Sequential Intravenous-Oral Therapy for Pediatric Streptococcus anginosus Intracranial Infections

Abstract

Introduction
Streptococcus anginosus group is a common cause of pediatric intracranial infections but treatment recommendations, including use of oral therapy, are poorly defined.

Methods
We performed a retrospective review from 2004-2019 of all patients with Streptococcus anginosus group pyogenic intracranial infections at Children’s Hospital Colorado, highlighting patients transitioned to oral therapy. The primary endpoint was worsening infection necessitating intravenous antibiotics or a source control procedure after transition to oral therapy.

Results
Of 107 patients with Streptococcus anginosus intracranial infections, 61 were transitioned to exclusive oral therapy after a median intravenous duration of 37 days, overwhelmingly with a levofloxacin-based regimen. Only one failure was noted in a patient who did not fill their prescription. Patients with epidural infections were more likely to be transitioned to oral therapy within the first 28 days of treatment (defined as “early”). Patients with parenchymal infections, bacteremia, co-pathogens, higher inflammatory markers, and requiring >1 source control procedure were less likely to be transitioned early to oral therapy. Complications of a central catheter and/or intravenous medications contributed to 56% of oral transitions.

Conclusions
Levofloxacin-based oral regimens were effective and well-tolerated. Patients with less severe infections were more likely to be transitioned early to oral therapy. Criteria for transitioning patients to oral antibiotics for intracranial infections should be established to minimize risks inherent with central catheters.

Full text

Oral Antibiotics for Intracranial Infections • OFID • 1
Open Forum Infectious Diseases
MAJOR ARTICLE
Received 4 August 2021; editorial decision 6 December 2021; accepted 8 December 2021; pub-
lished online 6 January 2022.
Correspondence: Daniel S. Dodson, MS, MD, Section of Pediatric Infectious Diseases,
Department of Pediatrics, University of California, Davis, 2516 Stockton Blvd, Sacramento, CA
95817, USA (dsdodson@ucdavis.edu).
Open Forum Infectious Diseases®2021
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases
Society of America.This is an Open Access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/
licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the
work, in any medium, provided the original work is not altered or transformed in any way, and that
the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
https://doi.org/10.1093/ofid/ofab628
Sequential Intravenous-Oral erapy for Pediatric
Streptococcus anginosus Intracranial Infections
Daniel S.Dodson,1,2, Heather R.Heizer,2 and James T.Gaensbauer2,3,
1Section of Pediatric Infectious Diseases, Department of Pediatrics, University of California, Davis, Sacramento, California, USA, 2Section of Infectious Diseases, Department of Pediatrics,
University of Colorado School of Medicine, Aurora, Colorado, USA, and 3Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester,
Minnesota, USA
Background. Streptococcus anginosus group is a common cause of pediatric intracranial infections but treatment recommenda-
tions, including use of oral therapy, are poorly dened.
Methods. We performed a retrospective review from 2004 to 2019 of all patients with S anginosus group pyogenic intracranial
infections at Children’s Hospital Colorado, highlighting patients transitioned to oral therapy. e primary endpoint was worsening
infection necessitating intravenous antibiotics or a source control procedure aer transition to oral therapy.
Results. Of 107 patients with S anginosus intracranial infections, 61 were transitioned to exclusive oral therapy aer a median
intravenous duration of 37 days, overwhelmingly with a levooxacin-based regimen. Only 1 treatment failure was noted in a patient
who did not ll their prescription. Patients with epidural infections were more likely to be transitioned to oral therapy within the
rst 28 days of treatment (dened as “early”). Patients with parenchymal infections, bacteremia, co-pathogens, higher inammatory
markers, and requiring >1 source control procedure were less likely to be transitioned early to oral therapy. Complications of a cen-
tral catheter and/or intravenous medications contributed to 56% of oral transitions.
Conclusions. Levooxacin-based oral regimens were eective and well tolerated. Patients with less severe infections were more
likely to be transitioned early to oral therapy. Criteria for transitioning patients to oral antibiotics for intracranial infections should
be established to minimize risks inherent with central catheters.
Keywords. intracranial infection; levooxacin; oral therapy; Streptococcus anginosus.
