Articles

Efficacy of adjunctive sertraline for the treatment of

HIV-associated cryptococcal meningitis: an open-label
dose-ranging study
Joshua Rhein, Bozena M Morawski, Kathy Huppler Hullsiek, Henry W Nabeta, Reuben Kiggundu, Lillian Tugume, Abdu Musubire,
Andrew Akampurira, Kyle D Smith, Ali Alhadab, Darlisha A Williams, Mahsa Abassi, Nathan C Bahr, Sruti S Velamakanni, James Fisher,
Kirsten Nielsen, David B Meya*, David R Boulware*, on behalf of ASTRO-CM Study Team

Summary
Background Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and Lancet Infect Dis 2016;
microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against 16: 809–18

cryptococcus. Published Online

March 9, 2016
http://dx.doi.org/10.1016/
Methods In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis S1473-3099(16)00074-8
who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and See Comment page 756
tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, *These authors contributed
or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional equally to this work
8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined University of Minnesota,
doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy Minneapolis, MN, USA
with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation (J Rhein MD, B M Morawski MPH,
K Huppler Hullsiek PhD,
stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome K D Smith BS,
was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in A Alhadab PharmD,
patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with D A Williams MPH, M Abassi DO,
ClinicalTrials.gov, number NCT01802385. N C Bahr MD,
S S Velamakanni BS, J Fisher BS,
K Nielsen PhD, D B Meya MMed,
Findings Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We D R Boulware MD); Infectious
gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to Disease Institute, Makerere
17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg University, Kampala, Uganda
(J Rhein, H W Nabeta MBChB,
(n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the R Kiggundu MBChB,
100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving L Tugume MBChB,
any sertraline dose averaged a CSF clearance rate of –0·37 colony forming units per mL per day (95% CI –0·41 to A Musubire MMed,
–0·33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting A Akampurira BS, D A Williams,
M Abassi, N C Bahr, D B Meya);
ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and Department of Medicine,
and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events Makerere University, Kampala,
in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants Uganda (D B Meya)
receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration- Correspondence to:
approved dosing of 100–200 mg/day and higher doses of 300–400 mg/day (hazard ratio 1·27, 95% CI 0·69–2·32; Dr Joshua Rhein, Infectious
Disease Institute, PO Box 22148,
p=0·45). Mulago Hospital Complex,
Kampala, Uganda
Interpretation Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of joshua.rhein@gmail.com
immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-
patent oral medication is a promising adjunctive antifungal therapy.

Funding National Institutes of Health, Grand Challenges Canada.

Introduction 2 weeks of amphotericin B combination therapy.3–5 For

Cryptococcal meningitis has emerged as the most common
cause of meningitis in adults in Africa, accounting for
15–20% of AIDS-related deaths.1,2 10-week mortality from
cryptococcal meningitis remains unacceptably high (≥35%
worldwide),3–5 largely because of the high cost, toxic effects,
and limited repertoire of effective antifungal drugs.
Furthermore, the rate of fungal clearance of cryptococcus
from cerebrospinal fluid (CSF) remains suboptimum,
with 60–70% of patients attaining CSF sterilisation after
these reasons, a crucial need exists for new effective
antifungal drugs that are readily accessible, especially in
resource-poor settings.
Evidence suggests that sertraline, the commonly used
selective serotonin reuptake inhibitor (SSRI) anti-
depressant, provides potent in-vitro and in-vivo
fungicidal activity against cryptococcus through dose-
dependent inhibition of protein synthesis via interaction
with eukaryotic translation initiation factor (Tif3).6–8

