Antimicrobial Susceptibility Trends in Staphylococcus aureus

isolated from Pediatric Patients in Military Treatment Facilities

Staphylococcus aureus (SA) is a ubiquitous pathogen which causes disease in healthy hosts of all ages. The epidemic of disease

caused by community associated S. aureus commonly resistant to anti-staphylococcal beta-lactam antibiotics has led

pediatricians to choose alternate therapies such as clindamycin for first-line empiric treatment of both cutaneous and invasive

infections. Recently rates of methicillin-resistant Staphylococcus aureus (MRSA) infections have been declining in adult

populations but other studies have reported increasing rates of MRSA in children. Patient age, infection type, inpatient status and

geographic location are variables which may differ with respect to antimicrobial susceptibility.

The goals of this study are to describe antimicrobial susceptibility of S. aureus isolates from pediatric patients receiving care in

Department of Defense (DoD) fixed military treatment facilities between 2005 and 2013, evaluating temporal trends in

antimicrobial susceptibility. Additional goals include evaluation of differences between demographic groups in susceptibility to

oxacillin, clindamycin, and ciprofloxacin, as well as describing relevant differences and trends in antimicrobial susceptibilities

between oxacillin-susceptible and –resistant isolates.

Uzo Chukwuma1, Emma Schaller1, Nicole Dzialowy1, Ashley M Maranich2, Deena E Sutter2

1Epidata Center Department, Navy and Marine Corps Public Health Center , Portsmouth VA 2 Department of Pediatrics, San Antonio Military Medical Center, Ft. Sam Houston, TX

Conclusions

Disclaimer: The opinions expressed herein are those of the author(s), and are not necessarily representative of those of the Department of Defense

(DOD); or, the United States Army, Navy, or Air Force.

Table 2. Antimicrobial susceptibility of Staphylococcus aureus isolated from pediatric patients, 2005-2013

Antibiotics 2005 2006 2007 2008 2009 2010 2011 2012 2013 P-value

Ciprofloxacin (n=18,780)

86.2% 83.8% 81.2% 79.0% 77.2% 77.3% 75.4% 78.8% 81.2% < .0001

Clindamycin (n=36,256)

90.9% 90.6% 91.2% 89.6% 89.0% 87.9% 87.9% 86.0% 85.8% < .0001

Erythromycin

(n=40,079) 44.1% 42.5% 40.5% 39.8% 42.3% 43.4% 43.5% 44.4% 48.2% < .0001

Gentamicin (n=22,967)

96.8% 96.6% 95.9% 97.7% 97.2% 97.5% 98.0% 99.3% 99.0% < .0001

Oxacillin (n=41,602)

60.4% 56.2% 54.9% 55.9% 57.8% 59.6% 58.6% 61.6% 65.4% < .0001

Penicillin (n=33,317)

7.4% 7.4% 6.6% 6.8% 7.1% 7.1% 6.5% 6.9% 7.5% 0.5153

Rifampin (n=21,805)

99.6% 99.5% 99.6% 99.4% 99.5% 99.3% 99.6% 99.2% 99.2% 0.036

Tetracycline (n=34,756)

94.4% 95.2% 95.8% 95.9% 95.8% 96.4% 96.1% 96.1% 95.5% 0.0007

Trimethoprim/

Sulfamethoxazole (n=40,842)

98.6% 100.0% 99.2% 99.4% 99.0% 99.0% 98.7% 98.4% 98.5% 0.0174

This retrospective observational surveillance study analyzed S aureus isolates identified among pediatric patients in the Military

Health System (MHS) from 1 January 2005 to 31 December 2013. Pediatric patients were defined as DoD dependent beneficiaries

less than 18 years of age. MHS is composed of 266 fixed military treatment facilities in the United States and limited locations

overseas.

Isolates classified as colonization or surveillance cultures at sites typically not indicative of a true infection were excluded. These

included nasal cultures, mouth or oral cavity cultures, nasopharynx, oropharynx, pharynx or throat cultures and axilla or groin

cultures.

Susceptibility data from S. aureus culture isolates were identified from the Navy Marine Corps Public Health Center (NMCPHC)

Health Level 7 (HL7) formatted microbiology data from the Composite Health Care System at fixed MTFs based on the Clinical and

Laboratory Standards Institute (CLSI) testing guidelines. Only the first S. aureus isolate per patient per year were included in the

analyses.

Antibiograms were constructed using laboratory interpretation susceptibility results obtained from HL7 formatted microbiology data.

To examine antibiotic susceptibility trends across the nine-year time period for each population in this analysis, a Cochrane-

Armitage trend test was conducted. Trends were considered statistically significant at p-value < 0.05.

Ciprofloxacin, clindamycin, and oxacillin susceptibility trends were further investigated by analyzing covariates including age, status

(inpatient vs outpatient), infection classification, and geographic location. Infections were classified into respiratory, skin and soft

tissue, sterile site, and other infections, as defined in Table 1. Potential association of these covariates was evaluated using two

time periods: historical (2005-2012) and recent (2013).

