Recent Declines in ß-Lactam and MLSB Resistances Among S. pneumoniae and Age-Related Effects: Report from the SENTRY Antimicrobial Surveillance Program (North America, 1997 - 2002) RN JONES, DM JOHNSON, HS SADER, TR FRITSCHE The JONES Group/JMI Laboratories, North Liberty, IA A M E N D E D A B S T R A C T M A T E R I A L S A C D S ( C o n t i n u e d ) Background: The SENTRY Program has monitored emerging resistance (R) in S. pneumoniae (SPN) since 1997.
prepare a suspension equal to a 0.5 MacFarland turbidity standard. Using an autoinoculator, 100 µl of the inoculum
Consistent increases in penicillin (PEN), erythromycin (ER) and clindamycin (CC) R have been documented each
suspension was diluted in an appropriate broth for delivery of 5 x 104 CFU/well. Cation-adjusted Mueller-Hinton
Change in macrolide resistance phenotype occurrence among S. pneumoniae isolates from North
year, however year 2002 results indicate a shift to greater susceptibility (S). Details of this change were analyzed
Activity and susceptibility rates for 6-7 selected antimicrobial agents against H. influenzae, M. catarrhalis, and S. pneumoniae
broth with lysed horse blood for S. pneumoniae was dispensed into the wells of validated panels (TREK Diagnostics,
America (2001 to 2002) listed by patient age group.
in the SENTRY Program-North America (2000-2002).
to determine patient populations and other demographics contributing to these reductions in R.
Cleveland, Ohio, USA). Panels were incubated in ambient air for 20 - 24 hours. MIC endpoints were determined
as a lack of visible growth as outlined in the NCCLS approved standard. Interpretive criteria used were those of
Methods: Among 16,489 community-acquired respiratory tract (CARTI) pathogens processed from North America
NCCLS M100-S13. Daily quality control was performed by the routine testing of ATCC strains including S. pneumoniae
(NA) (1997 - 2002), a total of 6,562 SPN (1001 - 1201/year from > 30 sites) were tested by reference broth
microdilution method against 27 - 32 drugs/year. All tests were interpreted by NCCLS criteria (2003) for S, R and
intermediate (I). SPN was recovered from 38 - 42% of CARTI samples, similar to that of H. influenzae (39 - 42%)
and 2-fold greater than M. catarrhalis (18 - 22%) that remained unchanged over the six year period.
Impact of age on susceptibility profiles. Demographic information obtained with each isolate was grouped by subset
analysis into three age classes (0 - 5 years, 6 - 64 years and ≥ 65 years) and compared with trends in antimicrobial
Results: The results follow in the table:
susceptibility patterns, specifically examining results for ß-lactam and macrolide agents during each of the last three
MLS resistance phenotype, representing resistance to macrolides, lincosamides, and streptogramin B agents. Conferred by methylation of a single
adenine in the bacterial 50s ribosome (erm genes).
M-phenotype representing resistance to macrolides, but not clindamycin, which involves a macrolide efflux pump (mef).
• S. pneumoniae was isolated from 38 - 42% of community-acquired respiratory tract infections, varying
by year (p >0.05). The rates of occurrence for H. influenzae and M. catarrhalis were 39 - 42% and 18 -
C O N C L U S I O N S
• Resistance to penicillin and other ß-lactams among S. pneumoniae, decreased in 2002
• Resistance rates among H. influenzae and M. catarrhalis CARTI isolates remained stable over the last
for the first time in the six-year interval driven by a reduction in high-level resistant isolates.
six respiratory disease seasons. Ampicillin-resistant (ß-lactamase-positive) H. influenzae averaged 29%,
The extreme age groups (0-5 and ≥ 65 years) showed the greatest reduction in R to PEN, ER and CC with minimal
change occurring in isolates from those 6-64 years.
slightly less in the last three years. ß-lactamase production by M. catarrhalis isolates consistently exceeded
• Macrolide resistance decreased in 2002 via combined decreases in all MLS
but showed a slight increase in the M-phenotype strains (69.6%). Conclusions: The increase in PEN S was mainly associated with a decrease in the occurrence of isolates with high level R (MIC,
≥2 µg/ml). The net increase in S to macrolides and lincosamides was due to a simultaneous
• A consistent trend toward increasing resistance in S. pneumoniae to ß-lactams and MLS agents was
MIC and MIC in µg/ml at which 50 and 90% of the isolates, respectively,
MIC <0.06 negative ß-lactamase production; MIC > 0.06 is positive for
reduction in the MLS phenotype (ER- and CC-R) and a lesser magnitude increase in the M-phenotype (ER-R and
were inhibited. % S, percent of isolates susceptible and % R, percent of
• Reductions in resistance was greatest in age groups at the extremes of life, e.g. 0 - 5
observed from 1999 through 2001 (Figure 1). However, in 2002 the non-susceptible rates for penicillin
CC-S). The potential impact of vaccine usage and prescription discipline on changes to the susceptibility pattern
isolates resistant using NCCLS criteria.
