Page 19 - SAHCS HIVMed Journal Vol 20 No 1 2019

Page 6 of 16 Guideline

the antifungal regimens for a first episode are standardised Monitoring response to treatment
and not influenced by the CrAg titre (refer to Resolution of symptoms and signs should be used to monitor
Recommendation 3). A point-of-care CrAg LFA may be the response to treatment. An LP should not be routinely
performed on CSF at the bedside if laboratory facilities are performed after 7 (or 14) days of induction antifungal
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not immediately available. Antifungal susceptibility treatment to document conversion of CSF from culture-
testing should not be routinely requested for a first episode positive to culture-negative because the expert panel advises
because the vast majority of antifungal minimum inhibitory routinely changing from induction to consolidation phase
concentrations (MICs) are low at first diagnosis and, even if treatment at 14 days. Given that a fungal culture result may
elevated, the relevance is difficult to interpret in this take up to 14 days to become available, the culture result will
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setting. If opening pressure was not measured at the time not affect the timing of this change. If symptoms persist or
of diagnostic LP, an LP should be repeated to measure the recur during induction or at day 7 or 14, an LP should be
pressure once a diagnosis of CM is confirmed (refer to
Recommendation 6). Cerebrospinal fluid obtained from repeated to re-measure the opening pressure, which may
therapeutic LPs during the course of a hospital admission increase despite successful CSF sterilisation. There is no
should not be routinely submitted for laboratory analysis evidence to support extending the duration of induction
because this is a waste of resources and does not impact on treatment. The patient should be investigated for other
treatment management. causes of a poor clinical response, the most common being
raised intracranial pressure. Patients with raised intracranial
Diagnosis of cryptococcal meningitis if focal neurological pressure should be managed according to Recommendation 6.
signs are present or if lumbar puncture is not Daily therapeutic lumbar puncture, and a CT brain scan if
immediately available possible, is advised. If the cause of a poor clinical response
Focal neurological signs are relatively uncommon in CM, cannot be found, consider referral to a secondary or tertiary
except for a sixth cranial nerve palsy. Where focal centre for review unless the patient’s prognosis is already
neurological signs are present, a computed tomography deemed to be very poor. Cerebrospinal fluid CrAg tests may
(CT) brain scan should be performed before LP to exclude remain positive for months to years and CrAg titres are not
the presence of space-occupying lesions. If a CT brain scan recommended to be routinely measured to monitor the
cannot be performed immediately in the case of focal response to treatment. Blood CrAg titres are also not useful to
neurological signs or if an LP is not immediately available monitor the response to treatment for both CM and
to make a diagnosis of meningitis, serum/plasma/whole asymptomatic antigenaemia. 36,37
blood may be tested for CrAg to determine if the patient has
disseminated cryptococcal disease. Patients with a positive Suspected antifungal-resistant isolates
blood CrAg test and symptoms and signs of meningitis are
very likely to have CM and should be started empirically on Antifungal susceptibility testing should be considered if
antifungal treatment (refer to Recommendation 3). Patients the patient has a relapse episode and the causes listed in
without focal neurological signs should then be referred to Table 10 have been excluded. Isolates with elevated
a centre where LP can be performed, while patients with fluconazole MICs have been described from relapse
focal neurological signs need to have a CT brain scan episodes – especially where fluconazole monotherapy is
performed first followed by an LP (if this is not initially given – and are unusual if amphotericin B-based
contraindicated by CT brain findings). Although the expert induction treatment was administered during the first
panel is aware that it may be difficult to access a CT brain episode. 35,38 Because there are no established clinical
scan in rural settings, the panel recommends that there breakpoints for C. neoformans and fluconazole, it is useful to
should be urgent referral for a CT scan before LP in blood test isolates from the initial and subsequent episodes in
CrAg-positive patients with focal neurologic signs, parallel in an academic or reference laboratory and
whenever possible. document a fourfold (double dilution) change in MIC that
may suggest resistance. This requires that the initial
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Diagnosis of a subsequent episode of cryptococcal isolate is stored, which may not always be possible at a
meningitis diagnostic laboratory. Minimum inhibitory concentrations
A careful history should be taken including dates of previous should be interpreted by an experienced clinical
episodes of CM and the patient should be assessed clinically microbiologist in conjunction with the clinical history. In
for signs and symptoms of meningitis. An LP is indicated the absence of paired isolates, epidemiologic cut-off values
if the patient has signs and symptoms of meningitis. can be applied to distinguish wild-type and mutant
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Cerebrospinal fluid should be submitted for fungal culture, strains. Refer to Recommendation 7 for the management
with plates incubated for at least 14 days to detect slow of patients with fluconazole-resistant isolates. Non-
fungal growth. Rapid tests are not useful for the diagnosis of susceptibility to amphotericin B is very unusual and
subsequent episodes because both CSF India ink and CSF/ susceptibility testing for this antifungal agent should not be
blood CrAg tests may remain positive for months to performed. Flucytosine resistance develops with
years even if treatment has been successful. Antifungal monotherapy; hence, combination treatment is always
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susceptibility testing may be considered for a first relapse recommended. Baseline flucytosine MIC testing is not
episode (see below and refer to Recommendation 7). routinely recommended at present.

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