Amotrex400 mg

Amotrex 400 mg is a broad-spectrum antimicrobial agent with potent activity against anaerobic bacteria and protozoa. It is indicated for a wide range of parasitic, protozoal, and anaerobic bacterial infections across multiple organ systems and medical specialties.

Anaerobic Bacterial Infections

• Surgical Prophylaxis — prevention of postoperative infections due to anaerobic bacteria, particularly Bacteroides species and anaerobic streptococci. Amotrex 400 mg is one of the most widely used agents for surgical prophylaxis in abdominal, pelvic, and colorectal surgery.
• Septicemia and Bacteremia — systemic bloodstream infections caused by susceptible anaerobic organisms
• Peritonitis — intra-abdominal infection and inflammation of the peritoneum caused by anaerobes
• Brain Abscess — intracranial abscess caused by anaerobic bacteria, where Amotrex 400 mg's excellent CNS penetration is a key clinical advantage
• Pelvic Abscess — localized pelvic collections of pus caused by anaerobic organisms
• Pelvic Cellulitis — spreading bacterial infection of pelvic soft tissues
• Postoperative Wound Infections — anaerobic infections of surgical wounds
• Anaerobically Infected Leg Ulcers and Pressure Sores — chronic wound infections with anaerobic organisms, including malodorous infected ulcers where Amotrex 400 mg gel may be applied topically
• Antibiotic-Associated Pseudomembranous Colitis — caused by Clostridioides difficile (formerly Clostridium difficile) toxin; Amotrex 400 mg is used as first-line or alternative therapy for mild to moderate C. difficile-associated diarrhea (CDAD)

Protozoal and Parasitic Infections

• Amoebiasis — All Forms
  • Intestinal amoebiasis — dysentery and colitis caused by Entamoeba histolytica
  • Extra-intestinal amoebiasis — hepatic amoebic abscess and other invasive forms
  • Asymptomatic cyst passers — treatment of carrier state to eradicate the organism and prevent spread
• Giardiasis — intestinal infection with Giardia lamblia (Giardia intestinalis), causing chronic diarrhea, bloating, and malabsorption
• Urogenital Trichomoniasis — sexually transmitted infection caused by Trichomonas vaginalis, causing vaginitis in women and urethritis in men; both sexual partners should be treated simultaneously to prevent reinfection

Gynecological Infections

• Bacterial Vaginosis — also known as non-specific vaginitis, caused by the overgrowth of anaerobic bacteria (including Gardnerella vaginalis) in the vaginal flora; treated effectively with oral or vaginal Amotrex 400 mg

Oral and Dental Infections

• Acute Ulcerative Gingivitis — also known as necrotizing ulcerative gingivitis (NUG) or Vincent's angina; a painful bacterial infection of the gums caused by anaerobic oral flora including Fusobacterium and Spirochetes
• Acute Dental Infections — periapical abscesses, periodontal infections, and other dental infections caused by anaerobic oral bacteria

Amoebicides / Antiprotozoal Drugs / Anti-diarrhoeal Antimicrobials / Antibacterial Agents (Anaerobes)

Amotrex 400 mg is a synthetic 5-nitroimidazole antimicrobial agent that belongs to the imidazole class of antibacterial drugs. It is classified therapeutically as both an antiprotozoal agent and an antianaerobic antibacterial. It is unique among antimicrobials in its highly selective activity against obligate anaerobic organisms and certain protozoa — organisms that exist and thrive in low-oxygen or oxygen-free environments.

Mechanism of Action

Amotrex 400 mg is a prodrug that requires intracellular activation to exert its antimicrobial effect. The activation mechanism is selective for anaerobic or microaerophilic organisms:

1. Intracellular Reduction: The 5-nitro group of the Amotrex 400 mg molecule is reduced intracellularly by electron transport proteins unique to anaerobic organisms — specifically by low-redox-potential electron carriers such as ferredoxin, flavodoxin, and pyruvate-ferredoxin oxidoreductase (PFOR). This reductive activation only occurs in cells with sufficiently low intracellular redox potential — which is characteristic of obligate anaerobes and certain protozoa, but not of aerobic mammalian cells.
2. Formation of Cytotoxic Reactive Intermediates: Reduction generates short-lived, highly reactive nitro radical anions and other reduced toxic intermediates.
3. DNA Strand Break and Disruption: These reduced metabolites interact directly with microbial DNA — causing single-strand and double-strand breaks in the DNA helix, inhibiting DNA synthesis and repair, and leading to rapid bacterial cell death. This mechanism produces a bactericidal and protozoicidal effect.