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Research in context
Evidence before this study
Effective, widely available therapy for cryptococcal meningitis
remains one of the most important unmet clinical needs in the
field of medical mycology. The development of new antifungals
against cryptococcus has been slow, and most recent clinical
trials have therefore focused on investigating new combinations
of half-century-old drugs. For example, a search of the terms
“cryptococcosis”, “antifungal”, and “clinical trial” in PubMed over
the past 10 years gives 51 hits. Although a few of these trials
focus on efficacy of newer triazole antifungals, alternative
formulations of amphotericin B, and two trials of adjunctive
interferon-γ immunotherapy, there have been no clinical trials
assessing the efficacy of antifungal drugs from novel classes. For
this reason, one alternative strategy has been to repurpose
existing medicines to identify novel drugs with antifungal
activity. Sertraline, for instance, was identified in a previous
laboratory study as active against cryptococcus by interfering
with protein synthesis. We searched PubMed using the terms
“sertraline” and “cryptococcus” without any date or language
restrictions on Jan 15, 2016. We identified three articles, which
demonstrate in-vitro activity (n=3) and murine in-vivo activity
Sertraline concentration in blood is subtherapeutic, yet
sertraline is concentrated into brain tissue at a median
of 16·5-times higher concentrations than in plasma.9 In
vitro, sertraline inhibited Cryptococcus neoformans growth
with minimum inhibitory concentrations (MICs)
between 2 and 6 μg/mL;6–8 and unlike fluconazole,
sertraline was fungicidal, with killing independent of
cell proliferation.6 The inhibitory effect of sertraline in
the brains of infected mice, when treated with sertraline
for 7 days before infection, was particularly potent, with
efficacy similar to that of fluconazole.6 The combination
of sertraline and fluconazole was either additive or
synergistic in vitro, and in mice models led to accelerated
fungal clearance at a greater rate than either drug
alone.6,10,11 Taken together, these data suggest that
sertraline might offer a promising therapeutic option for
cryptococcal meningitis.
We postulated that sertraline, when added to standard
induction therapy, consisting of amphotericin plus
fluconazole, would result in faster rates of fungal
clearance from CSF and better clinical outcomes. To test
this hypothesis, we assessed the safety, microbiological
efficacy, and pharmacokinetics of adjunctive sertraline in
HIV-infected Ugandans with cryptococcal meningitis.
Methods
Study design and participants
In this prospective, open-label, dose-finding pilot study, we
prospectively enrolled HIV-infected adults (aged ≥18 years)
with cryptococcal meningitis, who presented to Mulago
Hospital in Kampala, Uganda, between Aug 13, 2013, and
Aug 30, 2014. Patients were excluded from participating in
810
(n=2). No studies involved human beings. In mice, sertraline had
antifungal activity and was synergistic with fluconazole, such
that when both medicines were used, there was more killing of
yeast than when either medicine was used alone. This provided
the impetus for this study.
Added value of this study
This is the first clinical study in human beings to assess the
efficacy of adjunctive sertraline for cryptococcal meningitis,
when added to standard amphotericin B and high-dose
fluconazole antifungal therapies. This is also the first clinical
study to assess antifungal activity against cryptococcus using a
strategy of drug repurposing.
Implications of all the available evidence
It is important that studies showing promising antifungal
properties of repurposed drugs are followed through to the
clinical trial stage. This study provides a promising first step in
the evaluation of sertraline as a novel antifungal. Additional
randomised clinical trials are needed to assess if the improved
cerebrospinal fluid clearance of yeasts will translate into
better survival.
the study if they had received more than three doses of
amphotericin B, had jaundice or known liver cirrhosis,
were pregnant, or were breastfeeding. Due to delay in
procuring a suitable matched placebo for the follow-up
phase 3 trial, this open-label pilot study was extended to
include a so-called mock randomisation of sertraline doses
for two purposes: to accrue additional pharmacokinetic and
safety data and to provide procedural experience for an
anticipated phase 3 randomised trial. This extension began
in Nov 29, 2013, and continued until the matched placebo
became available on Aug 30, 2014.
All study participants provided written informed
consent. Uganda and Minnesota institutional review
boards approved the protocol.
Procedures
Cryptococcal diagnosis was made via CSF cryptococcal
antigen lateral flow assay (Immy Inc, Norman, OK,
USA), and confirmed by quantitative CSF fungal culture.
Participants received standard antifungal therapy plus
adjunctive sertraline at doses of 100–400 mg/day for
12 weeks. Standard therapy included amphotericin B
(0·7–1·0 mg/kg per day) for up to 14 days and fluconazole
(800 mg/day) for 4 weeks, followed by fluconazole
400 mg/day for 8 weeks of consolidation therapy.
Fluconazole dose was increased by 50% in participants
who were receiving rifampicin. Amphotericin could be
discontinued after 7 days if baseline CSF culture was
sterile at 7 days post collection, with continuation of
fluconazole and sertraline. For antiretroviral therapy
(ART)-naive people or those on a failing regimen, ART
was initiated or changed at 4–6 weeks.
www.thelancet.com/infection Vol 16 July 2016

