Azithromycin uses in toddlers


Clinical Pearls

Fluoroquinolones

A recent US Food and Drug Administration (FDA) safety alert (and subsequent label revision) cautions against the use of fluoroquinolones for common infections when other alternatives are available, owing to potential adverse effects, including CNS toxicity. The FDA recommends that patients watch for signs and symptoms of confusion or hallucinations.[5]

Beta-Lactams

Beta-lactams differ in their propensity to cause mental status changes, possibly because of side chain differences. Neurotoxicity is more likely with beta-lactams with more basic side chains, owing to increased GABA receptor binding.[6] This difference may explain why meropenem is less neurotoxic than imipenem, which has a more basic side chain.[6]

Differences in neurotoxicity may guide treatment choices for patients with increased neurotoxic risk, such as seizure disorders. For example, ceftazidime and meropenem are less neurotoxic than cefepime and imipenem.[7]

Cephalosporins

One retrospective study of 100 patients treated with intravenous cefepime in the intensive care unit between 2009 and 2011 found that 15% experienced cefepime-associated neurotoxicity.[3] These patients were less likely to have appropriate renal dose adjustments and more likely to have a history of chronic kidney disease. Although cephalosporin neurotoxicity is more common with cefepime than other cephalosporins, such as ceftriaxone, it is less likely to be identified, and delayed diagnosis is common.[8]

Metronidazole

The combination of metronidazole and disulfiram has been linked to psychosis; this is thought to be due to the coinhibition of aldehyde dehydrogenase. In a study of 58 men receiving disulfiram for chronic alcoholism, 20% who were also given metronidazole developed an acute psychosis/confusional state.[9]

Metronidazole neurologic toxicity appears to be associated with increasing cumulative doses and exposures.[2] Because of the risk for neurotoxicity with repeat exposures to metronidazole, limiting its duration of use is recommended.

Oxazolidinones (Linezolid)

Because linezolid inhibits monoamine oxidase A and B, concomitant use with medications that increase serotonin levels can lead to serotonin syndrome and subsequent adverse neurologic effects.[2] Toxicities due to serotonin syndrome can range from tremors to altered mental status, coma, or death.[10] Up to 25% of infectious disease practitioners have reported observing serotonin syndrome when linezolid is administered concomitantly with selective serotonin reuptake inhibitors or serotonin/norepinephrine reuptake inhibitors.[10]

In 2011, the FDA issued a warning about CNS reactions with linezolid, and later strengthened this alert to say that "linezolid generally should not be given to patients taking serotonergic drugs"[11]—although avoidance of combination use or use without a "washout" period is often problematic in the clinical setting.

Azole Antifungals

Among the azole antifungals, voriconazole appears to be particularly associated with neurotoxicity. Reports show that 20%-33% of patients treated with voriconazole experience these effects when serum concentrations are > 5.5 µg/mL.[2]

Recent guidelines from the Infectious Diseases Society of America for the treatment of Aspergillosis recommend therapeutic drug monitoring to maintain a voriconazole level < 5-6 µg/mL because of the risk for CNS toxicity.[12]

Antivirals (Oseltamivir)

The association between oseltamivir and mental status change is controversial, owing to inadequate or /conflicting data and because influenza itself is associated with similar symptoms. The reported incidence rates are generally low (5%-12%) but can be as high as 67% in patients with specific genotypes.[13]

Children and adolescents may be more likely to experience adverse neurologic effects; whereas age is not addressed in the US labeling, oseltamivir is contraindicated in this age group in Japan.[14] A study from London found that 18% of schoolchildren given prophylactic oseltamivir reported adverse neuropsychiatric effects; however, all of these effects were mild to moderate in severity and resolved with drug discontinuation.[15]

A review by the FDA concluded that the high incidence of these adverse effects was an artifact of "an increased awareness of influenza-associated encephalopathy, increased access to oseltamivir in that population, and a coincident period of intensive monitoring adverse events."[16]

A summary of mental status changes associated with antimicrobials, along with other common neurologic adverse reactions, is provided in the Table.