Key selectivity: Aerobic mammalian cells cannot reduce Amotrex 400 mg's nitro group at physiologically normal redox potentials, explaining why the drug is selectively toxic to anaerobes and protozoa while being well tolerated in humans at therapeutic doses.

Spectrum of Activity

• Anaerobic bacteria: Bacteroides fragilis and the entire Bacteroides group, Fusobacterium spp., Clostridium spp. (including C. difficile and C. perfringens), anaerobic streptococci (peptostreptococci), Veillonella spp., and other obligate anaerobes
• Protozoa: Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis, Blastocystis hominis
• Microaerophilic bacteria (off-label use): Helicobacter pylori (as part of combination regimens), Gardnerella vaginalis
• Not active against: Aerobic bacteria, fungi, viruses, and spirochetes

Pharmacokinetics

• Absorption: Amotrex 400 mg is rapidly and almost completely absorbed following oral administration, with bioavailability approaching 100%. Food may delay but does not significantly reduce absorption. Peak plasma concentrations are reached within 1 to 2 hours after an oral dose.
• Distribution: Amotrex 400 mg distributes widely throughout body tissues and fluids. It achieves excellent concentrations in:
  • Cerebrospinal fluid (CSF) — excellent CNS penetration, making it the drug of choice for brain abscesses and CNS anaerobic infections (CSF concentrations are approximately 100% of serum levels)
  • Saliva, bile, peritoneal fluid, vaginal secretions, seminal fluid, bone, and breast milk
  • Liver abscesses (achieving high intracavitary concentrations)
  Plasma protein binding is low — approximately 20%.
• Metabolism: Extensively metabolized in the liver by oxidation and glucuronide conjugation. The major metabolite — hydroxy-Amotrex 400 mg — retains significant antibacterial activity (approximately 30–65% of parent drug activity). Other metabolites are largely inactive. This hepatic metabolism is clinically important: significant hepatic impairment reduces drug clearance and requires dose reduction.
• Half-life: Approximately 6 to 8 hours in adults with normal hepatic function — allowing three-times-daily or twice-daily dosing. The active hydroxy-metabolite has a similar half-life.
• Elimination: Amotrex 400 mg and its metabolites are excreted primarily in the urine (approximately 60–80% of the dose) and to a lesser extent in feces (6–15%). Only a small fraction of unchanged parent drug appears in the urine. Urine may appear dark or brown due to the presence of Amotrex 400 mg metabolites — patients should be warned of this harmless discoloration.

Oral Tablets

• Amotrex 400 mg tablets should be taken with or after food to reduce the risk of gastrointestinal side effects (nausea, stomach discomfort).
• Swallow tablets whole with a full glass of water. Do not crush or chew film-coated tablets if applicable.
• For twice-daily or three-times-daily regimens, space doses as evenly as possible throughout the day (e.g., every 8 hours for TID dosing) to maintain consistent blood levels.
• Complete the full prescribed course even if symptoms improve early — incomplete courses may cause relapse and promote antimicrobial resistance.
• Do not consume alcohol during treatment or for at least 24–48 hours after completing the course — a disulfiram-like reaction will occur (see Drug Interactions).

Oral Suspension

• Shake the bottle well before each use to ensure uniform distribution.
• Use the calibrated measuring device provided — do not use a regular household teaspoon.
• May be given with or after food to minimize GI side effects.
• Store as directed on the label — typically at room temperature; do not freeze.

Vaginal Gel

• Use the applicator provided to administer the gel intravaginally. Fill the applicator as instructed and insert it into the vagina as far as it will comfortably go, then slowly push the plunger to deposit the gel.
• For once-daily dosing, apply at bedtime to maximize retention and improve local drug contact time within the vagina.
• A thin sanitary pad may be worn to protect clothing from any vaginal discharge.
• Do not use tampons, douche, or use other vaginal products during treatment unless directed by a physician.
• Wash hands thoroughly before and after use.
• Do not use Amotrex 400 mg vaginal gel for trichomoniasis — the vaginal route does not achieve adequate therapeutic levels in the urogenital tract for this infection; oral systemic therapy is required.