At week 9, a 3-week sertraline taper was started, so that
participants discontinued sertraline 1 week before study
termination at 12 weeks. After 12 weeks, participants
were passively followed up and instructed to contact
study personnel if they had recurrent CNS symptoms.
To assess safety and tolerability, the first 60 participants
were given sertraline at escalating doses of 100 mg/day,
200 mg/day, 300 mg/day, or 400 mg/day as induction
therapy for 2 weeks, followed by consolidation therapy
with 200 mg/day for 8 weeks. Dose escalation occurred
only after five ART-naive individuals with a first episode
of cryptococcosis completed 2 weeks of induction therapy.
Each dose escalation cohort varied in size according to
differences in enrolment pace, 2-week survival, and
proportion of people receiving ART. Patients receiving
ART at time of enrolment, with a previous history of
cryptococcosis, or who died before receiving 14 doses of
amphotericin, were included in the overall analysis, but
did not count toward the five patients needed to complete
each dose cohort prespecified in our protocol.
For the so-called mock randomisation of sertraline
doses, beginning on Nov 29, 2013, participants with a
first episode of cryptococcal meningitis were assigned to
receive open-label sertraline at predetermined doses of
200 mg/day, 300 mg/day, or 400 mg/day as induction
therapy for 2 weeks, followed by consolidation therapy
with 200 mg/day for 8 weeks. Dose assignment was
made via computer-generated, permuted block
randomisation stratified by ART status for people with
first episode of meningitis. Participants with a second
episode of cryptococcal meningitis (eg, relapse or
paradoxical immune reconstitution inflammatory
syndrome) received 200 mg/day.
Therapeutic lumbar punctures were routinely done
using manometers at diagnosis, and on days 3, 7, 10, and
14. Quantitative CSF cultures were done with five serial
dilutions (1:10) of 100 μL CSF.12 Details of the methods
used for determining quantitative CSF cultures have
been previously described.13 We defined CSF culture
sterility as no growth of cryptococcus, with a limit of
detection of 10 colony forming units (CFU) per mL.
Cryptococcus isolates were stored in glycerol at –80°C,
and shipped on dry ice (–20°C) to the University of
Minnesota (Minneapolis, MN, USA). Susceptibility
testing was done by broth microdilution in RPMI1640
media per protocol.14 We defined sertraline MIC as the
concentration at which no growth was observed on the
basis of photometric absorbance at 600 nm (OD600), as
further described.7
We quantified plasma sertraline concentrations using
reversed-phase liquid chromatography with Agilent 1200
series HPLC pump (Agilent, Santa Clara, CA, USA),
auto sampler, and column oven with triple quadrupole
mass spectrometer (appendix). We attempted to measure
sertraline concentrations directly in CSF, but this
measurement was abandoned after discovering very low
concentrations in CSF compared with those in plasma.
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Articles
Because sertraline is a highly lipophilic molecule, we
postulated that sertraline diffused from CSF into brain
tissue, rendering it undetectable in CSF. Indeed,
sertraline concentrations in human CSF have never
been published. We thus estimated sertraline brain con-
centrations on the basis of published post-mortem tissue
levels, which were shown to have a median 16·5-fold
(IQR 13·0–21·3) higher concentration in brain tissue
than in plasma.9
Outcomes
The primary outcome was the 2-week CSF clearance rate
of cryptococcus, termed early fungicidal activity. Secondary
clinical endpoints included incidence of CSF culture
sterility at 2 weeks, paradoxical immune reconstitution
inflammatory syndrome per consensus criteria,15 culture-
positive relapse, and safety up to 12 weeks. Participants
with a previous history of cryptococcosis were only
included in the analyses for survival, safety, and relapse.
We calculated the incidence of paradoxical immune
reconstitution inflammatory syndrome in people with a
first episode of cryptococcal meningitis, who were ART-
naive at baseline and survived to initiate ART, and in those
who switched to second-line ART after hospital admission.
We used the National Institute of Allergy and Infectious
Diseases Division of AIDS toxicity scale, version 2009, to
assess adverse events in all participants. Because of an
expected 80% incidence of grade 3–5 adverse events with
amphotericin B deoxycholate, we only captured grade 4–5
adverse events, which had an expected incidence of
35–40%, dominated by amphotericin-related toxic
effects.3,5 Additional protocol-specified secondary
outcomes of neurocognitive performance, depression,
and cost-effectiveness are the focus of future publications.
Secondary laboratory endpoints included plasma sertra-
line concentrations and in-vitro sertraline susceptibility of
cryptococcus isolates. Previous genotyping of cryptococcus
clinical isolates in Uganda during 2006–12 has determined
that more than 99% of clinical isolates are Cryptococcus
neoformans var grubii strains.7,16
Statistical analysis
We assessed baseline characteristics across sertraline
doses using χ² or Kruskal-Wallis tests as appropriate. We
calculated overall and dose-specific CSF clearance rate
over 2 weeks (early fungicidal activity) in participants
with a culture-positive first episode of cryptococcosis,
and at least two quantitative CSF cultures via longitudinal
mixed-effect models, which included participant-specific
random intercept and random slope. Models used
restricted maximum likelihood estimation and an un-
structured covariance matrix. We used the Satterthwaite
method to determine denominator degrees of freedom
for p value estimation. Because multiple cohorts have See Online for appendix
reported mean early fungicidal activity by patient-specific
linear regression,4,17,18 we also estimated early fungicidal
activity by linear regression.
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We compared secondary outcomes across sertraline grade 5 cryptococcal-related and non-cryptococcal adverse
doses with χ² or Kruskal-Wallis tests. To assess efficacy of events separately. For other safety outcomes, we calculated
consolidation therapy with sertraline added, we used Cox risk differences for cryptococcal and non-cryptococcal
proportional hazard regression to compare 12-week all- related deaths, one or more occurrences of nausea,
cause mortality between participants who achieved CSF vomiting, or diarrhoea; premature sertraline dose
sterility by 2 weeks versus those who did not, in reduction; premature sertraline discontinuation; and loss
participants who survived 14 days after enrolment. Age- to follow-up between dosing of sertraline 100–200 mg/day
adjusted and sex-adjusted competing-risks regression and higher doses at 300–400 mg/day. We did the analyses
assessed grade 4 or 5 adverse event incidence between using SAS version 9.3 (SAS Institute, Cary, NC) and
current US Food and Drug Administration (FDA) dosing assessed against type I error lower than 0·05.
guidelines of 100–200 mg/day and higher doses of We did the pharmacokinetic analyses using non-linear
300–400 mg/day, using the Fine and Grey method where mixed-effects models to simultaneously estimate
non-adverse event all-cause mortality was a competing parameters of a one-compartment pharmacokinetic
risk. We also calculated risk differences between model by including all available sertraline concentrations
FDA-approved dose groups for grade 4 adverse events and from all doses. We used a likelihood ratio test to
determine the significance of including ART in the
model (χ² test, α=0·05, df=1). A Monte Carlo simulation
330 suspected meningitis for 50 000 simulated individuals determined the
proportion with projected therapeutic steady state
sertraline brain concentrations, based on the distributions
158 excluded
104 alternate diagnosis of steady state plasma concentrations, published fold-
1 decline to participate change concentration into the brain,9 and cryptococcus
53 cryptococcosis but ineligible
population MICs (appendix). We did pharmacokinetic
analyses to determine ART effect in NONMEM
172 enrolled version 7.2 (ICON Development Solutions, Dublin,
Ireland). This study is registered with ClinicalTrials.gov,
number NCT01802385.
60 safety and tolerability 112 mock randomisation
17 in 100 mg daily group 0 in 100 mg daily group Role of the funding source
12 in 200 mg daily group 48 in 200 mg daily group The funder of the study had no role in study design, data
14 in 300 mg daily group 36 in 300 mg daily group
17 in 400 mg daily group 28 in 400 mg daily group
collection, data analysis, data interpretation, or writing of
the report. The corresponding author had full access to
all the data in the study and had final responsibility for
the decision to submit for publication.
172 included in the safety population
17 in 100 mg daily group
60 in 200 mg daily group Results
50 in 300 mg daily group Of the 330 individuals presenting with suspected
45 in 400 mg daily group
meningitis, 172 HIV-infected adults with a positive CSF
cryptococcal antigen consented and were enrolled, from
44 excluded from early fungicidal Aug 14, 2013, until Aug 30, 2014. Of these, 22 had a
activity analysis previous history of cryptococcal meningitis (appendix).
22 previous history of cryptococcal
meningitis To assess safety and tolerability, the first 60 participants
12 sterile initial diagnostic CSF were given sertraline at escalating doses of 100 mg/day
culture
10 received only one lumbar
(n=17), 200 mg/day (n=12), 300 mg/day (n=14), or
puncture 400 mg/day (n=17) as induction therapy for 2 weeks,
followed by consolidation therapy with 200 mg/day for
8 weeks (figure 1).
128 included in early fungicidal
activity analysis The following 112 participants were randomly assigned
13 in 100 mg daily group to receive sertraline at 200 mg (n=48), 300 mg (n=36), or
40 in 200 mg daily group
39 in 300 mg daily group
400 mg (n=28) daily for the first 2 weeks, and 200 mg/day
36 in 400 mg daily group thereafter. The final population consisted of 100 mg
(n=17), 200 mg (n=60), 300 mg (n=50), or 400 mg (n=45)
Figure 1: Trial profile daily for the first 2 weeks, and 200 mg/day thereafter
60 participants were assessed for safety and tolerability of adjunctive sertraline (n=134 survivors).
and an additional 112 participants either underwent a so-called mock
The demographic and baseline clinical characteristics
randomisation of open-label sertraline (n=96; participants with first episode of
cryptococcal meningitis) or received 200 mg daily of adjunctive sertraline for a of the study participants are presented in table 1. By
second episode of cryptococcal meningitis (n=16). CSF=cerebrospinal fluid. contrast with previous large cohorts of HIV-associated