Pediatric intracranial pyogenic infections are an uncommon but
morbid condition [1–3]. Among such infections, Streptococcus
anginosus group is the most frequently identified organism in
several case series with contiguous sources such as sinusitis and
mastoiditis frequent predisposing conditions [4–9]. Treatment re-
commendations for these infections vary considerably and no pe-
diatric guidelines exist. Suggested length of antimicrobial therapy
varies from 2 weeks to beyond 3 months, with 4–8 weeks being
most common and recommended by the Working Party in the
United Kingdom in 2000 [2, 7, 8, 10–16]. Effectiveness and timing
of oral therapy are debated, though patients have been successfully
transitioned to oral antibiotics at 1–2 weeks of therapy [1, 17–21].
Oral therapy eliminates the risks of a central catheter in-
cluding bloodstream infection, venous thrombosis, and
catheter malfunction, and is now routine for conditions pre-
viously treated with prolonged intravenous (IV) therapy such
as pediatric osteomyelitis [22]. Given the advantages of oral
therapy, we sought to identify patients with S anginosus group
purulent intracranial infections and analyze characteristics and
outcomes of patients transitioned to oral therapy.
METHODS
Study Population
We performed a retrospective review of pyogenic intracranial
infections caused by S anginosus group at Children’s Hospital
Colorado from January 2004 through February 2019 for pa-
tients 21 years of age or younger. A list of all positive cultures for
S anginosus group from any source was obtained from an elec-
tronic medical record–based database. Medical records of these
patients were individually reviewed for inclusion. Inclusion cri-
teria were radiologic evidence of an infected intracranial paren-
chymal, subdural, or epidural fluid collection AND a positive
culture for S anginosus group from an intracranial source, spe-
cific extracranial sources (sinus, scalp abscess, orbit), or from
blood. Patients with “dural enhancement” or similar radiologic
findings not clearly a fluid collection were excluded. Our labo-
ratory identifies S anginosus to the group level, so species data
were not available.
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2 • OFID • Dodson et al
Data Collection and Definitions
We reviewed inpatient clinical course, outpatient infectious
disease clinic notes, and other available encounters for demo-
graphic, clinical, radiologic, laboratory, and outcomes data. All
outpatients were followed in the infectious disease clinic unless
lost to follow-up. Location of intracranial infection, presumed
primary source of infection, and infectious complications were
determined from radiology reports and medical documenta-
tion. Co-pathogens were defined as additional organisms found
in cultures except coagulase-negative Staphylococcus spp from
blood, which was considered a contaminant. Beginning of
therapy was defined as the date of the last intracranial source
control procedure or, if no source control procedure was done,
the beginning of directed antibiotic therapy. Sinus aspiration,
orbital abscess drainage, and other extracranial procedures
were not considered intracranial source control procedures.
Date of oral transition was defined as the first day the patient
was treated exclusively with oral antibiotics. Data were stored
using the REDCap electronic database [23].
Endpoints and Analysis
The primary endpoint was failure of oral therapy, de-
fined as worsening infection while on oral antibiotics re-
quiring reinitiating IV therapy or a source control procedure.
Additional endpoints were timing of transition to oral therapy
and reason for transition to oral therapy. Transition to exclu-
sive oral therapy was defined as “early” if done at <28 days
from the beginning of therapy and “late” if done at ≥28 days.
Comparisons of endpoints with categorical variables were done
using Fisher exact test. Comparisons using continuous variables
were done using Wilcox-Mann-Whitney test. Significance was
defined as P < .05. Statistical analysis was done using Stata soft-
ware version 16. Patients with missing data were excluded from
analysis using the missing variable (eg, patients without a repeat
C-reactive protein [CRP] prior to starting oral therapy were
not included in calculating median CRP prior to oral therapy).
The lowest CRP reported by our laboratory is <5mg/L. Values
<5mg/L were treated as 5mg/L for statistical analysis.
is study was approved by the Colorado Multiple
Institutional Review Board and was deemed exempt due to ret-
rospective nature.