Suppositories (Rectal)

• Wash hands before and after insertion.
• If the suppository is too soft, refrigerate briefly before use.
• Remove the foil wrapper and insert the suppository pointed end first, gently into the rectum.
• Remain still for a few minutes after insertion to allow adequate absorption and retention.
• Suppositories are useful when oral administration is not possible or when rectal absorption is preferred (e.g., vomiting patients or perioperative use).
• Store suppositories below 25°C — avoid excessive heat.

IV Infusion

• Amotrex 400 mg IV infusion is for intravenous administration only and is ready to use — do not dilute the infusion solution further.
• Must not be mixed with any other drug in the same infusion bag or line. Administer as a separate infusion through a dedicated line, or flush the line before and after administration.
• Administer at a rate of 5 ml per minute (a 100 ml bag containing 500 mg should be infused over approximately 20 minutes).
• Inspect the infusion solution for particulate matter and discoloration before use. Discard if the solution appears cloudy or contains visible particles.
• Switch to oral Amotrex 400 mg as soon as the patient can tolerate oral medication.
• Discard any unused portion of an opened infusion bottle — single use only.

Alcohol — Critical Interaction (Disulfiram-Like Reaction)

This is the most widely known and practically important drug interaction with Amotrex 400 mg. Amotrex 400 mg inhibits the enzyme acetaldehyde dehydrogenase, which is responsible for the second step in alcohol metabolism (conversion of acetaldehyde to acetate). When alcohol is consumed concurrently with Amotrex 400 mg, acetaldehyde accumulates in the blood, causing a highly unpleasant and potentially dangerous disulfiram-like (Antabuse) reaction, including:

• Severe flushing and facial redness
• Intense nausea and vomiting
• Tachycardia (rapid heart rate) and palpitations
• Headache and dizziness
• Hypotension and sweating
• In severe cases: arrhythmias and cardiovascular collapse

Patients must not consume alcoholic beverages or any medications or preparations containing alcohol (including mouthwashes, cough syrups, and some liquid medications) during Amotrex 400 mg treatment and for at least 24–48 hours after the last dose.

Disulfiram (Avoid Combination — Contraindicated)

The concurrent use of Amotrex 400 mg and Disulfiram (a drug used to treat alcohol dependence) has been associated with psychotic reactions and confusion. This combination is clinically contraindicated. A washout period of at least 2 weeks between disulfiram and Amotrex 400 mg is recommended.

Warfarin and Oral Anticoagulants (Important Interaction)

Amotrex 400 mg significantly potentiates the anticoagulant effect of warfarin by inhibiting its hepatic catabolism (through CYP2C9 inhibition), leading to increased warfarin plasma levels and a substantially elevated risk of hemorrhagic events. This interaction can lead to life-threatening bleeding if not managed. In patients who must receive both drugs:

• Monitor INR/prothrombin time more frequently — at least every 2–3 days during concurrent Amotrex 400 mg treatment
• Reduce the warfarin dose as clinically indicated based on INR monitoring
• Resume normal anticoagulation monitoring after completing the Amotrex 400 mg course

Lithium

Amotrex 400 mg may increase plasma lithium concentrations, raising the risk of lithium toxicity (tremor, confusion, nausea, polyuria, cardiac arrhythmias). Serum lithium levels should be closely monitored when Amotrex 400 mg is added to or removed from a lithium regimen.

Cyclosporin

When co-administration of Amotrex 400 mg and cyclosporin is necessary, both serum cyclosporin and serum creatinine levels should be closely monitored. Amotrex 400 mg may increase cyclosporin plasma concentrations, with potential nephrotoxic consequences in transplant recipients.

Phenytoin and Phenobarbital (CYP Enzyme Inducers)

Phenytoin and phenobarbital are potent inducers of hepatic cytochrome P450 enzymes that metabolize Amotrex 400 mg. Co-administration results in increased elimination of Amotrex 400 mg, leading to reduced Amotrex 400 mg plasma concentrations and potentially insufficient therapeutic drug levels. If concurrent use is necessary, monitor clinical response and consider increasing the Amotrex 400 mg dose.

