiving antimicrobials during the 12 months prior to study entry (n=1315) for the 1993, 1998 and 2003 studies, by the number of weeks from the last antimicrobial treatment.
Competing interests:
None declared
Competing interests: No competing interests