Resistance rates in parenthesis are based on Chen et al. criteria (1999)
Interpretative criteria not established by the NCCLS.
and erythromycin decreased 5.8 and 4.3%, respectively. In contrast, levofloxacin resistance increased
of SPN in NA should be further investigated.
from 0.9 in 2000 to 1.4% in 2002 (Table 1).
• Resistance reductions appears to be related in time to pneumococcal vaccination
Susceptibilities of select antimicrobials tested against S. pneumoniae isolates from North America (2001-2002) listed by patient
• The other ß-lactams (oral agents amoxicillin/clavulanate, cefdinir, cefuroxime axetil) also showed improved
success in the two targeted age groups. I N T R O D U C T I O N
spectrums versus S. pneumoniae in 2002 (Table 1).
• Further investigations are urged into the continued impact of vaccine usage and
Penicillin resistance among S. pneumoniae has increased continuously in the USA in the last decade. Additionally,penicillin-resistant strains have become increasingly more resistant to other antimicrobial agents. Rates may vary
• Age group related changes in resistance for 2002 were most evident in the young (0 - 5 years) and the
prescription discipline on pneumococcal resistance rates in CARTI and hospitalized
according to the geographic region and in some areas more than one-third of S. pneumoniae isolates have resistance
elderly (≥ 65 years) with susceptibility increases for ß-lactams. Macrolides showed a decrease in
to penicillin. Resistance rates may also vary according to patient age group, the higher rates have usually been
susceptibility for the young children (-2.1% for erythromycin) compared to favorable increases in
found in children and in the elderly. The continuous increase in the resistance rates among pneumococci has been
susceptibility for the isolates from adult patients (Table 2).
attributed to several factors, mainly the dissemination of resistant clones and local or national patterns of antimicrobial
use. Moreover, the influence of the increasing use of the pneumococcal conjugate vaccine on the pneumococcal
S E L E C T E D R E F E R E N C E S
resistance rates has not been fully evaluated. Since the vaccine has shown to be highly effective against invasive
• Table 3 shows the resistance variation among 2001 and 2002 pneumococcal isolates by age and level
disease in young children and elderly people, and the serotypes included in the 7- or 23-valent vaccines account
of penicillin susceptibility. The greatest decrease in resistance occurred among the elderly patient isolates
American Academy of Pediatrics. Policy Statement: Recommendations for the Prevention of Pneumococcal Infections, Including the Use of Pneumococcal
Conjugate Vaccine (Prevnar), Pneumococcal Polysaccharide Vaccine, and Antibiotic Prophylaxis (RE9960). Pediatrics 2000; 106:362-366.
for most penicillin-resistant or multi-resistant clones causing infection in the USA, we may expect a reduction in
and the proportion of high-level resistant strains (penicillin MIC, ≥ 2 µg/ml).
resistant pneumococci as the vaccine becomes widely used.
Center for Disease Control and Prevention. Facilitating influenza and pneumococcal vaccination through standing orders programs. Morbidity and MortalityWeekly Report. 2003; 52:68-69.
• Changes in 2002 for MLS resistance phenotypes indicated an increase in mef A, efflux M-phenotypes
The objective of this presented study was to evaluate the contemporary in vitro activity and spectrum for leading
Chen DK, McGeer A, De Azavedo JC, Low DE. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. New England Journal of
orally administered antimicrobials available for the treatment of community-acquired respiratory tract infections
in the children (60.9 to 67.4%) and in the elderly (69.2 to 74.3%), see Table 4.