5-Fluorouracil (5-FU)

Amotrex 400 mg reduces the clearance of 5-fluorouracil, resulting in increased plasma levels and potentially significantly increased toxicity of 5-FU (myelosuppression, mucositis, diarrhea, nausea). This interaction requires careful dose adjustment and close monitoring when both drugs are used in oncology combination regimens.

Busulfan

Amotrex 400 mg may increase plasma levels of busulfan (a chemotherapy agent used in conditioning regimens for hematopoietic stem cell transplantation). Elevated busulfan levels can lead to severe busulfan toxicity — including veno-occlusive disease of the liver, seizures, and severe myelosuppression. Co-administration should be avoided; if unavoidable, busulfan plasma levels must be closely monitored.

Amotrex 400 mg is generally well tolerated at standard doses for usual treatment durations. Most adverse effects are dose-related and more likely with prolonged therapy. The following have been reported:

Gastrointestinal Effects (Most Common)

• Metallic or bitter taste — one of the most frequently reported and characteristic adverse effects; usually mild and transient
• Nausea — very common; taking Amotrex 400 mg with food significantly reduces this
• Vomiting
• Diarrhea
• Abdominal pain and cramping
• Anorexia (loss of appetite)
• Furring of the tongue and oral thrush (candidiasis) — particularly with prolonged therapy
• Rarely: pancreatitis

Central Nervous System Effects

• Drowsiness and sedation
• Dizziness and vertigo
• Headache
• Rare: Peripheral neuropathy — numbness, tingling, burning, and paresthesia of the hands and feet; more common with prolonged or high-dose therapy. Usually reversible upon discontinuation, but may be irreversible in severe cases.
• Rare: Central neuropathy — including ataxia (coordination problems), encephalopathy, confusion, and seizures/convulsions; associated with high doses or prolonged treatment. Discontinue Amotrex 400 mg immediately if significant CNS effects occur.

Skin and Hypersensitivity Reactions

• Skin rash, urticaria (hives), and pruritus (itching)
• Flushing
• Angioedema — rare
• Anaphylaxis — very rare but has been reported

Urinary Effects

• Dark or brownish discoloration of urine — due to the presence of Amotrex 400 mg metabolites; harmless and reversible; patients should be warned in advance
• Dysuria (painful urination) — reported occasionally
• Rarely: cystitis (bladder inflammation)

Hematological Effects (Rare)

• Leukopenia (decreased white blood cell count) — more common with prolonged therapy; usually reversible
• Neutropenia — regular leucocyte count monitoring is recommended during extended treatment courses
• Thrombocytopenia (rare)

Hepatic Effects (Rare)

• Transient elevation of liver enzymes (ALT, AST, alkaline phosphatase)
• Cholestatic hepatitis — rarely reported

Vaginal Gel-Specific Side Effects

• Vaginal discharge, burning, and irritation at the application site
• Vulvar or vaginal pruritus
• Rarely: pelvic discomfort
• Systemic side effects are significantly less frequent with vaginal gel due to lower systemic absorption compared to oral formulations

Important warning: If signs of significant central or peripheral neuropathy develop (ataxia, confusion, convulsions, severe paresthesia), Amotrex 400 mg should be discontinued immediately and the patient evaluated.

Pregnancy

The US FDA Pregnancy Category of Amotrex 400 mg is Category B. Animal reproduction studies have not demonstrated evidence of fetal harm, teratogenicity, or impaired fertility. However, there are no adequate and well-controlled studies of Amotrex 400 mg in pregnant women. Because animal reproductive toxicology studies are not always predictive of human outcomes, Amotrex 400 mg should be used during pregnancy only if clearly needed and when the clinical benefit to the mother outweighs any theoretical risk to the fetus.

First trimester: Use should be avoided unless no suitable alternative exists. Amotrex 400 mg has been shown to be mutagenic in bacteria and carcinogenic in rodents at high doses — while human carcinogenicity has not been established, caution during organogenesis (first trimester) is prudent.

Second and third trimesters: Amotrex 400 mg may be used when clinically necessary, particularly for systemic anaerobic infections and trichomoniasis (for which it remains the most effective oral treatment). For trichomoniasis specifically, treatment should be deferred to the second trimester where possible.

Pregnant women with trichomoniasis who receive Amotrex 400 mg should be advised that the treatment is for symptomatic relief and infection clearance, and that their sexual partner must also be treated to prevent reinfection.

