Kari A. Mergenhagen, PharmD

Central nervous system effects of clarithromycin, beta-lactams, and fluoroquinolones occur because of their GABA-A antagonist action. Agents that have dose dependent activity include: Linezolid, which can exhibit CNS activity via its monoamine oxide (MAO) inhibitor activity; metronidazole, which causes neuropsychiatric effects with cumulative or supratherapeutic levels; and tetracyclines, which are more likely to cause CNS effects in patients with reduced CYP2C19 activity.

Nearly all antibiotic agents have been associated with CNS effects. Although uncommon, these events can be severe. Once the antibiotic is discontinued, effects are usually reversible. It is important for mental health care providers to recognize antibiotics as a potential cause of neuropsychiatric adverse effects, as discontinuation often leads to rapid recovery.

Beta-lactams include penicillins, cephalosporins, and carbapenems. Generally, they are considered broad spectrum antibiotic agents that may act as GABA-A antagonists in a dose dependent fashion to produce neurotoxicity. The beta-lactam ring is structurally similar to the GABA antagonist bicuculline. CNS effects include seizures, encephalopathy, tremors, hyperactivity, and excitability.

 Piperacillin/tazobactam and ampicillin are the penicillins most likely to contribute to CNS adverse effects. Quinton and colleagues

 examined the effects of a piperacillin/tazobactam continuous infusion and found symptoms such as decreased level of consciousness, delayed awakening after sedation cessation, myoclonus, seizures, and hallucinations. The onset of piperacillin/tazobactam neurotoxicity is usually within seven days, with renal impairment as a predisposing factor. Ampicillin neurotoxicity is more likely to occur in low-birthweight infants where there is increased permeability of the blood-brain barrier.

 Cefepime and ceftazidime are the most common cephalosporins to cause nonconvulsive status epilepticus, which presents as altered mental status. In critically ill patients, myoclonus and decreased consciousness were the most common symptoms of cefepime- associated neurotoxicity.

 Renal impairment appears to be the largest risk factor, and discontinuation of the cephalosporin results in resolution of symptoms.

 Carbapenems are associated with seizure activity because of its antagonism of the GABA-A receptor.

 Risk factors for seizure activity include renal insufficiency, advanced age, history of seizures, and stroke. Ertapenem has been associated with psychosis-patients have presented with delusions and both visual and auditory hallucinations. Neurotoxicity from ertapenem can persist for up to 14 days after discontinuation. Meropenem and ertapenem may also cause delirium.

Metronidazole is used for protozoal infections and bacterial vaginosis. It is also used for anaerobic coverage in intra-abdominal infections and for toxic megacolon caused by 

. Metronidazole can cause psychosis; it is thought to be a result of inhibition of monoamine oxidase (MAO), a dopamine catabolizing enzyme. Psychosis generally resolves within 14 days of discontinuation. Contributing factors for psychosis include the concurrent use of disulfiram and supratherapeutic metronidazole levels. Cumulative metronidazole exposure is believed to contribute to neurotoxicity (doses 13-228 g).

 Seizures have been linked to cumulative doses of more than 40 grams. Impaired renal or hepatic function are risk factors for supratherapeutic levels and cumulative exposure, thereby increasing the risk of adverse effects.

Other neurotoxic symptoms associated with metronidazole include peripheral neuropathy, paresthesia, ataxia, and encephalopathy. Slow onset myoclonus is a common feature of metronidazole induced encephalopathy. These adverse effects may be due to metabolites of metronidazole which inhibit the GABA receptor in the vestibular and cerebellar system.

Macrolides, including clarithromycin, azithromycin, and erythromycin, are used to treat respiratory infections, peptic ulcer disease caused by 

, sexually transmitted diseases, and mycobacterium avium complex. Of all the macrolides, clarithromycin has been associated with the most CNS adverse effects.