Table. Antimicrobials With Neurotoxic Presentations

Antimicrobial
Class Most Common Presentation of Neurotoxicitya Risk Factors Proposed
Mechanism Note to
Clinician
Fluoroquinolones[2,5] Acute psychosis
Confusion
Delirium
Hallucinations
Mania
Age (possibly) GABA
antagonism
Recent FDA
safety alert
(use with caution)
Cephalosporins[2,3,6,7,8]
Most common:
cefepime,
ceftazidime,
cefazolin
Confusion
Delirium
NCSE
Seizures
Age
Preexisting
neurologic
disease
Renal impairment/
improper dose for
patients
creatinine
clearance
GABA
antagonism
(beta-lactam
side chain)
Beta-lactam ring
interaction with
BZD receptor
Watch for
patients who
need renal
dosing
Penicillins[2,6]
Most common:
piperacillin/
tazobactam
Bizarre behavior
Confusion
Delirium
Disorientation
Hallucinations
NCSE
Seizures
Age
Preexisting
neurologic
disease
Renal impairment
(especially creatinine
clearance < 15
mL/min) and/or
dialysis
GABA
antagonism
(beta-lactam
side chain)
Beta-lactam ring
interaction with
BZD receptor
Watch for
patients who
need renal
dosing
Carbapenems[2,6,7,18,19]
Most common:
imipenem,
ertapenem
Cognitive
impairment
Delirium
Hallucinations
Psychosis
syndrome
Seizures
Age
Preexisting
neurologic
disease
Renal impairment
GABA
antagonism
(beta-lactam
side chain)
Beta-lactam ring
interaction with
BZD receptor
Meropenem
and doripenem
are less likely
offenders
Imipenem
metabolite has
prolonged half-
life in the
setting of renal
impairment
Macrolides[2,20]
Most common:
clarithromycin,
erythromycin
Acute psychosis
Delirium
Mania
Age
Cytochrome P450
3A4 substrates
Interactions with
GABA and
glutamate
Change in
cortisol and
prostaglandin
metabolism
Cytochrome
P450 drug
interactions
Case reports of
azithromycin-
associated
delirium in
elderly
patients;
however,
clarithromycin
and
erythromycin
are more
common
offenders
Sulfonamides[2,4,21]
Most common:
TMP/SMX
Acute psychosis
Aseptic meningitis
Hallucinations
Age (especially in
HIV-infected
patients)
Dose
Renal impairment
Unknown More likely in
high-dose
regimens (eg,
Pneumocystis
jirovecii

pneumonia
prophylaxis in
patients with
HIV)
Metronidazole[2,9,22,23,24] Agitation
Altered mental
status
Cerebellar
dysfunction
Encephalopathy
Ototoxicity
Peripheral
neuropathy
Psychosis
Seizures
Cumulative
exposure
Use in
combination with
disulfiram
Metabolite inhibition of
RNA protein
synthesis
Modification of
GABA receptor
Be aware of
cumulative
exposure
and/or large
doses
Oxazolidinones[2,10,11]
Most common:
linezolid
Delirium
Encephalopathy
Peripheral
neuropathy
Serotonin
syndrome
Age
Alcohol abuse
Concomitant
serotonergic
drugs
Diabetes
Preexisting
neurologic disease
Unknown Increased
postmarketing
reports
Watch for
concomitant
serotonergic
drugs
Azole antifungals[1,12]
Most common:
voriconazole
Delirium
Hallucinations
Serum voriconazole
concentration >
5.5 µg/mL
Unknown Posaconazole
and
fluconazole
less frequent
offenders
Acyclovir[25,26,27] Confusion
Impaired
consciousness
Dose
Renal impairment
Unknown Postmarketing
reports with
famciclovir and
valacyclovir;
however, both
are less
frequent
offenders than
acyclovir
Oseltamivir[13,14,15,16,28,29] Anxiety
Behavioral change
Delirium
Delusions
Convulsions
Encephalitis
Sleep disturbance
Suicidal ideation
Age
Genetic
differences (possibly)
Inhibition of
nicotinic
acetylcholine
receptor
Inhibition of
monoamine
oxidase A
More common
in children
Might be
underreported
Difficult to
distinguish
between
adverse drug
reaction and
symptoms of
the flu
Amantadine and
rimantadine[30]
Anxiety
Behavioral change
Delirium
Hallucinations
Nervousness
Age
Psychiatric
disorder
Renal impairment
Seizure disorder
Unknown Amantadine
more common
offender
Can be seen in
normal doses
in healthy,
young adults

BZD = benzodiazepine; FDA = US Food and Drug Administration; GABA = gamma-aminobutyric acid; NCSE = nonconvulsive status epilepticus; TMP/SMX = trimethoprim/sulfamethoxazole
aNeurotoxicity can present in many forms, such as abnormal behavior, agitation, altered mental status, confusion, delirium, hallucinations, mania, psychosis, seizures, and sleep disturbance. In the Table, the most common symptoms are listed; however, any change in mental status should prompt a review of all medications, including antimicrobials.

Prevention and Management

Prolonged delirium in the inpatient setting has been linked to increased length of hospital stay, increased risk for mortality, and increased costs.[1,17] The prevention of adverse neurologic effects entails prudent drug use and choice, appropriate individualized dosing and therapeutic monitoring, and limiting therapy duration as appropriate.

Patient and family counseling, clinician appreciation of the potential for adverse events, and careful patient observation for potential signs and symptoms will assist in early recognition.

If altered mental status related to antimicrobials is suspected, management may involve a decrease in the drug dose, selection of another antimicrobial, or discontinuation if possible. In most cases, discontinuing the offending agent will lead to resolution of symptoms within 48 hours.[2] The temporary use of supportive measures, including pharmacologic agents, may be necessary in some severe cases.


Source: http://www.medscape.com/viewarticle/873864_2


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