To identify regional changes in oxacillin susceptibility, annual mean susceptibility rates were calculated from 2005-2013 for 5

geographic areas of the United States. Ciprofloxacin and clindamycin susceptibility trends for methicillin-resistant S. aureus and

methicillin-sensitive S. aureus isolates were also compared. A chi-square test was conducted to calculate p-values for each of these

comparisons.

Statistics were conducted using SAS software version 9.2 (SAS Institute).

Note. Bold text indicates a significant (p < 0.05) difference between demographic characteristic and antibiotic for historical (2005-2012) and recent (2013) isolates. P-values were determined using a chi-square test. a In 2013 the number of sterile infection isolates tested for ciprofloxacin was below 30. Susceptibility results are not reliable with an isolate count less than 30.

Table 3. S aureus susceptibility to ciprofloxacin, clindamycin and oxacillin in demographic groups

Ciprofloxacin Clindamycin Oxacillin

Characteristics n isolates

(2005-2013) 2005-2012 2013 2005-2012 2013 2005-2012 2013

Age Group

Neonate (<1mo) 1,705 86.1% 88.3% 79.8% 74.8% 73.0% 80.3%

Infant (1-12mo) 4,963 80.3% 79.2% 89.0% 87.5% 61.2% 63.1%

Early Childhood (2-5yr) 16,326 77.6% 76.4% 90.5% 89.1% 52.0% 57.7%

Older child/adolescent (6-17yr) 19,621 81.3% 85.4% 88.8% 83.6% 61.3% 71.1%

Infection Type

Respiratory Infections 2,416 79.0% 84.4% 77.6% 77.3% 76.6% 75.5%

Skin and Soft Tissue Infections 32,097 78.7% 80.2% 90.3% 87.4% 53.7% 62.6%

Sterile Site Infections 737 83.9% -- 87.7% 81.5% 72.7% 70.2%

Other Infections 7,156 85.0% 84.7% 87.7% 82.2% 70.1% 72.9%

Patient Status

Inpatient 2,154 76.4% 80.0% 87.8% 84.3% 55.0% 61.5%

Outpatient 40,261 80.0% 81.3% 89.2% 85.9% 58.3% 65.6%

Geographic location

West (includes AK, HI) 11,122 77.5% 79.5% 87.9% 87.3% 62.3% 66.7%

Midwest 2,315 81.2% 76.7% 90.9% 89.3% 57.0% 69.1%

South 9,516 78.2% 78.9% 89.7% 83.9% 53.0% 61.3%

South Atlantic 14,415 79.2% 81.6% 90.1% 85.2% 55.6% 64.5%

Northeast 848 83.6% 84.5% 79.4% 79.7% 64.7% 68.7%

Other 4,199 86.7% 88.0% 89.2% 87.1% 66.9% 69.5%

50%

60%

70%

80%

90%

100%

2005 2006 2007 2008 2009 2010 2011 2012 2013

Pe

rce

nt

Su

sce

pti

bil

ity

MSSA- Ciprofloxacin

MSSA- Clindamycin

MRSA- Ciprofloxacin

MRSA- Clindamycin

Figure 2. Susceptibility to clindamycin and ciprofloxacin among MRSA and MSSA

isolated from pediatric patients in 2005-2013

Over the study period 42,415 annual first positive S. aureus isolates from 39,473 pediatric patients were identified. Among all

isolates 39.7% were methicillin-resistant, 58.4% were methicillin-sensitive and 1.9% had no oxacillin susceptibility results available.

Susceptibility trends from 2005-2013 showed a significant (p<0.05) overall decreasing trend in antibiotic susceptibility for

clindamycin, rifampin, and trimethoprim/sulfamethoxazole and an increasing trend occurred for erythromycin, gentamicin, and

tetracycline. (Table 2).

Susceptibility to both oxacillin and ciprofloxacin initially decreased, with a nadir in 2007 for oxacillin and 2009 for ciprofloxacin, and

a subsequent increase through 2013 (p<0.05).

S. aureus susceptibility to oxacillin in five geographic regions of the United States over 2005-2013 was calculated (Figure 1). The

majority of isolates were reported from the South Atlantic, West and South regions and relatively few isolates from the Northeast.

This distribution reflects the number of MTFs and patients receiving care in these regions. Oxacillin susceptibility declined in all

regions from 2005-2007, with lowest susceptibility rates in the South and South Atlantic regions. A subsequent trend towards

increasing susceptibility occurred in most regions, particularly from 2011-2013. The most dramatic increase in oxacillin susceptibility

occurred in the South, with a 9.1% increase from 2005-2013 (Figure 1). Significant differences in oxacillin susceptibility between

geographic regions existed from 2005-2012, with no significant differences in 2013 (table 3). Susceptibility to clindamycin and

ciprofloxacin also differed by geographic region in the aggregate 2005-2012 time period but did not differ significantly in 2013.

