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QUINOLONE DERIVATIVES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Information concerning this group is primarily about nalidixic acid. There is much less known concerning the toxic effects of the others. The quinolones are derivatives of the cinnoline (1-2,benzodizaine) ring system.

Specific Substances

    A) CINOXACIN
    1) 1-Ethyl-1,4-dihydro-4-oxo-1,3-dioxolol(4,5-g)
    2) cinnoline-3-carboxylic acid
    3) Azolinic acid
    4) Compound 64716
    5) Molecular Formula: C12-H10-N2-O5
    6) (1,3)dioxolo(4,5-g)cinnoline-3-carboxylic acid
    7) CAS 28657-80-9
    NALIDIXIC ACID
    1) 1-Ethyl-1,4-dihydro-7-methyl-4-oxo-
    2) 1,8-naphthyridine-3-carboxylic acid
    3) 1-ethyl-7-methyl-1,8-naphthyridin-4-one-3-
    4) carboxylic acid
    5) 1,8-naphthyridine-3-carboxylic acid
    6) Molecular Formula: C12-H12-N2-O3
    7) Nalidixinic acid
    8) WIN-18320
    9) CAS 389-08-2
    OXOLINIC ACID
    1) 1,3-dioxolo(4,5-g)quino-line-7-carboxylic acid
    2) 5-Ethyl-5,8-dihydro-8-oxo-1,3 dioxo(4,5-g)
    3) quinoline-7-carboxylic acid
    4) Molecular Formula: C13-H11-N-O5
    5) W-4565
    6) CAS 14698-29-4
    PIPEMIDIC ACID
    1) 1489-RB
    2) 8-Ethyl-5,8-dihydro-5-oxo-2-(piperazin-1-yl) pyrido[2,3-d]pyrimidine-6-carboxylic acid
    3) Acido pipemidico
    4) Acidum Pipemidicum Trihydricum
    5) Pipemidico, acido
    6) Piperamic acid
    7) Molecular Formuala: C14-H17-N5-O3
    8) CAS 51940-44-4 (anhydrous pipemidic acid)
    9) CAS 72571-82-5 (pipemidic acid trihydrate)
    ROSOXACIN
    1) Acrosoxacin
    2) Win-35213.
    3) 1-Ethyl-1,4-dihydro-4-oxo-7-(4-pyridyl)
    4) quinoline-3- -carboxylic acid.
    5) Molecular Formula: C17-H14-N2-O3
    6) CAS 40034-42-2.

Available Forms Sources

    A) FORMS
    1) NALIDIXIC ACID: Is available as 250 mg/5 mL oral suspension and 250 mg, 500 mg, 1 g caplets (Prod Info NegGram(R), nalidixic acid, 2000).
    2) CINOXACIN: Is available as 250 mg and 500 mg capsules (Prod Info Cinobac(R), cinoxacin, 1995).
    3) PIPEMIDIC ACID: Is not available in the US.
    4) ROSOXACIN: Is investigational in the United States with Sanofi Winthrop Pharmaceuticals.
    B) USES
    1) NALIDIXIC ACID: Is an antibacterial used primarily in urinary tract infections against gram negative organisms. It is not related to the sulfonamides, antibiotics, or nitrofurans (Islam & Sreedharan, 1965).
    2) OXOLINIC ACID: was developed about the same time as nalidixic acid and has a similar spectrum of efficacy and side effects. Oxolinic acid (Utibid(R); Parke-Davis) is no longer marketed in the United States.
    3) CINOXACIN: Is an antibacterial closely related structurally to nalidixic and oxolinic acids. It differs in that its activity is reduced only slightly in the presence of serum, has a lower incidence of side effects, less resistance development, and less CNS and neuromuscular toxicity (Sisca et al, 1985).
    4) ROSOXACIN: Is a 4-quinolone antibacterial agent, active against Neisseria gonorrhea (S Sweetman , 2001).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) The quinolone derivatives have similar toxicity, but differ in the incidence and extent of these effects.
    B) NALIDIXIC ACID - Nausea, vomiting, lethargy, toxic psychosis, convulsions, increased intracranial pressure, hyperglycemia, or metabolic acidosis may occur in overdose. Visual disturbances and photophobia have also been reported.
    C) The CNS effects of cinoxacin are primarily those of CNS depression, with seizures not reported in animal studies. Mydriasis and musculoskeletal changes were reported.
    0.2.4) HEENT
    A) Hazy vision, photophobia, halos, inability to focus, color perception changes, diplopia, and visual hallucinations have been reported.
    0.2.5) CARDIOVASCULAR
    A) Hypotension has been reported in overdose.
    0.2.7) NEUROLOGIC
    A) Seizures may occur with nalidixic acid.
    B) Coma with marked hypotonia, and increased intracranial pressure have been reported.
    0.2.8) GASTROINTESTINAL
    A) Vomiting has been reported in overdose.
    0.2.10) GENITOURINARY
    A) Crystalluria and nephrolithiasis have been reported with therapeutic use.
    0.2.11) ACID-BASE
    A) Metabolic acidosis has been reported with nalidixic acid poisoning.
    0.2.13) HEMATOLOGIC
    A) Hemolytic anemia, leukopenia, and thrombocytopenia have been reported.
    0.2.15) MUSCULOSKELETAL
    A) Arthralgias, myalgias, and polyarthritis have been reported.
    0.2.16) ENDOCRINE
    A) Hyperglycemia and glucosuria have been reported.
    0.2.18) PSYCHIATRIC
    A) Psychotic behavior has been reported.
    0.2.20) REPRODUCTIVE
    A) Nalidixic acid is classified as FDA pregnancy category C. In animal studies, nalidixic acid was teratogenic and embryocidal in rats. There was also a prolonged gestation, growth retardation, and fetal and neonatal death in rats at doses 4 times the human dose.
    B) Because nalidixic acid is found in the breast milk and the drug is contraindicated in infants less than 3 months of age, nalidixic acid is contraindicated in nursing mothers. Quinolones, including nalidixic acid, have been shown to cause arthropathy in juvenile animals.