Neurotoxicity associated with clarithromycin can manifest as mania, delirium, acute psychosis, and even hallucinations. It is also one of the most common causative agents of antibiomania, referring to antibiotics that can cause mania.

 A few case reports of clarithromycin-induced psychiatric manifestations in children describe a different clinical picture with symptoms that range from hypomania and aggression to insomnia and even hypersomnia.

 Visual hallucinations have been reported in patients taking clarithromycin in the setting of end-stage renal disease.

Although rare, there are case reports of azithromycin causing psychosis, delirium, and hallucinations in elderly patients who did not have an underlying psychiatric disorder.

It may be that the CNS effects of macrolides are due to GABA-A antagonism because of their ability to produce epileptogenic activity.7 Other theories include drug interactions and accumulation of clarithromycin’s active metabolite, as macrolides are substrates of CYP3A4 (clarithromycin and erythromycin are also CYP3A4 inhibitors).

It is unclear whether the CNS effects are dose dependent-neurotoxicity has occurred at low doses and supratherapeutic ranges have produced no CNS adverse effects. Often when CNS toxicity developed the patient had a pre-existing psychiatric disorder, which confers greater risk.

Fluoroquinolones are among the most frequently reported causes of antibiotic-induced neuropsychiatric reactions. Based on a recent study, fluoroquinolones may be more commonly associated with delirium and psychosis than previously thought.

 Like macrolides, it is suspected that GABA-A antagonism causes proconvulsant activity, leading to adverse CNS effects.6 Additionally, fluoroquinolones have been reported to affect N-methyl-d-aspartate (NMDA) receptors in vitro, but further studies are needed to fully elucidate its mechanism.

The most common neuropsychiatric-related adverse effects from fluoroquinolones are excitatory effects, including insomnia, dizziness, headache, nervousness, and restlessness, which usually resolve upon discontinuation. Fluoroquinolone antibiotics can also cause more serious reactions. They have a black-box warning for potentially disabling and irreversible adverse effects including CNS events.

Seizures and status epilepticus can occur due to GABA-A inhibition. Therefore, fluoroquinolones should be used with caution in patients with a history of epilepsy. Encephalopathy, antibiomania, delirium, hallucinations, and acute psychosis are among the other neurotoxic manifestations associated with fluoroquinolones.

Findings indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for neurotoxicity when given concomitantly with fluoroquinolones.

 A single-center, retrospective study of 631 hospitalized veterans who received a fluoroquinolone for at least 48 hours found that FQ-induced delirium or psychosis was more prevalent in elderly patients and in those who were prescribed a first-generation antipsychotic.9 Caution is advised when prescribing fluoroquinolones in this patient population.

Linezolid and tedizolid comprise the oxazolidinone class of antibiotics. These antibiotics are used for vancomycin-resistant 

 infections. Skin and skin structure infections and pneumonia are common indications for oxazolidinone antibiotics.

Linezolid exerts its CNS action through MAO inhibition, which is an enzyme responsible for the metabolism of monoamine neurotransmitters (dopamine, norepinephrine and serotonin). Tyramine-rich foods and co-administration with other serotonergic medications may enhance the risk of hypertensive crises and serotonin syndrome. The significance of this interaction, however, has been questioned due to linezolid’s low affinity for MAO and subsequent low degree of MAO inhibition.

There are limited neuropsychiatric data available for tedizolid, however, in vitro testing showed that tedizolid reversibly inhibited MAO enzymes similar to linezolid. Therefore, similar precautions are advised for tedizolid.

Linezolid has also been associated with peripheral and optic neuropathy, with vision loss in adults and children.

 This adverse reaction appears to primarily occur with extended courses of therapy (ie, longer than 28 days). Peripheral neuropathy appears to be most commonly reported and can be permanent.

 Optic neuropathy typically improves or completely resolves after discontinuation of linezolid, although it may occasionally be permanent.

