EPIDEMIOLOGY AND SURVEILLANCE

Reduced Ceftaroline Susceptibility among Invasive MRSA

Infections in Children: a Clinical and Genomic Investigation
J. Chase McNeil,a Lauren M. Sommer,a Jesus G. Vallejo,a Kristina G. Hulten,a Sheldon L. Kaplan,a Anthony R. Floresb

Division of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA
a

b Division of Infectious Diseases, Department of Pediatrics, McGovern Medical School, UTHealth Houston, Children’s Memorial Hermann Hospital, Houston, Texas, USA

ABSTRACT Ceftaroline represents an attractive therapy option for methicillin-resistant

Staphylococcus aureus (MRSA). Little data is available, however, regarding the frequency of
reduced susceptibility (RS) to ceftaroline among pediatric MRSA infections. We screened
invasive MRSA isolates at a tertiary children’s hospital for ceftaroline RS. Ceftaroline RS
occurred in 2.9% of isolates and only among health care associated infections. Ceftaroline
RS isolates were more often clindamycin-resistant. Sequencing data indicated the predom-
inance of the CC5 lineage among ceftaroline RS isolates.

KEYWORDS MRSA, ceftaroline, health care associated, resistance, pediatric, invasive, mecR

M ethicillin-resistant Staphylococcus aureus (MRSA) isolates exhibiting ceftaroline reduced

susceptibility (RS) have been described after prolonged exposure to this agent (1, 2).
These isolates have been associated with mutations in penicillin binding protein (PBP)-2a
(2, 3) as well as with other PBPs and their regulatory elements (4). Little clinical data is available
regarding the frequency of ceftaroline RS among pediatric MRSA. Invasive MRSA isolates
obtained from pediatric patients at Texas Children’s Hospital (TCH) from 2015–2018 were
screened for ceftaroline RS.
6 out of 201 invasive MRSA isolates had a ceftaroline minimum inhibitory concentration
(MIC) if $2 m g/mL (2.9%), with two having MICs of $8 m g/mL (0.9%). Isolates exhibiting cef-
taroline RS were all health care-associated, PVL-negative, often resistant to clindamycin, and
belonging to agrII (Table 1). None of the subjects with a ceftaroline RS isolate experienced
prior ceftaroline use.
The following variables were included in a stepwise multivariable logistic regression Copyright © 2022 American Society for
model for ceftaroline RS infection: medical comorbidities, health care-associated infection, Microbiology. All Rights Reserved.
presence of a central venous line (CVL), diagnosis of central line associated bloodstream Address correspondence to J. Chase McNeil,
Jm140109@bcm.edu.
infections (CLABSI), previous ICU admission, surgery, cephalosporin exposure, and/or MRSA
The authors declare a conflict of interest.
infection. Only a diagnosis of CLABSI (P = 0.009, adjusted odds ratio [aOR] 1.6, 95% confidence Ceftaroline powder was provided by Allergan
interval [CI]:1.1 to 18.4) and a prior MRSA infection (P = 0.01, aOR 5.6, 95% CI:1.8 to 41.6) through an investigator initiated research
program for which J.C.M. was the PI; Allergan
remained statistically significant.
had no direct role in the conduct of the study
The whole-genome sequencing (WGS) of ceftaroline RS isolates (Table 2) revealed or data analysis. J.C.M. receives grant funding
that 5 out of 6 strains belonged to clonal complex (CC) 5. Mutations in genes previously from the Agency for Healthcare Research and
Quality (AHRQ R01HS026896). J.C.M. is the local
associated with ceftaroline RS were noted, including those encoding PBP2a (E447K) and
PI on a multicentre clinical trial sponsored by
lytD. One isolate had multiple mutations within mecR, although it had no previously Nabriva Therapeutics unrelated to the work
reported mutations associated with ceftaroline resistance. One subject had a ceftaroline under consideration. S.L.K. and K.G.H. receive
research support through Pfizer unrelated to
susceptible MRSA CLABSI (TCH32767) treated with line retention, followed 37 days later
the work under consideration. A.R.F. receives
by a ceftaroline resistant CLABSI (TCH32929). Both isolates were of sequence type (ST) 5. grant funding through NIAID R01AI25216,
The complete genomes of TCH32767 (CP064772) and TCH32929 (CP072116) were resolved R21AI153663, R21AI142126, R21AI59059.
using published techniques (5), revealing in TCH32767 a frameshift mutation in mutL, a com- Received 27 May 2022
Returned for modification 6 July 2022
ponent of the DNA mismatch repair system. There were 24 single nucleotide polymorphisms Accepted 5 September 2022
[SNPs]/InDels in TCH32929 relative to TCH32767, although there were none in genes predicted Published 27 September 2022
to confer ceftaroline resistance (Supplemental File 1).