812 www.thelancet.com/infection Vol 16 July 2016

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Sertraline dose cohort Sertraline, all Sertraline, p value

(n=172) (n=172)
100 mg (n=17) 200 mg (n=60) 300 mg (n=50) 400 mg (n=45)
Demographics
Age, years 36 (32–41) 37 (32–43) 38 (33–42) 33 (29–38) 36 (32–42) 0·08
Male sex 11 (65%) 41 (68%) 31 (62%) 30 (67%) 113 (66%) 0·92
Previous cryptococcal meningitis 1 (6%) 16 (27%) 3 (6%) 2 (4%) 22 (13%) 0·002
Receiving antiretroviral therapy 9 (53%) 33 (55%) 21 (42%) 21 (47%) 84 (49%) 0·58
Receiving treatment for tuberculosis 0 2 (3%) 7 (14%) 3 (7%) 12 (7%) 0·14
Baseline clinical parameters
Glasgow Coma Scale score <15 6 (35%) 25 (42%) 16 (32%) 13 (29%) 60 (35%) 0·58
Weight, kg 52 (49–57) 52 (44–61) 50 (47–55) 52 (45–56) 52 (47–57) 0·91
CD4 count, cells/μL 19 (7–114) 25 (9–54) 16 (6–50) 20 (9–59) 19 (7–57) 0·57
CSF opening pressure, >250 mm H2O 8/15 (53%) 36/52 (69%) 24/45 (53%) 25/41 (61%) 93/153 (61%) 0·40
CSF quantitative culture, log10CFU/mL* 4·8 (4·1–5·4) 4·4 (3·1–5·4) 4·9 (4·0–5·5) 4·3 (3·3–5·5) 4·6 (3·8–5·4) 0·46
CSF white blood cells ≥5 cells/μL 9 (53%) 15/55 (27%) 19/47 (40%) 12/43 (28%) 55/162 (34%) 0·14

Data are median (IQR), n (%), or n/N (%) when the denominator differs from that stated at the top of each column. p values are for the comparison across all four sertraline dosing groups. IRIS=immune
reconstitution inflammatory syndrome. CSF=cerebrospinal fluid. CFU=colony forming units. *Excludes those with sterile culture at diagnosis (n=19); the cultures of four people were unable to be quantified.

Table 1: Baseline characteristics by daily sertraline dose

cryptococcal meningitis,3–5 about half of participants were
receiving ART before hospital admission (50 [29%] of
172 patients were receiving efavirenz-containing ART),
about a third presented with altered mental status
(Glasgow Coma Scale <15), and fewer patients were
women than men (table 1). High baseline fungal burdens
and raised CSF opening pressure (median 300 mm H2O,
IQR 190–480) were common. Of those with a first episode
of cryptococcal meningitis, 12 (8%) of 150 had sterile CSF
with a positive CSF cryptococcal capsular polysaccharide
antigen. Apart from previous cryptococcal meningitis,
demographics did not differ significantly between dosing
groups (table 1).
Of the 172 individuals who received sertraline,
44 participants (26%) were excluded from early fungicidal
activity analysis because of previous cryptococcal
occurred during 12 weeks of follow-up. Two participants
developed CSF culture-positive relapse after 12 weeks,
with one due to fluconazole non-compliance.
Adverse events and deaths in this critically ill
population were common (table 3). The numbers of
individual grade 4 adverse events occurring in each dose
group were: six events in 17 participants receiving 100 mg
sertraline, 14 events in 60 participants receiving
200 mg sertraline, 19 events in 50 participants receiving
300 mg sertraline, and eight events in 45 participants
receiving 400 mg sertraline. More broadly, grade 4 or 5
adverse event risk did not differ between current FDA-
approved dosing of 100–200 mg/day and higher doses of
Statistical methods of
0·60 estimation
GLM linear regression
fungicidal activity (–log10CFU/mL per day)

meningitis (n=22), sterile diagnostic CSF cultures (n=12),

Rate of CSF Cryptococcus clearance early

0·49 Mixed-effects model

or fewer than two CSF cultures done (n=10). With 0·50
0·44 0·43
sertraline, the overall mixed-effect early fungicidal 0·40 0·40
0·40 0·37 0·37 0·38 0·37
activity was –0·37 log10 CFU/mL CSF per day (95% CI 0·34
–0·41 to –0·33). There were no significant differences in 0·30
early fungicidal activity between sertraline doses
(figure 2). 0·20
Overall 2-week mortality was 22% (38 of 172), and
12-week mortality was 40% (69 of 172), and did not differ 0·10
by sertraline dose group (table 2). Hospital admission
0
duration, 2-week CSF sterility, or symptomatic recurrence 100 mg (n=13) 200 mg (n=40) 300 mg (n=39) 400 mg (n=36) Any sertraline
(eg, paradoxical immune reconstitution inflammatory (n=128)
syndrome, culture-positive relapse) did not differ across Sertraline daily dose