Other covariates of interest including infection type, patient age and patient status (inpatient vs outpatient) demonstrated significant

differences in antimicrobial susceptibility. Notably, rates of oxacillin susceptibility was lower in SSTIs than in other infection types,

and isolates from young children aged 2-5 years had significantly lower rates of susceptibility to oxacillin than in neonates, infants

and older children. Isolates cultured from inpatients were slightly more likely to be resistant to oxacillin and clindamycin. Differences

between MRSA and MSSA susceptibility to clindamycin and ciprofloxacin over time were evaluated (Figure 2). Susceptibility to

ciprofloxacin was approximately 40% percent higher in MSSA isolates when compared with MRSA. The clindamycin susceptibility

rates of MRSA and MSSA were similar until 2009 when MSSA clindamycin susceptibility declined while MRSA rates remained

stable. In 2013 90.3% of MRSA and 83.2% of MSSA remained clindamycin-susceptible Erythromycin resistance among MSSA

isolates remained stable throughout the study period (data not shown).

Discussion

The current data include over 40,000 clinical S. aureus isolates from children receiving care in the military healthcare system,

demonstrating demographic differences and epidemiologic trends in resistance to commonly used antimicrobials. Oxacillin

susceptibility declined to 54.9% in 2007 with a subsequent rise to 65.4% in 2013. Clindamycin remains an appropriate first-line

therapy for most invasive S. aureus infections, but lower rates of clindamycin susceptibility in MSSA vs MRSA (83 vs 91%) were

noted. A trend demonstrated over the final four years of the study suggests a progressive decline in clindamycin susceptibility among

MSSA. Stable rates of erythromycin susceptibility during this time period suggest that the decline may be due to increasing

compliance of clinical microbiology laboratories with CLSI guidelines for testing for inducible clindamycin resistance and reporting

these isolates as resistant.

S. aureus remains highly susceptible to tetracycline and TMP/SMX. Fluoroquinolone susceptibility remains high among MSSA,

although fewer than 60% of MRSA are susceptible.

An unique finding of this study is that oxacillin resistance rates are higher in isolates from children aged 2-5 years. This may reflect

higher use of β-lactam antibiotics in this age group, but may also be due to differences in host immunity and pathogenicity and/or

provider practices in culturing isolates. Resistance to ciprofloxacin, an antibiotic rarely used in pre-school children, was also higher in

isolates from this age group, presumably due to higher quinolone resistance among MRSA.

Regional differences in various clonal S. aureus types have been well described, with highest rates of MRSA consistently reported in

southern and midwestern states. Our study identified a recent convergence of rates of oxacillin-susceptibility, with insignificant

differences between regions by 2013. This suggests that much of the overall increase in oxacillin susceptibility among S. aureus was

driven by decreasing resistance in these historically high-MRSA regions.

There are some limitations to this study. It was designed as a retrospective review of clinical laboratory data from numerous sites,

and therefore was limited due to inability to identify molecular types, to determine prevalence of inducible versus constitutive

resistance to clindamycin, and fewer isolates available from some regions (Northeast US) where fewer military treatment facilities

exist. Additionally, isolates from inpatients may be underrepresented in regions with limited capacity to provided inpatient care for

children and subsequent referral to civilian hospitals.

Table 1. Infection Classification for Pediatric Antibiogram among Pediatric Patients Accessing the Military Health System

Infection Classification If Body Site or Specimen Source Sample Taken From:

Respiratory Tract Infection Ears, nasal sinuses, trachea, sputum, bronchi, and any fluid related to these terms, including lung

fluid

Skin and Soft Tissue Infection Abscess, aspirate, discharge, drainage, exudate, pus, skin, surgical, tissue, and wound2

Sterile Site Infection Blood, cerebrospinal fluid, pleural fluid, peritoneal fluid, bone, joint/synovial fluid, bone marrow, or

internal body sites

Other Infections All other terms not classified, which include eye, gastrointestinal, reproductive tract, and urine

specimens

Background

Materials and Methods

Results

Results Results

• Clinical isolates of S. aureus are increasingly oxacillin-susceptible with a 10% increase from 2007 to 2013.

• Clindamycin susceptibility is declining among MSSA to a low of 83.2% in 2013. This decline may be a result of increased

reporting of inducible clindamycin resistance. MRSA susceptibility to clindamycin remains stable and exceeds 90%.

• Susceptibility to tetracycline and TMP/SMX remains high (>95%).

• Children aged 2-5 years have significantly higher rates of oxacillin-resistant infections than other age groups.

• Skin and soft tissue isolates are significantly more resistant to oxacillin than other infection types, although

susceptibility is increasing in this subgroup.

• S. aureus from the south US is increasingly susceptible to oxacillin, with current resistance rates similar to those seen

in other US regions.

• Ongoing national surveillance of clinical S. aureus isolates is necessary to identify trends in antimicrobial resistance.

Increasing relative rates of MSSA with associated clindamycin resistance may require alternative antimicrobials for

empiric therapy, with potentially increasing utility of β -lactam antibiotics for empiric therapy