Laboratory Monitoring

    A) Therapeutic nalidixic acid levels are thought to be 20 to 50 mcg/mL.
    B) Monitor blood sugar and acid-base status.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) There is no specific antidote for toxicity due to the quinolone antibiotics. Treatment is directed at controlling seizures, correcting acidosis, and respiratory support during coma.
    B) Adequate hydration may prevent crystalluria.
    C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    D) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    F) Patient should be monitored for the potential of increased intracranial pressure, hyperglycemia, and metabolic acidosis.

Range Of Toxicity

    A) SURVIVAL - A 19-year-old developed coma, hypotonia, and severe metabolic acidosis after taking as much as 28 grams of nalidixic acid. The patient survived following supportive therapy.
    B) SEIZURES - Have been reported in children receiving 50 mg/kg per day or greater of nalidixic acid. Seizures may also be seen at therapeutic doses.
    C) SERUM LEVELS - Serious symptoms have occurred at nalidixic acid serum levels between 146 to 185 mcg/mL, but symptoms have been noted with as little as 25 mcg/mL.

Clinical Effects

Summary Of Exposure

    A) The quinolone derivatives have similar toxicity, but differ in the incidence and extent of these effects.
    B) NALIDIXIC ACID - Nausea, vomiting, lethargy, toxic psychosis, convulsions, increased intracranial pressure, hyperglycemia, or metabolic acidosis may occur in overdose. Visual disturbances and photophobia have also been reported.
    C) The CNS effects of cinoxacin are primarily those of CNS depression, with seizures not reported in animal studies. Mydriasis and musculoskeletal changes were reported.

Heent

    3.4.1) SUMMARY
    A) Hazy vision, photophobia, halos, inability to focus, color perception changes, diplopia, and visual hallucinations have been reported.
    3.4.3) EYES
    A) NALIDIXIC ACID is especially prone to cause hazy vision and sensitivity to bright lights, even at therapeutic doses (Philips et al, 1979). Photophobia, halo formation, flashing lights, inability to focus, color perception changes, diplopia, and visual hallucinations have also been noted with these agents (Gleckman et al, 1979).
    B) CINOXACIN - Mydriasis was a sign reported in animal toxicity studies (Sisca et al, 1983).
    C) ROSOXACIN - Vision disturbances may infrequently occur with therapeutic ingestion (S Sweetman , 2001).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypotension has been reported in overdose.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) NALIDIXIC ACID - Hypotension has been reported in overdose cases of nalidixic acid (Leslie et al, 1984).