Lactation

Amotrex 400 mg is excreted into human breast milk and achieves concentrations similar to maternal plasma levels. The estimated infant dose from breastfeeding is approximately 10–13% of the maternal weight-adjusted dose — which is below the typical therapeutic dose given to infants directly.

While no adverse effects on breastfed infants have been definitively established at the doses used to treat the mother, caution should be exercised when Amotrex 400 mg is administered to a nursing woman. Options to consider include:

• For short-course treatment (e.g., single 2 g dose for trichomoniasis): a feeding "pump and discard" strategy for 12–24 hours after the dose, while expressing and discarding breast milk, can reduce infant exposure. Resume breastfeeding after this washout period.
• For prolonged courses: temporarily discontinuing breastfeeding for the duration of Amotrex 400 mg treatment should be considered, with the physician weighing the significant benefits of breastfeeding for both mother and infant against the low but uncertain risk of infant exposure.
• A clinical decision should always be made in consultation with the treating physician.

Prolonged and High-Dose Therapy — Neurological Monitoring

If Amotrex 400 mg must be administered for longer than the usually recommended treatment duration — due to compelling clinical necessity — the following monitoring is mandatory:

• Regular hematological monitoring — complete blood count with leucocyte count should be performed periodically, as neutropenia and leukopenia may develop
• Neurological monitoring — patients should be closely monitored for signs of peripheral neuropathy (paresthesia, numbness, tingling) or central neuropathy (ataxia, dizziness, confusion, convulsions). If significant neurological adverse reactions develop, Amotrex 400 mg should be discontinued immediately.

Hepatic Impairment — Dose Reduction Required

Amotrex 400 mg is primarily metabolized by hepatic oxidation. In patients with advanced hepatic insufficiency, Amotrex 400 mg clearance may be substantially impaired, leading to significant drug accumulation. In patients with hepatic encephalopathy, high plasma concentrations of Amotrex 400 mg may worsen encephalopathic symptoms — creating a particularly dangerous cycle. Therefore:

• Amotrex 400 mg should be administered with caution in patients with hepatic impairment
• The daily dosage should be reduced to one-third of the normal dose and administered as a single daily dose in patients with advanced hepatic disease
• Liver function should be monitored during therapy

Alcohol — Absolute Prohibition

Patients must be explicitly and clearly warned that they must not consume any alcoholic beverages or alcohol-containing preparations (including certain mouthwashes, cough mixtures, and topical medications) during treatment with Amotrex 400 mg and for at least 24–48 hours after the final dose. The disulfiram-like reaction can be severe and potentially dangerous.

Urine Discoloration

Patients should be warned that Amotrex 400 mg may cause their urine to appear dark or brownish in color. This is caused by Amotrex 400 mg metabolites excreted in the urine and is a harmless and reversible phenomenon — it does not indicate kidney damage or hematuria and requires no clinical action.

Treatment of Sexual Partners in Trichomoniasis

In trichomoniasis, treatment of the patient alone is often insufficient to achieve a cure. Both sexual partners must be treated simultaneously to eliminate the infection and prevent reinfection. If the partner is not treated concurrently, reinfection of the treated patient is highly likely.

Candida Superinfection

Amotrex 400 mg may cause overgrowth of Candida species (oral or vaginal thrush) — particularly with prolonged use. Monitor for signs of candidiasis during extended therapy and treat appropriately with antifungal agents if needed.

Carcinogenicity Considerations

Amotrex 400 mg has been shown to be mutagenic in bacteria (Ames test) and carcinogenic in rodents at doses substantially higher than those used therapeutically in humans. The clinical relevance of these findings to short-course human therapeutic use is uncertain, and no increased incidence of cancer has been definitively established from clinical or epidemiological data in humans. Nevertheless, unnecessary use of Amotrex 400 mg should be avoided, and prolonged therapy should only be undertaken when clearly indicated and with appropriate clinical monitoring.