RESULTS
Patient Population
We identified 1221 unique patients with any positive culture
for S anginosus group. Of these, 107 met inclusion criteria, 45
completed treatment with IV therapy, 61 were transitioned to
exclusive oral therapy, and 1 patient was lost to follow-up imme-
diately after hospital discharge (excluded from comparative ana-
lyses as oral transition is unknown). One patient, a 3-year-old
with a subdural abscess treated intravenously, died due to com-
plications of a massive stroke within 1 week of diagnosis. The
Table 1. Patient Demographics and Infection Characteristics (N = 107)
Characteristic No. (%)
Overall 107 (100)
Age, y, median (IQR) 11.5 (8.1–13.8)
Female sex 37 (35)
Race
American Indian or Alaskan Native 1 (1)
Asian 6 (6)
Black or African American 9 (8)
White 76 (71)
Other 12 (11)
Not stated 3 (3)
Ethnicity
Hispanic or Latino 19 (18)
Not Hispanic or Latino 84 (79)
Other 1 (1)
Not stated 3 (3)
Location of infection
Epidural collection 61 (57)
Subdural collection 42 (39)
Parenchymal collection 33 (31)
Mutually exclusive intracranial diagnoses
Epidural collection only 42 (39)
Subdural collection only 20 (19)
Parenchymal collection only 20 (19)
Epidural and subdural collection 12 (11)
Epidural and parenchymal collection 3 (3)
Subdural and parenchymal collection 6 (6)
Epidural, subdural, and parenchymal collection 4 (4)
Presumed source of infection
Sinus 78 (73)
Otogenic 8 (7)
Trauma 3 (3)
Hematogenous or unknown 18 (17)
Infectious complications
Dural venous sinus thrombosis 14 (13)
Cavernous venous sinus thrombosis 5 (5)
Orbital abscess 16 (15)
Osteomyelitis 31 (29)
Bacteremia 14 (13)
Coinfections
Any coinfection 64 (60)
Any coinfections except CoNS 52 (49)
MSSA 15 (14)
MRSA 2 (2)
CoNS 27 (25)
Other Streptococcus spp 12 (11)
Other gram-positive aerobes 5 (5)
Gram-negative aerobes 15 (14)
Gram-positive anaerobes 12 (11)
Gram-negative anaerobes 10 (9)
Year diagnosed
2011 or before 34 (32)
2012–2015 37 (35)
2016 or after 36 (34)
Source control procedures
Any 64 (60)
>1 16 (15)
Abbreviations: CoNS, coagulase-negative staphylococci; IQR, interquartile range; MRSA, methicillin-
resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus.
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Oral Antibiotics for Intracranial Infections • OFID • 3
median patient age was 11.5 years and 35% of patients were fe-
male (Table 1). Differences in treatment based on demographics
were not statistically significant. Of the 61 patients transitioned
to oral antibiotics, 7 (11%) were transitioned at <14 days from
initiation of therapy, 13 (21%) between 14 and 27 days, 15 (25%)
between 28 and 41 days, and 26 (43%) at ≥42 days.
Outcomes
Of the 61 patients treated with oral therapy, 1 patient met cri-
teria for failure. This patient had an epidural abscess with source
control and was initially treated with ceftriaxone, metronida-
zole, and vancomycin. They were prescribed oral levofloxacin
and metronidazole at ≥42 days of therapy but did not fill their
prescription and subsequently developed worsening infection
necessitating restarting IV antibiotics and a source control
procedure. A second patient restarted IV ceftriaxone after a
presumed drug reaction to oral levofloxacin but did not have
worsening infection. No other patient needed to restart IV anti-
biotics after oral transition, though 5 patients were lost to fol-
low-up after oral transition (4 patients transitioned early vs 1
patient transitioned late; P = .04) prior to completion of therapy.
Of note, 1 patient treated exclusively with IV therapy needed
to restart antibiotics 4 months after therapy completion due a
bone flap infection but did not have recrudescence of intracra-
nial infection. No other patients are known to have restarted
antibiotics after therapy completion.
e median total duration of therapy was 59 days (73 days for
those treated orally vs 50 days for those treated exclusively IV;
P < .001). ose transitioned early to oral therapy had a median
total duration of 48 days (33 days orally) compared to 83 days
(35 days orally) for those transitioned later (P < .001 for total
duration, not signicant for oral duration).