The mechanism of neuropathy is thought to be due to inhibition of protein synthesis and subsequent mitochondrial injury, in addition to its ability to penetrate the CNS. Several reviews indicate risk factors for developing linezolid associated-neuropathy are pre-existing neurologic disease, alcohol abuse, diabetes, chemotherapy, and antiviral therapy.

Nitrofurantoin is used for the treatment and prophylaxis of cystitis. This antibiotic has been associated with peripheral neuropathy. Although the association of nitrofurantoin with peripheral neuropathy is rare, the risk appears to be increased in patients with anemia, renal impairment (CrCl < 60 mL/m), diabetes mellitus, vitamin B deficiency, debilitating disease, or electrolyte imbalance.

 The onset of neuropathy also appears to be dose and duration independent.

The exact mechanism inciting nitrofurantoin-associated neuropathy is unknown; however, it may be due to axon loss. A literature review found that neuropathy developed primarily in patients who had impaired renal function, noted by uremia.

 The combination of uremia and serum accumulation of nitrofurantoin could potentially contribute to neuropathy. Caution should be used when using nitrofurantoin in patients with these conditions.

Sulfamethoxazole-trimethoprim is a sulfonamide antibiotic that works via interference of folic acid synthesis. It has gram negative and positive activity and is approved for the treatment of a variety of infections including skin and skin structure, urinary tract, and some respiratory tract infections.

Psychiatric effects of sulfamethoxazole-trimethoprim have been well described, with reports dating as far back as 1942. Originally, most psychiatric symptoms were associated with use of sulfamethoxazole-trimethoprim for treatment of urinary tract infections. However, immunocompromised patients are at increased risk for acute psychosis. Geriatric patients also appear to be at an increased risk for neuropsychiatric effects, specifically hallucinations and psychosis, which is likely due to increased rates of renal impairment.

Other neuropsychiatric effects include neurotoxicity, hallucinations, depression, apathy, nervousness, and other general psychotic symptoms.

 Sulfonamide antibiotics have the ability to cross the blood-brain barrier, which may account for the development of such effects. A glutathione and tetrahydrobiopterin deficiency has also been postulated. Episodes of aseptic eosinophilic meningitis have additionally been described, possibly due to a type 1 hypersensitivity reaction.

It appears that a temporal relationship exists, with neuropsychiatric symptoms often developing between 3 to 10 days following initiation of therapy.

 Effects have been shown to be dose dependent and resolve upon discontinuation of therapy. Reduction in infusion rate or change from intravenous to oral therapy has been shown to decrease the risk of or improve neuropsychiatric effects.

Tetracycline antibiotics, including doxycycline and minocycline, are approved for the treatment of respiratory infections, skin and soft tissue infections, and several tick-borne diseases. While there are some reports that tetracycline antibiotics-doxycycline, in particular-may have beneficial neuropsychiatric effects, the majority of the literature regarding tetracyclines does not support this.

Most of the literature regarding neuropsychiatric effects is on minocycline. The effects include vestibular symptoms such as tinnitus, blurred vision, light headedness, dizziness, vertigo, and loss of balance. The mechanism of injury from minocycline was originally thought to be due to changes in liquid volume and ion concentration secondary to its osmotic activity. Female gender and those of advanced age are at an increased risk for the development of these symptoms, probably because of the higher serum concentrations as a result of smaller body size and the lipophilic nature of minocycline.

Other neuropsychiatric adverse effects of tetracyclines vary in severity, with the most serious resulting in suicide. The suspected mechanism of action is supratherapeutic levels as a result of CYP2C19 mutations. Pseudotumor cerebri is also a rare but serious adverse effect that may be due to decreased cerebrospinal fluid absorption. This is also a noteworthy reaction as related symptoms may be irreversible, despite discontinuation of therapy. Aside from pseudotumor cerebri and suicidality, neuropsychiatric symptoms are generally reversible with discontinuation of tetracycline therapy.