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Reduced Ceftaroline Susceptibility in Pediatric MRSA Antimicrobial Agents and Chemotherapy

TABLE 1 Comparison of clinical variables by ceftaroline MIC

Ceftaroline Ceftaroline Ceftaroline
All cases, MIC ‡ 8 mg/mL, MIC 2 to 4 mg/mL, MIC £ 1 mg/mL,
Clinical/microbiologic characteristics n = 201 n=2 n=4 n = 195 P value
Age, yrs (IQR)a 3.5 (0.8 to 9.6) 5.4 (0.8 to 10.1) 9.3 (1.4 to 17) 3.5 (0.8 to 9.6) 0.55
Female gender 80 (39.8) 0 2 (50) 78 (40) 0.66

Race 1
White 128 (63.7) 2 (100) 3 (75) 123 (63.1)
Black 51 (25.4) 0 1 (25) 50 (25.6)
Asian 13 (6.5) 0 0 13 (16.7)
Other 1 (0.5) 0 0 1 (0.5)
Unknown 7 (3.5) 0 0 7 (3.6)

Hispanic ethnicity 64 (31.8) 0 1 (25) 63 (32.3) 1

Underlying conditions 111 (55.2) 2 (100) 4 (100) 105 (53.8) 0.08

Acquisition 0.02
Community-acquired 97 (48.3) 0 0 97 (49.7)
Community-onset health care associated 61 (30.3) 2 (100) 3 (75) 56 (28.7)
Hospital acquired 43 (21.4) 0 1 (25) 42 (21.5)

CVL in situ 55 (27.4) 2 (100) 3 (75) 50 (25.6) 0.009

Median symptom duration at presentation, days 2 (1 to 5) 1 (1 to 1) 1 (1 to 2) 2 (1 to 2) 0.19
Hospitalization in prior 90 days 94 (46.8) 2 (100) 3 (75) 89 (45.6) 0.17
ICU stay in prior 90 days 65 (32.3) 2 (100) 3 (75) 60 (30.8) 0.02
Surgery in prior 90 days 61 (30.3) 1 (50) 3 (75) 57 (29.2) 0.09
Antibiotics in prior 90 days 123 (61.2) 2 (100) 4 (100) 117 (60) 0.11
Any b -lactam antibiotics in prior 90 days 109 (54.2) 2 (100) 4 (100) 103 (52.8) 0.08
Any cephalosporins in prior 90 days 66 (32.8) 2 (100) 3 (75) 61 (31.3) 0.001
Any ceftaroline use 3 (1.5) 0 0 3 (1.5) 1
MRSA infection in prior 90 days 21 (10.4) 2 (100) 1 (25) 18 (9.2) 0.007
Relapse of infection at end of therapy 13 (6.5) 0 1 (25) 12 (6.2) 0.33
Thrombosis 27 (13.4) 1 (50) 1 (25) 25 (12.8) 0.18
Length of stay, days 12 (6 to 40) 11 (8 to 14) 10.5 (10 to 112) 12.5 (6 to 40) 0.8
Attributable mortality 11 (5.5) 0 1 (25) 10 (5.1) 0.29

Infectious diagnosis 0.03

Osteomyelitis 63 (31.3) 0 1 (25) 62 (31.8)
CLABSI 36 (17.9) 2 (100) 1 (25) 33 (16.9)
Pneumonia 17 (8.5) 0 0 17 (8.7)
Endocarditis 14 (6.9) 0 2 (50) 12 (6.2)
Bacteremia without a focus 12 (5.9) 0 0 12 (6.1)
Other diagnoses 59 (29.4) 0 0 59 (30.2)