Diagnoses
Of the 107 overall patients, an epidural fluid collection (61 pa-
tients [57%]) was the most common intracranial diagnosis, fol-
lowed by subdural and parenchymal infections (39% and 31%,
respectively) (Table 1). Though transition to oral therapy was
not statistically different between those with epidural, subdural,
and parenchymal fluid collections, patients with epidural col-
lections were more likely to be treated with early oral therapy
(P < .001) and patients with parenchymal infections were less
likely to treated with early oral therapy (P =.006) (Table 2). Most
infections were attributed to complicated sinusitis (78 patients
[73%]). Infectious complications included dural venous sinus
thrombosis (14 patients [13%]), cavernous venous sinus throm-
bosis (5 patients [5%]), orbital abscesses (16 patients [15%]),
osteomyelitis (31 patients [29%]), and bacteremia (14 patients
[13%]) (Table 1). Patients with bacteremia were less likely to be
treated with early oral therapy (P = .04) (Table 2). Otherwise,
differences in treatment course by complication were not sig-
nificant, though sample sizes were low.
Microbiology
Of the 107 overall patients, the most common co-pathogen
was coagulase-negative Staphylococcus species (27 patients
[25%]). Other organisms included methicillin-susceptible
Staphylococcus aureus (MSSA) (15 patients [14%]), gram-neg-
ative aerobes (15 patients [14%]), other Streptococcus spp (12
patients [11%]), and gram-positive anaerobes (12 patients
[11%]) (Table 1). Two patients (2%) had methicillin-resistant
S aureus (MRSA) and were treated entirely with IV therapy. No
Streptococcus pyogenes was found. Patients with a co-pathogen
were less likely to transition to early oral therapy (P = .03). This
difference did not remain significant if coagulase-negative
Staphylococcus was excluded (Table 2).
Our S anginosus group isolates were 96% susceptible to pen-
icillin (76 isolates tested), 99% susceptible to ceriaxone (72
isolates tested), 100% susceptible to vancomycin (75 isolates
tested), and 100% susceptible to levooxacin (25 isolates tested).
Levooxacin susceptibility was not associated with transition to
oral therapy.
Laboratory and Imaging Data
Peak CRP and erythrocyte sedimentation rate (ESR) values, and
values prior to oral transition (obtained at a median of 30 days
of therapy), are shown in Table 3. The median peak CRP was
110 mg/L and decreased to <5 mg/L in those transitioned to
oral therapy. Of the 58 patients transitioned to oral therapy with
a CRP value prior to transition, 51 (88%) had a CRP ≤10mg/L
at the time of oral transition. The median peak ESR was 67mm/
hour and decreased to 12mm/hour in those transitioned to oral
therapy. Of the 57 patients transitioned to oral therapy with an
ESR obtained prior to transition, 41 (68%) had an ESR ≤20mm/
hour at the time of transition. No difference in peak CRP or ESR
was seen when comparing those transitioned to oral therapy to
those treated with exclusive IV therapy. However, patients tran-
sitioned to early oral therapy had a lower peak CRP (61mg/L
vs 157mg/L; P = .01) and ESR (38mm/hour vs 77mm/hour;
P = .04) than those transitioned later. Conversely, patients tran-
sitioned early to oral therapy had higher CRP and ESR at the
time of oral transition than those transitioned later.
Of the 61 patients transitioned to oral therapy, 44 (72%) had
repeat imaging prior to transition (excluding immediate post-
operative imaging). Of these 44 patients, 12 (27%) had resolu-
tion or near resolution of intracranial purulence, 29 (66%) had
improvement, 2 (5%) were stable, and 1 (2%) appeared worse.
Repeat imaging done about 1 week aer oral transition showed
interval improvement in this patient with worsening imaging.
Initial Therapy
The most used IV antibiotics in the 107 overall patients were
ceftriaxone (102 patients [95%]), metronidazole (102 patients
[95%]), and vancomycin (103 patients [96%]). At least 1 intracra-
nial source control procedure was performed in 64 patients (62%).
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4 • OFID • Dodson et al
Table 2. Patient Characteristics Stratified by Treatment Course (n = 106)
Characteristic (No.)