dosing groups. The incidence of paradoxical immune
reconstitution inflammatory syndrome was 5%
(two of 43) in participants with a first episode of
cryptococcosis who were ART-naive and survived to
initiate ART or those switched to second-line therapy
because of virological failure. No cryptococcal relapse
Figure 2: Rate of CSF clearance of cryptococcus, by sertraline dose
No significant difference was observed in the early fungicidal activity between doses of sertraline. Due to the small
sample sizes of the dose groups and inherent differences in statistical methods of estimating early fungicidal
activity (ie, linear regression vs mixed-model using longitudinal repeated measures), the 95% CIs of each sertraline
dose group overlap, and the 95% CI should be appreciated instead of any exact point estimate. The appendix
provides early fungicidal activity plots by sertraline dose. CFU=colony-forming units. CSF=cerebrospinal fluid.
GLM=generalised linear model.

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300–400 mg/day (hazard ratio [HR] for grade 4 or 5
adverse events 1·27, 95% CI 0·69–2·32; p=0·45). Most
grade 4 or 5 adverse events were related to amphotericin
toxic effects or AIDS (53 of 59) including anaemia (n=28),
electrolyte abnormalities (n=15), cytopenia (n=4), and
acute kidney injury (n=2). Cryptococcal-related deaths
occurred in 24–25% of participants up to 12 weeks, and
non-cryptococcal deaths occurred in 14–17% of enrolled
participants (table 2). The appendix provides a summary
of adverse events by dose group and line listing of the
incident grade 4–5 adverse events.
A mild-to-moderate serotonin syndrome occurred in
one participant who unintentionally self-administered
800 mg/day of sertraline for 3 days over a weekend,
which was a protocol deviation. Sertraline was held for
3 days, and then restarted at 200 mg/day with an
uneventful course thereafter. Overall tolerability was
excellent with six (4%) of 150 participants with no
previous history of cryptococcal meningitis having early
discontinuation .
Of 101 participants with no previous history of
cryptococcosis or sterile diagnostic quantitative cultures
who survived 2 weeks after enrolment, 68 (67%) achieved
CSF sterility by the end of induction therapy. 23 deaths
occurred between 2 and 12 weeks, 16 deaths (24%) in
68 participants who were sterile, and seven deaths (21%)
in the 33 participants who were not sterile. Unlike
previous studies, CSF culture positivity at the end of
induction therapy was not significantly associated with
mortality (HR 0·88, 95% CI 0·36–2·15; p=0·78; figure 3).
Sertraline concentrations in plasma were quantified in
143 participants. Sertraline reached steady state in plasma
by at least day 7, with median levels of 201 ng/mL
(IQR 90–300; n=49 participants) when taking 200 mg/day
and 399 ng/mL (278–560; n=30 participants) when taking
400 mg/day during days 7–14 of the induction period

Sertraline dose cohort Sertraline, all Sertraline, p value

(n=172) (n=172)
100 mg (n=17) 200 mg (n=60) 300 mg (n=50) 400 mg (n=45)
14-day CSF sterility* 6/14 (43%) 25/41 (61%) 22/43 (51%) 20/40 (50%) 73/138 (53%) 0·61
Paradoxical IRIS† 0/3 (0%) 1/14 (7%) 0/15 (0%) 1/11 (9%) 2/43 (5%) 0·58
Culture-positive relapse‡ 0 0 0 0 0 ··
2-week mortality 5/17 (29%) 8/60 (13%) 12/50 (24%) 13/45 (29%) 38/172 (22%) 0·21
12-week mortality 10/17 (59%) 20/60 (33%) 21/50 (42%) 18/45 (40%) 69/172 (40%) 0·30

CSF=cerebrospinal fluid. IRIS=immune reconstitution inflammatory syndrome. *Excludes those who started with sterile CSF culture (n=12) or previous history of cryptococcal
meningitis (n=22); includes all quantitative culture data collected within 14 days of enrolment in 138 participants given sertraline. †IRIS incidence in individuals with first episode
of cryptococcal meningitis, who were antiretroviral therapy (ART)-naive at baseline and who survived to initiate ART, or those who switched to second-line ART after hospital
admission; includes possible IRIS cases; no other paradoxical IRIS cases occurred in those excluded (eg, second episodes of cryptococcosis, those already receiving effective ART).
‡Two culture-positive cases of relapse occurred beyond the 12-week study follow-up period, one in the 100 mg dose group and another with fluconazole non-compliance.