Respiratory

    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DYSPNEA
    a) CINOXACIN - Delayed respirations were reported in animal models studying the toxicity of cinoxacin (Sisca et al, 1983).

Neurologic

    3.7.1) SUMMARY
    A) Seizures may occur with nalidixic acid.
    B) Coma with marked hypotonia, and increased intracranial pressure have been reported.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) Side effects reported during quinolone therapy include headache, confusion, hallucinations, tremulousness, drowsiness, and dizziness. The frequency of these side effects is roughly: oxolinic acid greater than nalidixic acid greater than cinoxacin (Gleckman et al, 1979; Mohring & Madsen, 1971). It is unclear which of these side effects might occur in overdose. Dizziness and drowsiness may occur with therapeutic rosoxacin ingestion (S Sweetman , 2001).
    B) BENIGN INTRACRANIAL HYPERTENSION
    1) Increased intracranial pressure has been reported in infants, children, adolescents, and adults (Boreus & Sundstrom, 1967; Gedroye & Shorvon, 1982; Deonna & Guignard, 1974; Kremer et al, 1967). Anderson et al (1971) reported papilledema and palsy of the 6th nerve in a 5-year-old given 43.5 g in therapeutic doses over 58 days (Anderson et al, 1971).
    C) SEIZURE
    1) NALIDIXIC ACID - Seizures may occur while on nalidixic acid therapy. This primarily occurs with patients with underlying seizure disorders, but may also occur with healthy individuals (Poe et al, 1984; Fraser & Harrower, 1977).
    a) Seizures have also been reported in overdose (Jo et al, 1979; Fraser & Harrower, 1977).
    D) COMA
    1) CASE REPORT - Coma with marked hypotonia and absence of corneal reflexes was reported in a 19-year-old who ingested 28 g of nalidixic acid (Nogue et al, 1979), and has occurred with much lower doses (Granstrom & Santesson, 1984).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS DEPRESSION
    a) CINOXACIN - Human overdose cases were not found, but animal studies indicate sedation, inhibition of somatic behavior, ataxia, and hypoactivity to be the primary effects. These effects were less severe than with nalidixic acid (Sisca et al, 1983).

Gastrointestinal

    3.8.1) SUMMARY
    A) Vomiting has been reported in overdose.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) NALIDIXIC ACID - Vomiting has been reported in overdoses of nalidixic acid (Jo et al, 1979).

Genitourinary

    3.10.1) SUMMARY
    A) Crystalluria and nephrolithiasis have been reported with therapeutic use.
    3.10.2) CLINICAL EFFECTS
    A) CRYSTALLURIA
    1) OXOLINIC ACID - Crystalluria and nephrolithiasis have been reported with therapeutic doses of oxolinic acid (Daudon et al, 1987).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEMORRHAGE
    a) CINOXACIN (RAT) - Renal hemorrhage has been reported in rat studies of cinoxacin. Studies done on other animals have not demonstrated this effect, and it may be a symptom specific to that species (Sisca et al, 1983). This effect has not been reported in human overdose.

Acid-Base

    3.11.1) SUMMARY
    A) Metabolic acidosis has been reported with nalidixic acid poisoning.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) NALIDIXIC ACID - Metabolic acidosis has been reported in several cases of nalidixic acid poisoning, and might be expected during overdose with the other agents (Nogue et al, 1979; Dash & Mills, 1976).
    B) LACTIC ACIDOSIS
    1) NALIDIXIC ACID - Lactic acidosis has been reported in several nalidixic acid overdose cases, but the exact relationship to nalidixic acid itself is yet unclear (Phillips et al, 1979).

