Antibiotics and Mental Status Changes

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 Neurotoxicity^a	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.

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