Microbiologic Characteristics
PVL-positive 137 (68.2) 0 0 137 (70.3) 0.001
Clindamycin-resistant 57 (28.4) 2 (100) 3 (75) 52 (26.7) 0.01b
Daptomycin MIC . 1 m g/mLc 1 (0.5) 0 0 1 (0.5) 1
Vancomycin MIC $ 2 m g/mLd 63 (31.3) 2 (100) 2 (50) 59 (30.3) 0.07

agr Group 0.009

agrI 158 (78.6) 0 1 (25) 157 (80.5)
agrII 35 (17.4) 2 (100) 3 (75) 30 (15.4)
agrIII 5 (2.5) 0 0 5 (2.6)
agrIV 0 0 0 0
agr nontypeable 3 (1.5) 0 0 3 (1.5)
aContinuous variables are presented as median with interquartile range (IQR); categorical variables are presented as n (%). Categorical variables are compared using Fisher’s
exact test; continuous variables are compared using the Kruskal-Wallis test.
bWhen ceftaroline RS (MIC $ 2 m g/mL) and susceptible are compared, the rates of clindamycin resistance are 83.3% versus 26.7%; P = 0.008.
cDaptomycin MICs determined by Etest.

dVancomycin MICs determined with Etest. No isolate had a vancomycin Etest MIC of .3 m g/mL.

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 TABLE 2 Characteristics of MRSA isolates with high MIC to ceftaroline
Hospitalization Ceftaroline PBP Other notablec agr Clindamycin-
a
Subject Strain Diagnosis Acquisition in prior 90 days Comorbiditiese MIC (ug/mL) CC/ST mutationsb mutationsb SCCmec PVL group resistant
A TCH29587 Endocarditis HA Yes Prematurity, congenital 2 CC5/ST5 II (2A) Negative II Y
diaphragmatic hernia

October 2022 Volume 66 Issue 10

B TCH29768 Chronic CO-HCA No Myelomeningocele 4 CC8/ST8 lytD – Y228F IV (2B) Negative I N
osteomyelitis
C TCH30045 CLABSI CO-HCA Yes CF, lung transplant 8 CC5/ST5 mecA/pbp2a – II (2A) Negative II Y
E447K
D TCH30354 CLABSI CO-HCA Yes Medulloblastoma, 2 CC5/ST1011 II (2A) Negative II Y
Reduced Ceftaroline Susceptibility in Pediatric MRSA

status post autologous

stem cell transplant,
ventriculoperitoneal
shunt
E TCH32569 Endocarditis CO-HCA Yes BMT 2 CC5/ST105 mecR (multiple) II (2A) Negative II Y
F1 TCH32767 CLABSId CO-HCA Yes Prematurity, short gut 0.75 CC5/ST105 mutL II (2A) Negative II Y
(D0) VIII (4A)
F2 TCH32929 CLABSI CO-HCA Yes Prematurity, short gut .32 CC5/ST105 II (2A) Negative II Y
(D36) VIII (4A)
aBased on epidemiologic definitions. HA, hospital-acquired; CO-HCA, community-onset healthcare associated.
bJH1 (CC5/ST5) or TCH1516 (CC8/ST8) were used as the reference genomes for the SNP/Indel analyses. Among CC5 isolates, the average SNP distance was .600.
cNotable mutations included those previously associated with or hypothesized to contribute to ceftaroline RS.

dThis subject was initially treated medically, without central venous line removal.

eCF, cystic fibrosis; BMT, bone marrow transplant.

10.1128/aac.00745-22
Antimicrobial Agents and Chemotherapy

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Reduced Ceftaroline Susceptibility in Pediatric MRSA Antimicrobial Agents and Chemotherapy