(CARTI) caused by S. pneumoniae as a component of the SENTRY Antimicrobial Surveillance Program. In addition,
Dagan R. Streptococcus pneumoniae in the potential effects of new vaccines on the pattern of antibiotic drug usage in pediatrics. Current Therapeutic Research
we evaluated the current resistance trends based on the annual results obtained from 1997 to 2002 and the influence
• These changes in resistance appear to correspond to literature cited expansion of the use of pneumococcal
Hoban D, Doern G, Fluit A, Roussel-Delvallez M, Jones RN. Worldwide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus
of patient age on S. pneumoniae susceptibility patterns during the monitored 6-year period (16,489 isolates).
vaccines in the most effected populations of patients illustrated in this report (0 - 5 and ≥ 65 years). influenzae, and Moraxella catarrhalis in the SENTRY Antimicrobial Surveillance Program, 1997-1999. Clinical Infectious Disease 2001; 32(Suppl 2):S81-93.
Jones RN, Pfaller MA. In vitro activity of newer fluoroquinolones for respiratory tract infections and emerging patterns of antimicrobial resistance: Data from the
M A T E R I A L S A N D M E T H O D S
SENTRY Antimicrobial Surveillance Program. Clinical Infectious Disease 2000; 31:S16-23. Figure 1: Trends in the susceptibility patterns of S. pneumoniae isolates in the SENTRY Program (1997 - 2002).
Jones RN, Biedenbach DJ, Beach ML. Influence of patient age on the susceptibility patterns of Streptococcus pneumoniae isolates in North America (2000-
2001): Report from the SENTRY Antimicrobial Surveillance Program. Diagnostic Microbiology and Infectious Disease 2003; 46:77-80.
Bacterial isolate collection. A total of 16,489 contemporary CARTI isolates were gathered from > 40 medical centers
Criteria for susceptibility applied from NCCLS tables.
(approximately 35/year) in North America during 1997 to 2002. Isolates were identified by the originating laboratories
Low DE. The new oral cephalosporins in community-acquired infections. Clinical Microbiology and Infection 2000; 6(Suppl 3):64-69.
and pure cultures were then forwarded in a semisolid transport medium containing charcoal to a central monitoring
National Committee for Clinical Laboratory Standards. (2003). Methods for dilution antimicrobial tests for bacteria that grows aerobically. Approved standard
site (JMI Laboratories, North Liberty, IA). Upon arrival, isolates were subcultured onto appropriate media to ensure
viability and purity, and incubated in a 3 - 5% CO environment. S. pneumoniae isolates were identified by examination
Change in the rate of penicillin resistance among S. pneumoniae isolates from North America (2001 to 2002) listed by patient
National Committee for Clinical Laboratory Standards. (2003). Performance standards for antimicrobial susceptibility testing. Supplemental tables, M100-S13.
of typical colonial characteristics and use of the bile (2% sodium desoxycholate) solubility test.
Whitney CG, Farley MM, Hadler J, Harrison LH, Bennett NM, Lynfield R, Reingold A, Cieslak PR, Pilishvili T, Jackson D, Facklam RR, Jorgensen JH, Schuchat
Determination of MICs. Susceptibility testing utilizing the National Committee for Clinical Laboratory Standards
A, for the Active Bacterial Core Surveillance of the Emerging Infections Program Network. Decline in invasive pneumococcal disease after the introduction of
protein-polysaccharide conjugate vaccine. New England Journal of Medicine 2003; 348:1737-1746.
(NCCLS) reference broth microdilution method was performed with a battery of broad-spectrum antimicrobial agents
(27 - 32 drug/year): penicillin, amoxicillin/clavulanic, numerous oral cephalosporins, macrolides, ampicillin, clindamycin,
Whitney CG, Farley MM, Hadler J, Harrison LH, Lexau C, Reingold A, Lefkowitz L, Cieslak PR, Cetron M, Zell ER, Jorgensen JH, Schuchat A, The Active Bacterial
Core Surveillance Program of the Emerging Infections Program Network. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United
ciprofloxacin and levofloxacin will be presented here. Colonies from fresh (< 24 hours) subcultures were used to
States. New England Journal of Medicine 2000; 343:1917-1924.
Efficacy of Hydroxyurea in Providing Transfusion Saqib H. Ansari, MBBS, DCH, DPGN, MPhil, Tahir S. Shamsi, MBBS, FRCPath, Mushtaq Ashraf, MBBS, MD, Kousar Perveen, BSc, MBA, CRA, Tasneem Farzana, MBBS, MCPS, Munira Borhany, MBBS, FCPS, Sajida Erum, Pharm D, CCRP, and Tabassum Mehboob, PhD in the general population with an increased risk of Background: Packed red blood cell (PRC) transfusion