Monitoring, early detection, and discontinuation of the offending agent is essential for antibiotics that have the potential for neuropsychiatric adverse effects. Neuropsychiatric complications may be curtailed if prescribers are aware of the potential psychiatric reactions that exist among the various antibiotics. The 

provides a synopsis of the various neuropsychiatric reactions potentially caused by antibiotics. Depending on the pathogen, however, some antibiotics may be unavoidable. Therefore, early detection of any psychiatric disturbance is essential.

We can avoid repeated exposure to antibiotics that have caused neuropsychiatric events in patients by utilizing the allergy and adverse reaction section of the patient’s medical record. Although this seems redundant, it is often overlooked and not done in practice.

Antibiotics have the potential to cause neuropsychiatric adverse events, which can complicate the treatment of infections in patients who have a preexisting psychiatric disorder. Individualizing antibiotic utilization for each infectious process may help avoid these potential neuropsychiatric complications. For example, if a patient with a psychiatric disorder who is treated with psychotropics is found to have a methicillin-resistant Staphylococcus aureus infection, it may be optimal to avoid a medication like linezolid and to utilize other available options.

Some antibiotics, like the fluoroquinolones, are notorious for causing CNS effects; therefore, it may be ideal to avoid using these agents in this patient population, or to use with caution.

The clinical picture becomes even more complex if the patient has a psychiatric disorder with concomitant allergies to antibiotics or if the pathogen is resistant. This will often require utilization of a particular antibiotic that may be known for its psychiatric adverse effects. Monitoring, early detection, and discontinuation will prevent these events from worsening or from becoming debilitating.

Dr Skelly is a Clinical Pharmacist, Pharmacy Department and Department of Psychiatry; Dr Wattengel is a Clinical Pharmacist, Pharmacy Department and Department of Infectious Diseases, Dr Starr is is a Clinical Pharmacist, Pharmacy Department, Dr Sellick is a Medical Doctor, Department of Infectious Diseases, and Dr Mergenhagen is a Clinical Pharmacist, Pharmacy Department and Department of Infectious Diseases, Veteran Affairs Western New York Healthcare System, Buffalo, NY.

The authors report no conflicts of interest concerning the subject matter of this article.

 Quinton MC, Bodeau S, Kontar L, et al. Neurotoxic concentration of piperacillin during continuous infusion in critically ill patients. 

 Fugate JE, Kalimullah EA, Hocker SE, et al. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. 

 Mattappalil A, Mergenhagen KA. Neurotoxicity with antimicrobials in the elderly: a review. 

 Bhattacharyya S, Darby RR, Raibagkar Pet al. Antibiotic-associated encephalopathy. 

 Norrby SR. Neurotoxicity of carbapenem antibacterials. 

 Lambrichts S, Van oudenhove L, Sienaert P. Antibiotics and mania: a systematic review. 

 Zareifopoulos N, Panayiotakopoulos G. Neuropsychiatric effects of antimicrobial agents. 

 Ma TK, Chow KM, Choy AS, et al. Clinical manifestation of macrolide antibiotic toxicity in CKD and dialysis patients. 

 Sellick J, Mergenhagen K, Morris L, et al. Fluoroquinolone-Related Neuropsychiatric Events in Hospitalized Veterans. 

 Zyvox (linezolid) [prescribing information]. New York, NY: Pharmacia and Upjohn; July 2018.

 Sivextro (tedizolid) [prescribing information]. Whithouse Station, NJ: Merck; March 2019.

 Macrobid (nitrofurantoin) [prescribing information]. Pine Brook, NJ: Almatica Pharma; June 2018.

 Toole JF, Parrish ML. Nitrofurantoin polyneuropathy. 

 Bactrim (sulfamethoxazole and trimethoprim) [prescribing information]. Philadelphia, PA: Mutual Pharmaceutical; June 2013.

Articles

Nearly all antibiotic agents have been associated with CNS effects. Although uncommon, these events can be severe.

Kari A. Mergenhagen, PharmD

Articles

Psychiatric Adverse Effects of Antibiotics