Ceftaroline RS was noted in 2.9% of the invasive MRSA cases at Texas Children’s Hospital
(TCH). However, all of the ceftaroline RS isolates occurred in patients without prior ceftaroline
exposure. These findings suggest the potential spontaneous emergence of ceftaroline RS
(6, 7). All ceftaroline RS isolates were from health care-associated infections. Moreover, in
the multivariable analyses, CLABSI and prior MRSA infection were significantly correlated
with ceftaroline RS.
All of the clindamycin-resistant, ceftaroline RS isolates in our study belonged to CC5
and carried agrII (5 out of 5). In a Korean study, agrII S. aureus disproportionately accounted
for ceftaroline RS strains (8). The reasons for the association of CC5/ST5 with ceftaroline
RS are unclear; however, this genotype has previously been associated with health care-
associated infections (9, 10). Likewise, the clinical risk factors for ceftaroline RS could be
considered the same for CC5 MRSA or for health care-associated MRSA, in general.
Ferguson et al. reported a case of a healthy toddler with a ceftaroline-resistant CA-
MRSA infection (7). This case, along with our own data, highlights the need for ceftaroline
susceptibility screening.
WGS revealed the existence of PBP and non-PBP mutations in ceftaroline RS isolates.
The well-described E447K mutation in PBP-2a was identified in one of the resistant iso-
lates, although multiple mutations in PBP-2a are typically described in ceftaroline resist-
ant strains (3). An additional ceftaroline RS isolate had mutations in lytD, encoding a
staphylococcal autolysin involved in peptidoglycan hydrolysis. In previous work, se-
rial exposure of S. aureus to ceftaroline was associated with the emergence of higher
MICs accompanied by lytD mutations (4). One isolate (TCH32569) with ceftaroline RS
had numerous mutations in mecR, a previously described regulator of mecA expres-
sion (11–14). These mutations may have resulted in altered expression of PBP2a con-
tributing to RS, although a mechanistic role cannot be confirmed. One patient with a
ceftaroline-susceptible infection (TCH32767) developed a relapse with a ceftaroline-resist-
ant isolate (TCH32929). Notably, TCH32767 possessed a mutation in mutL, similar to that
reported previously (1); however, while numerous mutations were noted in the resistant
isolate, none occurred in genes associated with PBPs. Thus, the precise mechanism of re-
sistance is unclear in this case. While the number of SNPs/Indels in TCH32929 relative to
TCH32767 is high for this time frame, this is potentially a consequence of alterations in
mutL and impaired DNA proofreading (1); alternatively, these strains may not represent lin-
eal descendants. A number of different non-PBP mutations have been associated with cef-
taroline RS in previous WGS and microbial genome-wide association studies but are of
unclear significance; thus, the mechanism of resistance is uncertain in select cases (15, 16).
Our study has limitations. Foremost, our center may not be reflective of the United States
pediatric population at large. Our retrospective design restricts the degree to which any clinical
risk factor can be linked with ceftaroline RS. Finally, given that not all isolates were subjected
to WGS, we are limited in the degree to which genetic background can be associated with cef-
taroline RS.
In conclusion, ceftaroline RS is rare in pediatric MRSA, occurring in ;3% of invasive
isolates with ,1% exhibiting true resistance. Ceftaroline RS was only seen in health care-asso-
ciated infections, was associated with clindamycin resistance, and was frequently associated
with non-PBP-based mechanisms of resistance.
All invasive MRSA were collected from January 1, 2015 to December 31, 2018, via an IRB
approved surveillance study at Texas Children’s Hospital, Houston, TX, were examined (17).
Cases were classified as community-acquired (CA), community onset health care-associated
(CO-HCA) (18), and hospital-acquired (HA) (19), as previously described. Both CO-HCA and
HA were collectively regarded as health care-associated infections.
CLSI defines ceftaroline susceptible S. aureus isolates as those with a ceftaroline
MIC of #1 m g/mL, ceftaroline-susceptible dose-dependent as those with a ceftaroline
MIC of 2 to 4 m g/mL, and ceftaroline-resistant as those with a ceftaroline MIC of
$8 m g/mL. For the purposes of this study, ceftaroline RS was regarded as a ceftaro-
line MIC of $2 m g/mL. All isolates were screened for ceftaroline susceptibility using

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Reduced Ceftaroline Susceptibility in Pediatric MRSA
Etest. Those with an Etest MIC of $1.5 m g/mL underwent susceptibility testing by
broth dilution. Allergan provided ceftaroline powder.
All isolates underwent a polymerase chain reaction (PCR) for the determination of the
accessory gene regulator (agr) group and of the carriage of Panton Valentine Leukocidin
(PVL) (20–22). The ceftaroline RS isolates underwent whole-genome sequencing (BioProject
PRJNA675653) using an Illumina MiSeq platform with bioinformatic analyses performed as
previously described (23–25).
SUPPLEMENTAL MATERIAL
Supplemental material is available online only.
SUPPLEMENTAL FILE 1, PDF file, 0.1 MB.
ACKNOWLEDGMENTS
Ceftaroline powder was provided by Allergan through an investigator initiated research
program (J.C.M.). Allergan had no direct role in the conduct of the study or in the data analysis.
J.C.M. receives grant funding from the Agency for Healthcare Research and Quality (AHRQ
R01HS026896). J.C.M. is the local principal investigator on a multicentre clinical trial sponsored
by Nabriva Therapeutics that is unrelated to the work under consideration. S.L.K. and K.G.H.
receive research support through Pfizer. A.R.F. receives grant funding through NIAID
R01AI25216, R21AI153663, R21AI142126, and R21AI59059.
These data were presented in part at the 2020 Infectious Diseases Society of America
IDWeek Meeting.
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