Hematologic

    3.13.1) SUMMARY
    A) Hemolytic anemia, leukopenia, and thrombocytopenia have been reported.
    3.13.2) CLINICAL EFFECTS
    A) HEMOLYTIC ANEMIA
    1) NALIDIXIC ACID - Hemolytic anemia has been reported in therapeutic and occupational exposures, primarily in patients exposed to nalidixic acid and with erythrocyte G-6-PD deficiency (Alessio & Morselli, 1972; Mandal & Stevenson, 1970) Tafani et al, 1982).
    B) LEUKOPENIA
    1) OXOLINIC ACID has caused transient leukopenia during therapy (Atlas et al, 1969).
    2) Adverse effects, following therapy with other quinolones, may include leukopenia, eosinophilia, thrombocytopenia, and pancytopenia (Gleckman et al, 1979).
    C) THROMBOCYTOPENIC DISORDER
    1) Six cases of thrombocytopenia secondary to nalidixic acid in elderly patients were reported by the Netherlands Centre for Monitoring of Adverse Reactions to Drugs. Thrombocytopenia occurred in all patients (53 to 91 years of age) receiving doses of 4 g daily of nalidixic acid for 10 to 15 days. Withdrawal of the drug resulted in recovery within 4 days to 1 week. Platelet counts ranged from 6 to 27 x 10(9)/L, and hemorrhagic complications occurred in 5 patients (petechiae, epistaxis, vaginal bleeding) (Meyboom, 1984).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) PHOTOSENSITIVITY
    1) Photosensitivity is a common side effect with therapeutic use of these agents (Sisca et al, 1983).
    B) ERUPTION
    1) Nalidixic acid may cause rash, pruritus, urticaria, and angioedema (Prod Info NEGRAM(R) caplets, 2004).

Musculoskeletal

    3.15.1) SUMMARY
    A) Arthralgias, myalgias, and polyarthritis have been reported.
    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) Adverse effects reported with quinolone derivatives while on therapy include arthralgia, myalgia, and polyarthritis (Gleckman et al, 1979; Carmichael & Martin, 1988).
    B) LACK OF EFFECT
    1) NALIDIXIC ACID is known to cause extensive damage to juvenile cartilage in animals, but is licensed for use in children over 3 months of age. Schaad & Wedgewood-Krucko (1987) found no increase in incidence of arthropathy in children receiving nalidixic acid for 9 to 600 days(Schaad & Wedgwood-Krucko, 1987).
    3.15.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ARTHROPATHY
    a) CINOXACIN - Animal data would indicate similar damage/malformations to cartilage and weight-bearing joints as reported with nalidixic acid (Sisca et al, 1983).

Endocrine

    3.16.1) SUMMARY
    A) Hyperglycemia and glucosuria have been reported.
    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) NALIDIXIC ACID - Hyperglycemia and glycosuria have been reported in several cases of nalidixic acid overdose (Fraser & Harrower, 1977; Islam & Sreedharan, 1965).
    a) There is some concern that these results may represent false-positives, but at least one report has demonstrated hyperglycemia using a glucose-specific method (Fraser & Harrower, 1977).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) NALIDIXIC ACID - At least 1 case of anaphylactic shock has been attributed to nalidixic acid.
    a) CASE REPORT - A 37-year-old male developed an acute anaphylactic reaction following a single 1 g oral dose for chronic pyelonephritis.
    1) Between 1 and 10 minutes after administration of the drug, the patient developed symptoms of dyspnea, generalized weakness, skin rash, dizziness, and heat sensation.
    2) At 20 to 25 minutes, he developed symptoms of cyanosis and acrocyanosis, facial edema, hoarseness, and hypotension (70/40 mmHg). The pulse rate was 130/min.
    3) The patient was treated with corticosteroids and assisted ventilation and recovered (Merkuriev et al, 1976).
    2) CASE SERIES - CINOXACIN has also caused anaphylaxis. Stricker et al (1988) reported 3 cases of anaphylactic reactions to cinoxacin, which started as soon as ten minutes post-dosing of a second course.
    B) ACUTE ALLERGIC REACTION
    1) Hypersensitivity reactions, including rash, pruritus, urticaria, angioedema, eosinophilia, arthralgia with joint stiffness and swelling, erythema multiforme and Stevens-Johnson syndrome have been reported with nalidixic acid and other drugs in this class (Prod Info NEGRAM(R) caplets, 2004).