Treatment Group
Transitioned to Oral
<28 Days (n = 20)
Transitioned to Oral
≥28 Days (n = 41)
P Value (<28
vs ≥28 Days)
All IV Therapy
(n = 45)
P Value (Any
Oral vs IV) No. (Row %) No. (Row %) No. (Row %)
Location of infection
Epidural collection (61) 19 (31) 20 (33) < .001 22 (36) .16
Subdural collection (42) 4 (10) 19 (45) .06 19 (45) .69
Parenchymal collection (32) 1 (3) 16 (50) .006 15 (47) .67
Mutually exclusive intracranial diagnoses
Epidural collection only (42) 15 (36) 13 (31) .002 14 (33) . 16
Subdural collection only (20) 1 (5) 7 (35) .25 12 (60) .09
Parenchymal collection only (19) 0 (0) 9 (47) .02 10 (53) .44
Epidural and subdural collection (12) 3 (25) 5 (42) 1. 0 4 (33) .55
Epidural and parenchymal collec-
tion (3)
1 (33) 0 (0) .33 2 (67) .57
Subdural and parenchymal collec-
tion (6)
0 (0) 5 (83) . 16 1 (17) .24
Epidural, subdural, and paren-
chymal collection (4)
0 (0) 2 (50) 1. 0 2 (50) 1.0
Presumed source of infection
Sinus (78) 17 (22) 29 (37) .34 32 (41) .66
Otogenic (8) 2 (25) 2 (25) .59 4 (50) .72
Trauma (3) 0 (0) 2 (67) 1. 0 1 (33) 1.0
Hematogenous or unknown (17) 1 (6) 8 (47) .25 8 (47) .79
Infectious complications
Dural venous sinus thrombosis
(14)
2 (14) 7 (50) .70 5 (36) .77
Cavernous venous sinus throm-
bosis (5)
0 (0) 1 (20) 1. 0 4 (80) .16
Orbital abscess (16) 5 (31) 7 (44) .51 4 (25) . 17
Osteomyelitis (31) 6 (19) 12 (39) 1. 0 13 (42) 1.0
Bacteremia (14) 0 (0) 8 (57) .04 6 (43) 1.0
Co-pathogens
Any co-pathogen (63) 7 (11) 27 (43) .03 29 (46) .43
Any co-pathogen except CoNS
(51)
6 (12) 21 (41) .17 24 (47) .43
MSSA (15) 3 (20) 6 (40) 1. 0 6 (40) 1.0
MRSA (2) 0 (0) 0 (0) NA 2 (100) .18
CoNS (27) 2 (7) 14 (52) .06 11 (41) 1. 0
Other Streptococcus spp (12) 2 (17) 4 (33) 1. 0 6 (50) . 76
Other gram-positive aerobes (5) 1 (20) 3 (60) 1. 0 1 (20) .39
Gram-negative aerobes (15) 1 (7) 7 (47) .25 7 (47) .78
Gram-positive anaerobes (11) 0 (0) 5 (45) .16 6 (55) .52
Gram-negative anaerobes (9) 1 (11) 4 (44) 1. 0 4 (44) 1. 0
Year diagnosed
2011 or before (34) 2 (6) 11 (33) .19 20 (61) .02
2012–2015 (37) 10 (27) 14 (38) .27 13 (35) .30
2016 or after (36) 8 (22) 16 (44) 1. 0 12 (33) .21
Source control procedures
Any (64) 9 (14) 28 (44) .10 26 (41) .84
>1 (16) 0 (0) 9 (56) .02 7 (44) 1. 0
Restarted IV antibiotics after oral
transition (2)
0 (0) 2 (100) 1.0 NA NA
Loss to follow-up after oral transi-
tion (5)
4 (80) 1 (20) .04 NA NA
Fisher exact test was used to compare patients transitioned to oral therapy at <28 days vs those transitioned at ≥28 days and to compare patients treated with oral therapy vs those treated
with exclusive IV therapy. Statistically significant differences (P < .05) are shown in bold. One patient was lost to follow-up immediately after discharge and is not included in this table as
oral transition is unknown.
Abbreviations: CoNS, coagulase-negative staphylococci; IV, intravenous; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; NA, not
applicable.
