EDITORIALS
SC
Can Rapid Molecular Streptococcus pyogenes
Testing Lead to Better Antimicrobial
Stewardship for Acute Pharyngitis?
Erin H. Graf1,2*
Increasing resistance to antimicrobials is presently
one of the largest public health challenges domesti-
cally and abroad. Overprescription of antibiotics for
inappropriate indications is a major driver in this
global crisis. In the US, acute respiratory conditions,
especially pharyngitis, are one of the largest culprits,
with roughly half of antibiotic prescriptions deemed
unnecessary (1). This is because most cases of phar-
yngitis are of viral etiology (2). Even the most com-
mon bacterial cause, Streptococcus pyogenes, results
in self-limiting infection in the vast majority of cases in
developed countries (3). However, the small possibil-
ity of S. pyogenes dissemination or severe sequelae,
including acute rheumatic fever or glomerulonephri-
tis, leaves guidance in favor of antibiotic treatment
for S. pyogenes pharyngitis (2). Current recommenda-
tions guide providers to test for S. pyogenes pharyn-
gitis via rapid antigen testing and, if negative, because
of the low sensitivity of rapid antigen assays, follow
with bacterial culture for children and adolescents 3
to 21 years of age. A positive result by either antigen
testing or culture requires treatment with penicillin
or amoxicillin. However, because of frequent self-/
parent-reported allergies to these first-line agents,
broad-spectrum treatment with macrolides is on the
rise, thus promoting resistance (4).
Given that only microbiologically proven S. pyo-
genes pharyngitis is indicated for treatment, the
1
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA; 2Department of Pathology and Labora-
tory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
*Address correspondence to the author at: 3401 Civic Center Blvd., Philadelphia, PA 19104. E-mail egraf@email.chop.edu.
DOI: 10.1373/jalm.2019.029983
© 2019 American Association for Clinical Chemistry
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140 JALM | 140 –142 | 04:02 | September 2019
exact reasons for overprescription for acute phar-
yngitis are not known. One likely possibility is that
clinicians are aware of the limited sensitivity of the
rapid antigen test and perhaps do not want to wait
the additional 24 to 48 h for culture results before
prescribing. A more sensitive, yet still rapid, diag-
nostic test to replace culture could, in theory, de-
crease overtreatment if negative results could be
trusted. New rapid molecular S. pyogenes tests are
emerging to possibly fill this diagnostic void (5).
Several of these tests are now waived by CLIA,
which means they can be performed at the point of
care by medical staff, resulting in turnaround times
comparable with rapid antigen testing. Although
the manufacturers' package inserts claim high sen-
sitivity and specificity compared with culture, there
are few data on their performance beyond this.
In this issue of The Journal of Applied Laboratory
Medicine, Parker et al. (6) evaluate 2 CLIA-waived
and 1 Food and Drug Administration-cleared/
moderate complexity rapid molecular assays for
diagnosis of S. pyogenes pharyngitis. Their study
includes a majority (65%) of pediatric patients dur-
ing the height of S. pyogenes pharyngitis season,
although clinical details were not provided. When
compared with culture, all 3 molecular tests per-
formed with high sensitivity (95%–100%) and spec-
ificity (97.4%–100%). This is in line with similar

studies evaluating 2 of the 3 tests, individually,
compared with culture (7, 8) and a third CLIA-
waived manufacturer not included in this study (9,
10). Importantly, this is the first study to evaluate
the Cepheid Xpert Xpress Strep A test and com-
pare these 3 rapid molecular tests head to head.
The results from this study support use of any 1 of
these tests as a replacement for antigen testing
and culture to speed diagnosis and ideally affect
antimicrobial stewardship.
There are several concerns with replacing both
rapid antigen testing and culture with rapid molec-
ular S. pyogenes testing. The first is that molecular
testing may prove to be more sensitive than cul-
ture and, thus, detect colonized carriers who are
not at risk for developing disease and/or nonviable
organisms that are shed after adequate treat-
ment. Either scenario could lead to inappropriate
management of a positive result. In their study,
Parker et al. (6) identified only a single positive pa-
tient of 39 culture-negative samples evaluated.
This patient was positive by 2 molecular assays
and, thus, considered to be a true positive; how-
ever, as clinical history was not provided, it cannot
be established whether this patient had symptoms
consistent with S. pyogenes pharyngitis. In other
studies, assessing rapid molecular S. pyogenes as-
says individually, similar specificities were shown,
suggesting increased detection of colonization
compared with culture is not a concern. This in-
cludes at least 1 study that was performed outside
the peak of S. pyogenes pharyngitis season, but
during respiratory virus season, when detection of
colonization might be more frequent, with a 97.8%
specificity compared with culture (7). One recent
study, using a Food and Drug Administration-
cleared isothermal amplification system that was
not evaluated in the Parker et al. article, showed
increased rates of S. pyogenes detection compared
with culture in healthy children (11). However, as
the studies referenced above have not shown in-
creased rates of detection, these findings may be
unique to the particular platform. Detection of
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September 2019 | 04:02 | 140 –142 | JALM
EDITORIALS
nonviable organisms after adequate treatment is a
possibility, and testing should be carefully consid-
ered if treatment failure is a concern. In 1 study,
20% of individuals treated for S. pyogenes pharyn-
gitis continued to test positive by PCR at 14 to 18
days after the initial positive test (12).
The second concern is the point-of-care adop-
tion of a molecular assay. Despite being waived by
CLIA, these are complex tests that require different
considerations than rapid antigen testing, includ-
ing amplicon contamination and inhibition/inter-
ference. In a recent study of the Roche Liat S.
pyogenes rapid molecular test (13), contamination
was not observed and test failure rates did not
exceed manufacturer expectations in an end user
setting. More studies with different assays and in
different settings are needed to fully evaluate
these concerns.
Finally, a third concern is reimbursement for a
more expensive test in place of rapid antigen test-
ing and culture. The true financial benefit of rapid
molecular testing is the linkage to appropriate an-
tibiotic usage, which can be difficult to empirically
measure. There is evidence that S. pyogenes molec-
ular testing is associated with lower usage of anti-
biotics in acute pharyngitis (5, 14). More studies are
needed to assess the impact of rapid molecular S.
pyogenes testing on antimicrobial stewardship.
In summary, the article by Parker et al. provides
much needed data to check at least 1 of the boxes
required for adoption of rapid molecular testing
for S. pyogenes pharyngitis. That is, the ability for a
clinician to have high confidence in the positive
and negative predictive value of the test results
and, thus, prescribe antibiotics accordingly. The
next revision of the Infectious Disease Society of
America's guidelines for S. pyogenes pharyngitis will
no doubt take these newly available methods of
testing into account with regard to testing and
treatment guidance. Further boxes to be checked
include impact on antimicrobial stewardship and
how that relates to potential cost savings when
balancing a more expensive diagnostic test.
141
EDITORIALS

Author Contributions: The author confirms they have contributed to the intellectual content of this paper and have met the following
4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b)
drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for
all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately
investigated and resolved.

Author’s Disclosures or Potential Conflicts of Interest: The author declared no potential conflicts of interest.

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