Table 2: Outcomes by daily sertraline dose

Sertraline 100 and Sertraline 300 and Absolute risk difference p value
200 mg/day (n=77) 400 mg/day (n=95) (95% CI)
Adverse events
Total number of grade 4 adverse events 20 27
Grade 4 adverse event, cumulative incidence 15 (19%) 22 (23%) 0·04 (–0·09 to 0·16) 0·56
Total number of grade 5 adverse events 3 9
Grade 5 adverse event, cryptococcal related 1 (1%) 3 (3%) 0·02 (–0·02 to 0·06) 0·42
Grade 5 adverse event, non-cryptococcal 2 (3%) 5 (5%) 0·03 (–0·03 to 0·08) 0·38
Overall 12-week outcomes
Cryptococcal-related mortality 19 (25%) 23 (24%) –0·0 (–0·13 to 0·12) 0·94
Non-cryptococcal related mortality 11 (14%) 16 (17%) 0·03 (–0·08 to 0·13) 0·65
Nausea, vomiting, or diarrhoea, one event or more 59 (77%) 61 (64%) –0·12 (–0·26 to 0·01) 0·08
Serotonin syndrome 0 (0%) 1 (1%)* ·· ··
Sertraline dose reduction, all cause 0 (0%) 1 (1%)* ·· ··
Early sertraline discontinuation† 1/60 (2%) 5/90 (6%) 0·04 (–0·02 to 0·10) 0·40
Lost to follow-up 3 (4%) 2 (2%) –0·02 (–0·07 to 0·03) 0·66

Details by individual dose group are provided in the appendix. Absolute risk difference represents the difference in proportions, with the p value calculated by the Fisher’s
exact χ² test.*Protocol deviation by a participant taking 800 mg/day for 3 days. †Excludes participants with a previous history of cryptococcal meningitis (n=17 for the
100–200 mg/day group and n=5 for the 300–400 mg/day group).

Table 3: Adverse events and clinical outcomes with adjunctive sertraline for 12 weeks

814 www.thelancet.com/infection Vol 16 July 2016

 Articles

(appendix). Plasma levels reached 82% of steady state
levels by day 3. With 400 mg/day, the median projected
steady state brain tissue concentration was 6·8 μg/mL
(IQR 4·6–9·7).
The presence of ART significantly increased sertraline
clearance (p<0·0001), particularly at lower doses. Among
121 participants who had steady state sertraline con-
centrations measured, 55 (45%) were receiving con-
current efavirenz or nevirapine. Steady state sertraline
concentrations were 27% (95% CI 11 to 43; p<0·0001)
lower in those receiving efavirenz and 13% (–3 to 29;
of sertraline and historical controls receiving the same
standard antifungal therapy at the same site did not
overlap.5 The comparison between sertraline dose groups
did not reveal any overtly, alarming problems with safety
or tolerability of the higher sertraline doses; however, the
small sample sizes of the individual dose groups preclude
100
90
80

Cumulative survival
70
p=0·10) lower in those receiving nevirapine when 60
measured between days 7 and 14. Yet, in patients receiving 50
400 mg/day sertraline, the median concentrations in 40
patients not receiving ART were 397 ng/mL (IQR 211–495) 30
versus 431 ng/mL (246–566) in those receiving ART. 20
Non-sterile
Sterile
In-vitro susceptibility testing was done in 128 clinical 10 HR 0·88 (95% CI 0·36–2·15); p=0·78
isolates obtained from baseline CSF cultures from 0
participants with a first episode of cryptococcal 0 2 3 4 5 6 7 8 9 10 11 12
Weeks from cryptococcal meningitis diagnosis
meningitis. The MIC for sertraline ranged from 1 to Number at risk
8 μg/mL, with 35 isolates (27%) having MICs of 2 μg/mL Sterile 68 64 61 59 56 54 50 49 48 48
Non-sterile 33 31 29 29 27 27 27 27 27 26
or lower, 108 (84%) having 4 μg/mL or lower, 117 (91%)
having 6 μg/mL or lower, and 128 (100%) having 8 μg/mL Figure 3: 12-week survival during consolidation therapy, stratified by 2-week CSF quantitative culture sterility
or lower. Figure 4 shows the proportion of people Participants received 200 mg/day sertraline with fluconazole for the duration of consolidation therapy.
Fluconazole was dosed at 800 mg for about 4 weeks until 2-week cultures were known to be sterile and
achieving therapeutic brain sertraline concentrations, antiretroviral therapy was initiated. Unlike traditional consolidation therapy using only 400 mg/day
according to cryptococcus susceptibility and sertraline fluconazole,21–23 we did not observe that 2-week CSF culture positivity was associated with excess mortality in
dose. With 400 mg/day of sertraline, 81% of a population participants who were receiving sertraline at 200 mg/day in combination with fluconazole. The shading around
would achieve probable therapeutic sertraline the lines represents the 95% CIs. HR=hazard ratio.

concentrations in the brain, based on the distributions of

MICs, drug levels, and variability in brain penetration. 100% 200 mg ART naive (n=24)
100 98% 98%
With the two-fold additive or synergistic effects of 200 mg on ART (n=25)
fluconazole, at sertraline 400 mg/day, the projected 91% 400 mg/day (n=30)
90
proportion of people achieving therapeutic sertraline 82%
concentrations in brain tissue rises from 81% to 97%. 80 78%
Proportion achieving therapeutic sertraline

70
Discussion
concentrations in brain (%)

62%
Sertraline, when added to standard amphotericin- 60% 59%
60
combination therapy for cryptococcal meningitis, might
50
improve CSF fungal clearance. In this pilot dose-finding
study, participants receiving any sertraline showed an 40 38%
average CSF clearance rate of –0·37 log10 CFU per mL 32%
29%
CSF per day (95% CI –0·41 to –0·33). By comparison, the 30
rate of CSF clearance was –0·30 log10 CFU per mL CSF
20
per day (–0·32 to –0·28) in 208 participants screened for 12%
15%
the Cryptococcal Optimal ART Timing (COAT) trial5 in 10
5%
Uganda and South Africa during 2010–12. This historical
0
cohort received the same background regimen of 1 2 4 6 8
amphotericin 0·7–1·0 mg/kg per day and fluconazole Sertraline minimum inhibitory concentration (μg/mL)
800 mg/day without sertraline.5 Similarly, the CSF
Figure 4: Probability of achieving therapeutic sertraline brain tissue levels according to cryptococcus
clearance rate in 99 participants in Vietnam receiving
susceptibility and sertraline dose in a population
amphotericin 1 mg/kg per day and fluconazole Based on the steady state levels achieved between day 7 and 14, as well as the distribution of minimum
800 mg/day was –0·32 (–0·34 to –0·29) log10 CFU per mL inhibitory concentrations (MICs), in Monte Carlo simulation 81% of a population would probably achieve
CSF per day.3 therapeutic sertraline levels in the brain with 400 mg/day, 65% of those who are antiretroviral therapy
(ART)-naive receiving 200 mg/day, and 35% of those receiving ART with 200 mg/day. In the presence of
The rate of cryptococcus clearance from the CSF is a
two-fold additive/synergistic effects of fluconazole, 97% at 400 mg/day, 90% at 200 mg/day without ART, and
powerful method to explore new drug combinations in 62% at 200 mg/day on ART would achieve therapeutic sertraline activity in the brain. Overall, 91% (117 of 128)
small phase 2 studies.17 The confidence intervals in the of cryptococcus isolates had an MIC of ≤6 μg/mL, 84% (108 of 128) had an MIC of ≤4 μg/mL, and 27% (35 of
rate of fungal clearance between those receiving any dose 128) had an MIC of ≤2 μg/mL.