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Oral Antibiotics for Intracranial Infections • OFID • 5
Having at least 1 source control procedure was not associated with
treatment group (Table 2). More than 1 source control procedure
was done on 16 patients (15%). No patients with multiple source
control procedures were treated with early oral therapy compared
to 9 of the 41 patients (22%) transitioned later (P = .02). Patients
diagnosed in 2011 or before were less likely to be transitioned to
oral therapy than those diagnosed after 2011 (P = .02).
Oral Therapy
Complications associated with IV therapy contributed to 34
(56%) of the 61 oral transitions including peripherally inserted
central catheter complications (10 patients [16%]), hematologic
abnormalities presumed secondary to an IV antibiotic (19 pa-
tients [31%]), and other presumed medication reactions to an
IV antibiotic (11 patients [18%]). The most used oral antibiotic
was levofloxacin (56 patients [92% of regimens]), followed by
metronidazole (47 patients [77%]). Other oral antibiotics in-
cluded ciprofloxacin (1 patient [2%]), amoxicillin-clavulanate
(2 patients [3%]), doxycycline (2 patients [3%]), trimethoprim-
sulfamethoxazole (3 patients [5%]), clindamycin (7 patients
[12%]), and linezolid (1 patient [2%]). Combination therapy
was common, with levofloxacin and metronidazole being used
in 45 patients (74%). Five patients (9%) stopped levofloxacin, at
least in part due to a presumed drug reaction, including 1 pa-
tient with arthralgias.
Levooxacin dosing varied based on age, with the most
common dose being 500mg/day (used in 32 regimens [57%]).
At our center, levooxacin is commonly dosed at 20mg/kg/day
divided every 12 hours for those <5 years of age, 15mg/kg/day
divided every 12 hours for those 5–10 years of age, and 10mg/
kg daily for children >10 years of age (maximum dose 500 or
750mg), without specic guidelines for intracranial infections.
Oral Therapy at <14 Days
Seven patients were transitioned to oral therapy prior to 14
days of treatment. Statistical comparisons were not attempted
due to the small number of patients. Their ages ranged from
7 to 14 years (median, 11 years). Five (71%) of these patients
had an epidural collection, 1 (14%) had a subdural collection,
and 1 (14%) had an epidural and subdural collection. Six (86%)
infections were presumed to have originated from the sinuses
and 1 (14%) was otogenic. Three (43%) were associated with a
periorbital abscess and none were associated with dural venous
sinus thrombosis, cavernous sinus thrombosis, osteomyelitis, or
bacteremia. Four patients (57%) had a coinfection. Identified
co-pathogens were MSSA, Streptococcus mitis, coryneform bac-
teria, coagulase-negative staphylococci, and Fusobacterium (1
patient each). Three patients (43%) had a source control pro-
cedure. Peak CRP ranged from 24mg/L to 283mg/L (median,
128mg/L); peak ESR ranged from 25mm/hour to 94mm/hour
(median, 42mm/hour). Median CRP and ESR before oral tran-
sition were 30mg/L (6 patients [range, 5–89]) and 45mm/hour
(5 patients [range, 14–81]), respectively. Patients were treated
for a median of 42 days (range, 16–92 days). Two patients were
lost to follow-up prior to completion of therapy. No patients
were known to have failed oral therapy.
DISCUSSION
Only a single patient out of 61 had worsening of intracranial
infection after transition to oral therapy, and this patient did
not fill their prescription. Such success is consistent with prior
series demonstrating oral transition as early as 2 weeks [24–27].
More recently, a large retrospective study in the United Kingdom
showed successful transition to oral therapy in 61 patients,
though these were not exclusively S anginosus and the details of
transition to oral therapy were not the focus of the study [28].