Reproductive

    3.20.1) SUMMARY
    A) Nalidixic acid is classified as FDA pregnancy category C. In animal studies, nalidixic acid was teratogenic and embryocidal in rats. There was also a prolonged gestation, growth retardation, and fetal and neonatal death in rats at doses 4 times the human dose.
    B) Because nalidixic acid is found in the breast milk and the drug is contraindicated in infants less than 3 months of age, nalidixic acid is contraindicated in nursing mothers. Quinolones, including nalidixic acid, have been shown to cause arthropathy in juvenile animals.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of nalidixic acid (Prod Info NegGram(R) oral caplets, 2008).
    B) LACK OF EFFECT
    1) In one study of pregnant women being treated with nalidixic acid (n=63), intracranial hypertension or defects attributable to nalidixic acid were not observed (Murray, 1981).
    C) ANIMAL STUDIES
    1) RATS - Nalidixic acid was teratogenic when rats were exposed to oral doses at 6 times the human dose (Prod Info NegGram(R) oral caplets, 2008).
    2) RATS - No increase in expected defects was identified in animal studies (Sato et al, 1980).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to nalidixic acid during pregnancy in humans (Prod Info NegGram(R) oral caplets, 2008).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified nalidixic acid as FDA Pregnancy Category C (Prod Info NegGram(R) oral caplets, 2008).
    C) PLACENTAL BARRIER
    1) Nalidixic acid is transported easily across the placenta, and alteration of kinetic parameters in the newborn results in delayed elimination of the drug (Peiker & Traeger, 1983).
    D) ANIMAL STUDIES
    1) RATS - Nalidixic acid was embryocidal when rats were exposed to oral doses at 6 times the human dose. Nalidixic acid also prolonged the duration of pregnancy, especially at 4 times the clinical dose (Prod Info NegGram(R) oral caplets, 2008).
    2) RATS - Growth retardation in the rat fetus was observed with doses of 200 to 300 mg/kg. Fetal and neonatal death in this study were unusually high with doses almost 4 times the usual human dose of nalidixic acid (Sato et al, 1980).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Nalidixic acid is contraindicated in infants less than 3 months of age and the drug has been shown to be excreted in human breast milk. Therefore, nalidixic acid is contraindicated in nursing mothers (Prod Info NegGram(R) oral caplets, 2008).
    2) Following an oral dose of 2 grams nalidixic acid, 0.003% of the dose was distributed in active form in the breast milk in 24 hours. Minimum inhibitory concentrations were never reached in the milk, and 6 to 8 hours after the dose the milk/plasma ratio was 0.061 (Traeger & Peiker, 1980).
    B) ANIMAL STUDIES
    1) Quinolones, including nalidixic acid, have been shown to cause arthropathy in juvenile animals
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to nalidixic acid (Prod Info NegGram(R) oral caplets, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Therapeutic nalidixic acid levels are thought to be 20 to 50 mcg/mL.
    B) Monitor blood sugar and acid-base status.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) NALIDIXIC ACID - Therapeutic levels are thought to be in the 20 to 50 mcg/mL range (Gleckman et al, 1979).
    2) HYPERGLYCEMIA and glucosuria may occur. A glucose-specific test should be used because the glucuronides of nalidixic acid present in the urine may produce glucuronic acid which would become a reducing agent and produce false-positives in some cases (Klumpp, 1965; Fraser & Harrower, 1977).
    B) ACID/BASE
    1) ACIDOSIS - Arterial blood gases and plasma lactate levels may be required to reveal metabolic acidosis.
    4.1.3) URINE
    A) URINALYSIS
    1) Glucosuria may occur. A glucose-specific test shouldbe used because the glucuronides of nalidixic acid present in the urine may produce glucuronic acid which would become a reducing agent and produce false-positives in some cases (Klumpp, 1965; Fraser & Harrower, 1977).

Methods

    A) SPECTROSCOPY/SPECTROMETRY
    1) The quinolones may be analyzed by spectrophotofluorometric assay (Boreus & Sundstrom, 1967).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Therapeutic nalidixic acid levels are thought to be 20 to 50 mcg/mL.
    B) Monitor blood sugar and acid-base status.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    C) ALKALINE DIURESIS
    1) Alkaline diuresis is thought to increase the rate of excretion of the quinolone antibiotics. It has never been shown to affect outcome after overdose and is NOT routinely recommended.
    2) SODIUM BICARBONATE/INITIAL DOSE
    a) Administer 1 to 2 milliequivalents/kilogram of sodium bicarbonate as an intravenous bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. In patients with underlying dehydration additional administration of 0.9% saline may be needed to maintain adequate urine output (1 to 2 milliliters/kilogram/hour). Manipulate bicarbonate infusion to maintain a urine pH of at least 7.5.
    3) SODIUM BICARBONATE/REPEAT DOSES
    a) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.
    4) CAUTION
    a) Obtain hourly intake/output and urine pH. Assure adequate hydration and renal function prior to alkalinization. Do not administer potassium to an oliguric or anuric patient. Monitor fluid and electrolyte balance carefully. Monitor blood pH, especially in intubated patients, to avoid severe alkalemia.
    D) MONITORING OF PATIENT
    1) Patients should be monitored for the potential of increased intracranial pressure, hyperglycemia, and metabolic acidosis. The metabolic acidosis may need correction.
    E) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Patients ingesting an overdose of a quinolone should be kept well hydrated to prevent crystalluria (Prod Info, 1990a).