www.thelancet.com/infection Vol 16 July 2016 815

 Articles
sufficient statistical power to detect possibly important
clinical differences.
Although the fungal clearance rate provides a relatively
objective outcome measure,17 these results should be
interpreted cautiously. Notably, patients receiving ART
were excluded in the historical cohort, although neither
receipt of ART in this study nor early ART in the COAT
trial were statistically associated with early fungicidal
activity.5 The early fungicidal activity observed with
amphotericin and fluconazole 800 mg/day in the COAT
trial5 (n=208) was similar to that observed by Day
and colleagues3 (n=99) using an identical statistical
methodology. Definitive declarations cannot be given
due to the overall small sample size and lack of direct
statistical comparison, yet we believe that these
observations provide ample justification for a further
phase 3 randomised clinical trial to test the use of
adjunctive sertraline.
The current standard therapy for cryptococcal
meningitis is based on antifungal regimens that are a
half-century old, are associated with a range of toxic
effects, and are largely inaccessible in areas of the world
where they are needed most. For this reason, the
discovery of a widely available, non-toxic, and affordable
drug effective against cryptococcus would represent a
substantial advance in preventing deaths. Sertraline
represents a promising adjunct and deserves further
investigation in randomised clinical trials.
The safety and tolerability of sertraline was good. The
incidence of grade 4–5 adverse events and gastrointestinal
side-effects, although seemingly high, were similar to or
less than previously reported.5 During the COAT trial over
12 weeks,5 there was a 50% cumulative incidence of grade 4
adverse events and a 68% (142 of 208) incidence of nausea,
vomiting, or diarrhoea, in contrast to higher doses of
sertraline (300–400 mg/day), which were associated with a
23% cumulative incidence of grade 4 adverse events and
64% incidence of nausea, vomiting, or diarrhoea.
Identifying effective and less toxic antifungal induction
regimens could lead to less dependence on completing a
full, 14-day course of amphotericin. By contrast, fluconazole
monotherapy remains a reality worldwide where
amphotericin is unavailable19 and leads to suboptimal
clearance, resistance, and symptomatic relapse.18,20 In view
of the widespread availability, low cost (US$0·05 per
100 mg tablet wholesale), and extensive safety record of
sertraline, the combination of sertraline with fluconazole
might offer a more efficacious and cost-effective, all-oral
option in such settings. Furthermore, unlike amphotericin
and flucytosine, the ability to safely administer sertraline
over a prolonged duration would allow antifungal benefits
to extend through the consolidation and maintenance
phases of therapy.
Unlike previous cohorts, we observed no excess
mortality over 12 weeks in people whose CSF culture
remained positive at 2 weeks,21–23 suggesting the benefit of
sertraline might be extended into the consolidation phase
816
due to the additive antimicrobial effects of combination
sertraline and fluconazole.6 Depression is common in this
population (77% prevalence),24 and sertraline would be the
obvious antidepressant of choice, if indicated. Additional
studies are needed to assess the role of sertraline in
consolidation and maintenance phases of therapy, during
induction therapy in the absence of amphotericin, and for
non-meningitis manifestations of cryptococcosis
including asymptomatic cryptococcal antigenaemia
identified as part of screening programmes.25,26
A possible, unanticipated benefit of extending
adjunctive sertraline beyond the induction period was
the observed low incidence of symptomatic recurrence,
including both culture-positive cryptococcal relapse and
paradoxical immune reconstitution inflammatory
syndrome. Although patients were only actively followed
up for 12 weeks and passively thereafter, the incidence of
about 5% paradoxical immune reconstitution inflam-
matory syndrome and two late relapse cases appeared to
be lower than the 17% immune reconstitution inflam-
matory syndrome incidence during the COAT trial,5 and
lower than the 25–30% paradoxical cryptococcal-immune
reconstitution inflammatory syndrome observed in two
cohorts using amphotericin alone as induction therapy
with fluconazole 400 mg/day consolidation therapy.23,27
The inability to achieve eventual CSF culture sterility is a
major risk factor for immune reconstitution
inflammatory syndrome and relapse.23 Improved overall
microbiological activity on active and quiescent yeasts
might be plausible explanations for the low level of
recurrence observed. It is also plausible that sertraline
might have immunoregulatory effects on immune
activation resulting in a decreased incidence of
paradoxical immune reconstitution inflammatory
syndrome.28 The possible decreased immune recon-
stitution inflammatory syndrome and relapse with
adjunctive sertraline is intriguing and requires further
investigation in a randomised trial.
The results of our in-vitro susceptibility testing confirm
previous studies that provided the impetus for this study,
with MICs of 4 μg/mL or less in about 80% of Ugandan
isolates, and reported bidirectional synergy with the
addition of fluconazole.6,10,11 Synergy might reflect additive
mechanisms of antifungal action. Fluconazole targets
the enzyme 14α-demethylase, with inhibition of
ergosterol synthesis and subsequent membrane
disruption. Sertraline, by contrast, inhibits mRNA
translation into protein synthesis.6 For these reasons, the
addition of sertraline to standard fluconazole-containing
regimens could be ideal for treating persistent or
recurrent infections with cryptococcus, factors associated
strongly with increased rates of fluconazole resistance.20
SSRIs are among the most prescribed drug classes
worldwide, and sertraline remains among the most
prescribed medications in the USA, with about 44 million
prescriptions in 2014.29 Although inter-person steady state
plasma concentrations vary substantially,30 observed plasma
www.thelancet.com/infection Vol 16 July 2016