Our typical patient was a middle-school-aged boy with infec-
tion presumed to have originated from sinuses, initially treated
with ceriaxone, metronidazole, and vancomycin, consistent
with prior studies [12, 29]. Patients transitioned early to oral
therapy had less severe infection as evidenced by more frequent
epidural infections, less frequent parenchymal infections, less
frequent bacteremia, lower peak inammatory markers, and
not requiring more than a single source control procedure. No
parenchymal infections were present in those transitioned to
oral therapy before 14 days. is reduced severity of infection is
also reected in the total duration of therapy, which was shorter
in patients transitioned early to oral therapy compared to those
transitioned later. ose transitioned late to oral therapy es-
sentially had normalization of inammatory markers, whereas
those transitioned early (and particularly <14 days), did not
Table 3. Patient Laboratory Values Stratified by Treatment Course
Laboratory Data
Transitioned to Oral
<28 Days
Transitioned to Oral
≥28 Days
P Value (<28
vs ≥28 Days) All IV Therapy
P Value (Any
Oral vs IV)
Highest CRP value, mg/L n = 20; 61 (25–128) n = 41; 157 (63–254) .01 n = 45; 120 (42–213) .70
CRP prior to oral transition, mg/L n = 18; <5 (<5–14) n = 40; <5 (<5–<5) .04 NA NA
Highest ESR value, mm/hour n = 20; 38 (25–68) n = 40; 77 (44–95) .01 n = 45; 67 (44–92) .67
ESR prior to oral transition, mm/hour n = 17; 18 (9–36) n = 40; 9 (5–18) .02 NA NA
Data are shown as No.; median (interquartile range) unless otherwise indicated. Wilcox-Mann-Whitney test was used to compare patients transitioned to oral therapy at <28 days vs those
transitioned at ≥28 days and to compare patients treated with oral therapy vs those treated with exclusive IV therapy. Statistically significant differences (P < .05) are shown in bold. The
lowest CRP reported by our laboratory is <5mg/L; such values were treated as 5 for statistical analysis.
Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IV, intravenous; NA, not applicable.
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6 • OFID • Dodson et al
have time for complete normalization of inammatory markers,
suggesting that complete normalization of inammatory
markers is not a prerequisite to oral transition. Most patients
showed imaging improvement or resolution of intracranial
ndings. Notably, 20% of patients with MSSA coinfection tran-
sitioned to oral therapy at <28 days, suggesting that MSSA is
not a contraindication to early oral therapy. Many patients with
MSSA coinfection had targeted antistaphylococcal therapy for a
least part of their antibiotic regimen (eg, nafcillin, doxycycline,
trimethoprim-sulfamethoxazole, and linezolid). Only 2 patients
had MRSA (both treated exclusively intravenously).
Most patients in our study were transitioned to oral therapy,
at least in part, due to central line complications or intoler-
ance of an IV antibiotic. Our results suggest that completion of
therapy with IV antibiotics is not necessary for many patients,
and the risk-benet consideration may favor transition to oral
therapy during their treatment course. Patients transitioned to
oral therapy at ≥28 days had a median duration of therapy 33
days longer than those maintained on IV therapy. e reasons
for this dierence are unclear but may either reect the use of
oral therapy to lengthen total duration or a desire to “compen-
sate” for oral antibiotics with longer a duration. However, as
patients in our study on oral therapy did well, such compensa-
tion may be unnecessary, and use of oral antibiotics to extend
therapy beyond resolution of infection is inappropriate.
Levooxacin was the most used oral antibiotic in our series.
Medical documentation did not provide insight into if other oral
medications were considered. ough data are lacking on dier-
ential penetration of levooxacin into epidural, subdural, and pa-
renchymal collections, no dierence in outcomes between abscess
sites was seen in our series. Levooxacin has favorable pharma-
cokinetic and pharmacodynamic characteristics for the treat-
ment of central nervous system (CNS) infections, including those
that are deep or parenchymal. e uoroquinolones are highly
orally absorbed and accumulate in multiple tissues, abscesses,
and phagocytes at levels above serum concentrations [30–33].
Levooxacin is lipophilic, which promotes CNS penetration, and
high cerebrospinal uid levels have been demonstrated for both
inamed and noninamed meninges [34–36]. Levooxacin is an
eective component of treatment regimens for CNS tuberculosis
[37–39]. Interestingly, susceptibility to levooxacin was unavail-
able for many patients. ough levooxacin resistance appears
rare, requesting susceptibility at the time of diagnosis is prudent
if oral transition is anticipated [40, 41].