Abstracts

Case Reports

    A) NALIDIXIC ACID
    1) ADULT
    a) Nogue et al (1979) describes a case of a 19-year-old girl who ingested 28 g of nalidixic acid (Nogue et al, 1979).
    1) She was admitted with severe metabolic acidosis and coma. After receiving 600 mEq of sodium bicarbonate, she developed respiratory alkalosis with secondary tetany.
    2) She regained consciousness after 9 hours, and the acid-base disturbance was resolved after sixty hours.
    b) Leslie et al (1984) report a woman who ingested 32 g nalidixic acid (Leslie et al, 1984a). She developed lactic acidosis, hyperglycemia, seizures, and abnormal behavior. Maximum plasma concentration of nalidixic acid was 185 mg/L. Patient was discharged after 36 hours.
    c) Dash & Mills (1976) describe a case of severe metabolic acidosis in an 18-year-old male following overdosage of nalidixic acid in a suicide attempt(Dash & Mills, 1976).
    1) The patient had concurrently overdosed with probenecid, ethanol, Bellergal(R) tablets, propoxyphene, and Combid(R).
    2) Clinical symptoms included Kussmaul's respirations, alternating with a stupurous state and a combative state. Serum nalidixic acid concentration was 297 mcg/mL.
    3) Arterial blood gases revealed metabolic acidosis (pCO2 15 mmHg, pO2 116 mmHg, pH 7.08). Serum sodium was 146 mEq, serum potassium was 3.8 mEq/L, serum chloride 100 mEq/L, and serum bicarbonate 4 mEq/L.
    4) Electrocardiogram revealed sinus tachycardia. The patient was given 50% dextrose (50 mL) and 0.8 mg naloxone with no effect. Diuresis was initiated with 50 mEq sodium bicarbonate and 25 g mannitol in normal saline.
    5) The patient eventually recovered, and renal function improved. Simultaneous ingestion of probenecid may have accentuated the effects of nalidixic acid by prolonging the serum half-life.
    2) PEDIATRIC
    a) Jost & Jungst (1972) report symptoms of acute intoxication from nalidixic acid in an 8-year-old female following a therapeutic overdose of 4 g over a period of 7.5 hours(Jost & Jungst, 1972).
    1) The patient was initially unconscious, and then developed symptoms of excitation and extrapyramidal symptoms. Motor restlessness was pronounced, and she was unable to speak intelligibly.
    2) No significant abnormalities were evident with reflex activity or circulation. Forced diuresis was initiated and the patient recovered within 1 day.
    b) Islam & Sreedharan (1965) describe a case of hyperglycemia, glycosuria, and seizures in a 14-year-old female following overdosage of nalidixic acid (6500 mg) as a single dose (Islam & Sreedharan, 1965).

Range Of Toxicity

Summary

    A) SURVIVAL - A 19-year-old developed coma, hypotonia, and severe metabolic acidosis after taking as much as 28 grams of nalidixic acid. The patient survived following supportive therapy.
    B) SEIZURES - Have been reported in children receiving 50 mg/kg per day or greater of nalidixic acid. Seizures may also be seen at therapeutic doses.
    C) SERUM LEVELS - Serious symptoms have occurred at nalidixic acid serum levels between 146 to 185 mcg/mL, but symptoms have been noted with as little as 25 mcg/mL.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) NALIDIXIC ACID - 1 gram four times daily for 1 or 2 weeks; total daily dose of 4 grams. May be reduced to total daily dose of 2 grams for prolonged therapy (Prod Info NegGram(R), nalidixic acid, 2000).
    2) CINOXACIN - Usual dose is 1 g/day in 2 to 4 divided doses for 7 to 14 days in patients with uncomplicated urinary tract infections; for prophylaxis therapy 250 mg at bedtime for up to 5 months is recommended (Prod Info Cinobac(R), cinoxacin, 1995).
    3) OXOLINIC ACID - 750 milligrams twice daily (Ghatikar, 1974)
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) NALIDIXIC ACID -
    a) For children 12 years of age and younger - 55 milligrams/kilogram/day in four equally divided doses
    b) For prolonged therapy, the total daily dose may be reduced to 33 milligrams/kilogram/day. Not recommended in children under three months of age (Prod Info NegGram(R), nalidixic acid, 2000).
    2) OXOLINIC ACID (Ghatikar, 1974) -
    a) 0 to 1 year = 50 milligrams twice daily
    b) 1 to 3 years of age = 100 milligrams twice daily
    c) 4 to 5 years of age = 200 milligrams twice daily
    d) 6 years old = 300 milligrams twice daily
    e) 7 to 12 years of age = 600 milligrams twice daily