concentrations in our population of Ugandan adults with
advanced AIDS were generally in the expected range.
Sertraline has minimal inhibitory effects on the major
cytochrome P450 enzymes, and few drug interactions of
clinical significance have been documented.31 On the basis
of limited observational studies, however, both efavirenz
and rifampin are suspected to lower sertraline levels when
co-administered.32,33 Our results support these observations,
with about 27% lower sertraline plasma concentrations
when receiving efavirenz, although the effect of this
interaction in the brain is unknown. Only three participants
received concurrent rifampin, and sertraline levels were too
variable to make firm conclusions. Further analyses of the
effect of these medications on sertraline concentrations
are needed.
Of particular interest regarding the use of sertraline for
fungal meningitis, previous pharmacokinetic studies in
animals report that sertraline concentrations are
20–50-times higher in the brain than in blood,34 and a
study of 11 victims of a fatal air crash revealed a mean
21-fold and median 16·5-fold higher concentration in
human brain tissue than in blood.9 Although sertraline is
concentrated into the brain tissue, we found low levels in
CSF, possibly because sertraline is a lipophilic compound
concentrated within the brain parenchyma itself, not
CSF. Because amphotericin penetrates poorly into brain
parenchyma,35 the overall benefit of sertraline might be
more substantial than the CSF findings suggest. Despite
our inability to measure sertraline concentrations in
CSF, the inferred pharmacokinetics suggest that brain
concentrations of sertraline probably exceed the
sertraline MICs reported in vitro when dosed at
400 mg/day. In the presence of at least a two-fold additive
effect of fluconazole,6 therapeutic levels of sertraline in
the brain should be achieved in 97% of people when
dosed at 400 mg/day, 90% of people dosed at 200 mg/day
without ART, and 62% of people dosed at 200 mg/day on
efavirenz. Similar therapeutic levels should be achieved
in liver, lung, and spleen tissue.9
In summary, an improved rate of fungal clearance
from the CSF, combined with acceptable concentrations
and the additive effects of sertraline used in combination
with fluconazole in vitro,6 suggest that sertraline may be
a useful adjunct for the treatment of cryptococcal
meningitis with further prevention of paradoxical
cryptococcal immune reconstitution inflammatory
syndrome and relapse. Given sertraline’s fungicidal
properties, safety profile, lack of relevant drug
interactions, probable novel mechanism of action, low
cost, and excellent brain penetration, sertraline fulfils
many of the characteristics required of a new antifungal
against cryptococcus. On the basis of the cryptococcus
MICs observed and probable brain concentrations of
400 mg/day sertraline, 81% of people would achieve
therapeutic sertraline activity in brain tissue. With the
two-fold additive and synergistic effects of fluconazole,
97% of a population would be predicted to achieve
www.thelancet.com/infection Vol 16 July 2016
Articles
therapeutic sertraline activity in brain tissue. The
Adjunctive Sertraline for the Treatment of Cryptococcal
Meningitis (ASTRO-CM) randomised clinical trial
(NCT01802385) began on March 9, 2015, and is testing if
sertraline dosed initially at 400 mg/day has a survival
benefit compared with placebo when receiving standard
induction therapy of amphotericin B deoxycholate and
fluconazole 800 mg/day.
Contributors
DRB, DBM, and JR participated in the study concept and design. JR,
HWN, RK, LT, AM, AAk, DAW, MA, NCB, SSV, JF, AAl, and KDS
participated in the acquisition of data. KHH, BMM, AAl, and DRB
participated in the statistical analysis. DRB, DBM, JR, AAl, and KN
participated in the interpretation of data. JR, SSV, and BMM participated
in initial manuscript drafting. DRB, DBM, JR, KN, and AM participated
in critical revisions for intellectual content. DRB, DBM, and JR
participated in obtaining funding. DAW participated in administrative,
technical, or material support.
Declaration of interests
We declare no competing interests.
ASTRO-CM team members
Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza,
Alisat Sadiq, Tadeo Kiiza Kandole, Tony Luggya, Julian Kaboggoza,
Eva Laker, Elissa K Butler, Jonathan Dyal, Julie M Neborak,
Alexa M King, A Wendy Fujita, Nathan Yueh, Alice Namudde,
Ryan Halupnick, Bilal Jawed, Priya Vedula, Marnie Peterson,
Paul R Bohjanen, and Andrew Kambugu.
Acknowledgments
This research was supported by the National Institute of Neurological
Disorders and Stroke (NINDS) and the Fogarty International Center
(R01NS086312, R25TW009345), Grand Challenges Canada (S4-0296-01),
and National Institute of Allergy and Infectious Diseases (T32AI055433,
K24AI096925). This work was supported in part by the Doris Duke
Charitable Foundation through a grant supporting the Doris Duke
International Clinical Research Fellows Program at the University of
Minnesota. Elissa K Butler, Jonathan Dyal, and A Wendy Fujita are
Doris Duke International Clinical Research Fellows.
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