We make special note of the 2 patients who did require
reinitiation of IV therapy aer oral transition. While unable
to draw conclusions from a single patient, worsening infection
in the patient who did not ll their oral prescription suggests
that not all patients transitioned to oral therapy would have
done well without continued therapy, though as many patients
were treated with prolonged IV therapy before oral transition,
many may have done well without additional antibiotics. By
transitioning to oral therapy, families may be tempted to con-
clude that the infection is no longer as “serious”. is is also sug-
gested by the 5 patients lost to follow-up prior to completion
of oral therapy. erefore, when transitioning to oral therapy,
providers should reinforce the importance of adherence and
avoid implying that oral transition represents de-escalation.
e second patient was restarted on IV therapy due to a pre-
sumed reaction to levooxacin. Intolerance of levooxacin was
uncommon and less frequent than intolerance of IV medica-
tions (though challenging to directly compare given dierence
in duration and drug combinations). Encouragingly, no in-
stances of tendon rupture, adverse mental health eects, or hy-
poglycemic coma (concerns prompting the US Food and Drug
Administration to warn against routine uoroquinolone use for
sinusitis, bronchitis, and urinary tract infection) were docu-
mented, though 1 patient had arthralgias.
Generalizability of our ndings is limited by the retrospective
study design, which introduces inherent selection bias regarding
which patients were transitioned to oral therapy. Additionally, as
this study was retrospective, there is signicant heterogeneity the
precise timing of oral transition—for example, between patients
with epidural and deeper infections—which prevents a precise
determination of when an oral transition can safely occur in
all circumstances. We note that many patients completed pro-
longed IV antibiotics prior to oral transition, and so additional
treatment may not have been necessary for many patients tran-
sitioned to oral antibiotics, notwithstanding the patient who
failed treatment aer not lling their prescription. Outcome as-
sessments were further limited by data obtainable from the elec-
tronic medical record and represent success through the end of
therapy, except for the 5 patients lost to follow-up prior to com-
pletion. While most patients had subsequent encounters aer
therapy completion without evidence of recrudescence of intra-
cranial infection, this was not able to be systematically assessed,
so it is possible we did not capture failure aer completion of
therapy or in the 5 patients lost to follow-up. Likewise, we did
not have complete data to assess neurologic outcomes or power
to compare patients with uncommon conditions such as MRSA
coinfection or cavernous sinus thrombosis.
Other limitations include considering coagulase-negative
Staphylococcus as a co-pathogen rather than a contaminant with
the understanding that interpretation of coagulase-negative
Staphylococcus is oen individualized for a given patient pres-
entation. Additionally, 46 patients (69% of the patients with a
source control procedure) received antibiotics at least 1 day prior
to source control (median, 1 day [interquartile range, 0–2 days];
high, 39 days). However, as clinicians oen determine antibiotic
start dates from source control, we believed that this was the most
clinically relevant start date. Frequency and median duration of
treatment prior to source control was not dierent between the
treatment groups. Finally, data were limited to what was avail-
able in the electronic medical record, and information such as
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Oral Antibiotics for Intracranial Infections • OFID • 7
size of initial uid collection, species-level data of S anginosus,
and complete susceptibility data were oen unavailable.
CONCLUSIONS
Levofloxacin-based oral antibiotic regimens were safe and well
tolerated for pediatric intracranial S anginosus group infections.
Early oral transition was successful for epidural infections, but
minimal data were available for parenchymal infections. Early
transition to oral therapy should be considered in patients with
epidural fluid collections, improving inflammatory markers
and imaging, and an uncomplicated neurosurgical course, par-
ticularly when a patient is unable to tolerate IV therapy and
susceptibility to oral antibiotics is confirmed. Such early tran-
sition would spare patients the inherent risk of a central venous
catheter, and the effectiveness of such therapy is increasingly
supported by literature.
Notes
Acknowledgments. e authors thank Samuel Dominguez, MD, PhD,
and Stacy Hamilton and the Children’s Hospital Colorado Microbiology
laboratory for assistance acquiring data.
Patient consent. e design of the work was been approved by the
Colorado Multiple Institutional Review Board and deemed exempt from
patient consent due to its retrospective nature.
Financial support. is work was supported by the National Institutes
of Health and the National Center for Advancing Translational Sciences
Colorado Clinical and Translational Sciences Awards program (grant
number UL1 TR002535).
Potential conicts of interest. All authors: No reported conicts of
interest.
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