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) SPECIFIC SUBSTANCE
    a) NALIDIXIC ACID -
    1) SEIZURES - A 4-year-old who had inadvertently ingested 800 milligrams (50 milligrams/kilogram) of nalidixic acid acutely (her normal dose was 50 milligrams/kilograms/day) developed vomiting, seizures, and abnormal movements 30 minutes after ingestion (Jo et al, 1979).
    2) Seizures have also occurred in a 6-month-old who received 61.7 milligrams/kilogram/day (Boreus & Sundstrom, 1967).
    3) A 24-year-old who ingested 32 grams of nalidixic acid developed severe metabolic acidosis, seizures, hyperglycemia, and increased plasma lactate, but survived with treatment (Leslie et al, 1984).
    b) COMA - 28 grams of nalidixic acid taken by a 19-year-old produced coma, hypotonia, and severe metabolic acidosis but was survived (Nogue et al, 1979).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) NALIDIXIC ACID -
    1) The therapeutic plasma range for nalidixic acid is 20 to 50 micrograms/milliliter (Gleckman et al, 1979).
    2) TOXIC LEVELS -
    a) A 6-month-old who had been on nalidixic acid 61.7 milligrams/kilogram/day developed increased intracranial pressure and had a plasma level of approximately 25 micrograms/milliliter (Boreus & Sundstrom, 1967).
    b) Another child who was taking 50 milligrams/kilogram/day and then acutely took another 50 milligrams/kilogram developed: a serum level at 90 minutes of 146.1 micrograms/milliliter for nalidixic acid and 48.9 micrograms/milliliter for hydroxynalidixic acid (Jo et al, 1979).
    3) PEAK PLASMA LEVEL -
    a) The peak plasma nalidixic acid level after a 32-gram-ingestion was 185 micrograms/milliliter at 6 hours (Leslie et al, 1984).
    b) The metabolite hydroxynalidixic acid peak was approximately 225 micrograms/milliliter at 14 hours, and the metabolite carboxynalidixic acid peaked at 5.9 micrograms/milliliter at approximately 13 hours postingestion (Leslie et al, 1984).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA CINOXACIN
    1) LD50- (ORAL)MOUSE:
    a) 2330 mg/kg (RTECS, 2000)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 900 mg/kg (RTECS, 2000)
    3) LD50- (ORAL)RAT:
    a) 3610 mg/kg (RTECS, 2000)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) 1380 mg/kg (RTECS, 2000)
    B) NALIDIXIC ACID
    1) LD50- (ORAL)MOUSE:
    a) 572 mg/kg (RTECS, 2000)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 500 mg/kg (RTECS, 2000)
    3) LD50- (ORAL)RAT:
    a) 2040 mg/kg (RTECS, 2000)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) 1584 mg/kg (RTECS, 2000)
    C) OXOLINIC ACID
    1) LD50- (ORAL)MOUSE:
    a) 1890 mg/kg (RTECS, 2000)
    2) LD50- (ORAL)RAT:
    a) 525 mg/kg (RTECS, 2000)
    3) LD50- (SKIN)RAT:
    a) >2 g/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) These agents are antibacterial, acting by inhibiting the synthesis of DNA. Specifically, it inhibits DNA gyrase and in higher concentrations inhibits transfer RNA synthetase (Sisca et al, 1983).

Physicochemical

Physical Characteristics

    A) CINOXACIN: light tan to yellow crystals, the sodium salt is a white crystalline solid.
    B) NALIDIXIC ACID: pale buff crystalline powder

Molecular Weight

    A) CINOXACIN: 262.22
    B) NALIDIXIC ACID: 232.23
    C) OXOLINIC ACID: 261.24

References

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