Amotrex 400 mg has a relatively wide safety margin at commonly available doses. The following is known from reported overdose cases:

• Single oral doses of Amotrex 400 mg up to 12 g have been reported in suicide attempts and accidental overdoses in adults.
• Symptoms observed in reported overdose cases were generally limited to:
  • Nausea and vomiting
  • Ataxia — difficulty with coordination and balance
  • Slight disorientation and confusion
  • Paresthesia (tingling/numbness) — reflecting the neurotoxic potential at high concentrations
  • In severe cases: convulsions and peripheral neuropathy

Management of Overdose

• There is no specific antidote for Amotrex 400 mg overdose
• Management is symptomatic and supportive:
  • Gastric lavage or activated charcoal if presented within 1 hour of ingestion (and patient is conscious with intact airway protection)
  • Monitor and maintain vital signs, neurological status, and respiratory function
  • Convulsions should be managed with appropriate anticonvulsants (e.g., IV diazepam)
  • Maintain adequate hydration
• Amotrex 400 mg is dialyzable — hemodialysis can effectively reduce plasma Amotrex 400 mg levels in cases of serious toxicity or in renally impaired patients

In the event of suspected Amotrex 400 mg overdose, contact a poison control center or seek emergency medical care immediately.

• Store tablets, suspension, and vaginal gel below 30°C, in a cool, dry place protected from direct light.
• Keep all formulations out of the reach of children.
• Do not use any formulation after the expiry date printed on the label or packaging.
• Oral suspension: Store at room temperature below 30°C. Keep the bottle tightly closed. Do not refrigerate unless specifically stated on the label; chilling may cause the suspension to thicken. Shake well before each use and use within the stated shelf-life after opening or reconstitution (typically 7–14 days).
• Vaginal gel: Store at room temperature below 25°C–30°C. Do not freeze. Keep the tube tightly closed after use. Discard within the period stated on the label after first opening.
• IV infusion bottles: Store below 30°C, protected from light, in original packaging. Do not freeze. Inspect for clarity before use and discard if solution is discolored or contains visible particulates. Single-use only — discard any unused portion immediately after use.
• Store all Amotrex 400 mg products away from moisture and heat sources (avoid bathroom cabinets).

Patients with Hepatic Impairment

Amotrex 400 mg is primarily metabolized in the liver by oxidative pathways. In patients with advanced hepatic insufficiency or hepatic encephalopathy:

• Substantial impairment of Amotrex 400 mg clearance occurs, leading to significant drug accumulation
• The resulting high plasma concentrations may worsen symptoms of hepatic encephalopathy
• Amotrex 400 mg should be administered with great caution in these patients
• The daily dosage should be reduced to one-third of the normal dose, administered as a single daily dose
• Liver function and clinical neurological status should be closely monitored during therapy
• In mild to moderate hepatic impairment, no dose adjustment is usually required, but monitoring is advisable

Patients with Renal Impairment

The elimination half-life of Amotrex 400 mg itself remains essentially unchanged in the presence of renal failure, as the parent drug is primarily eliminated via hepatic metabolism. Therefore, no dose adjustment is required for Amotrex 400 mg in patients with renal failure based on conventional pharmacokinetic principles.

However, Amotrex 400 mg metabolites (including the hydroxy-metabolite with residual antibacterial activity) are primarily renally excreted and accumulate in patients with renal failure. The clinical significance of this metabolite accumulation is not fully established, but caution is warranted in severe renal failure.

Hemodialysis: Amotrex 400 mg and its metabolites are efficiently removed during an 8-hour hemodialysis session. Therefore, Amotrex 400 mg should be re-administered immediately after each hemodialysis session to restore therapeutic plasma levels.

Peritoneal dialysis (IDP or CAPD): No routine dose adjustment or supplemental dosing is required in patients undergoing either intermittent peritoneal dialysis or continuous ambulatory peritoneal dialysis.

Elderly Patients

No specific age-based dose adjustment is recommended for elderly patients, as the pharmacokinetics of Amotrex 400 mg are not significantly altered by aging alone. However, elderly patients are more likely to have reduced hepatic metabolic capacity, and liver function should be considered when prescribing Amotrex 400 mg in this population. Use the lowest effective dose and be alert for accumulation effects — particularly neurological effects — in elderly patients with hepatic dysfunction.

Pediatric Patients

Amotrex 400 mg is approved for use in children across a wide range of indications with age-appropriate and weight-based dosing. The suspension formulation is preferred for infants and young children. The safety and efficacy of Amotrex 400 mg in children under 1 year of age are not as extensively studied — use in neonates and young infants should be under close specialist medical supervision, with awareness of the potential for CNS toxicity due to immature blood-brain barrier function in very young infants.