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IMIPENEM/CILASTATIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Imipenem, a thienamycin derivative, is a carbapenem beta-lactam antibiotic. It is developed from cultures of Streptomyces cattleya. Cilastatin is a renal dipeptidase inhibitor. It inhibits renal breakdown of imipenem and enhances efficacy. Imipenem is supplied in a 1:1 mixture with cilastatin.

Specific Substances

    A) IMIPENEM
    1) (5R,6S)-6-[(R)-1-Hydroxyethyl]-3-(2-iminomethyl
    2) aminoethylthio)-7-oxo-1-azabicyclo[3.2.0]hept
    3) -2-ene-2-carboxylic acid monohydrate
    4) N-formimidoyl Thienamycin
    5) Gorillamicin
    6) Imipemide
    7) MK 787
    8) MK-0787
    9) N-Formamidoylthienamycin monohydrate
    10) Thienamycin formamidine monohydrate
    11) Molecular Formula: C12-H17-N3-O4-S-H2O
    12) CAS 64221-86-9 (anhydrous imipenem)
    13) CAS 74431-23-5 (imipenem monohydrate)
    CILASTATIN
    1) Cilastatinum Natricum
    2) MK-791
    3) (Z)-(S)-6-Carboxy-6- -[(S)-2,2-dimethylcycl
    4) opropanecarboxamido]hex- -5-enyl-L-cysteine,
    5) monosodium salt
    6) Molecular Formula: C16-H25-N2-Na-O5-S
    7) CAS 82009-34-5 (cilastatin)
    8) CAS 81129-83-1 (cilastatin sodium)
    Group Terms
    1) Cilastatin/imipenem

Available Forms Sources

    A) FORMS
    1) Imipenem/cilastatin is available as a 1:1 mixture in powder for solution vials containing either 250, 500 or 750 mg of each component for IV or IM administration (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2012).
    B) USES
    1) Imipenem/cilastatin is indicated in treating severe infections due to multiresistant organisms. It may be used for serious mixed infections including lower respiratory tract, intra-abdominal, and gynecologic infections (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2012).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Imipenem/cilastatin is indicated in treating severe infections due to multiresistant organisms. It may be used for serious mixed infections including lower respiratory tract, intra-abdominal, and gynecologic infections.
    B) PHARMACOLOGY: Imipenem, a thienamycin antibiotic, inhibits bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs) 1A, 1B, 2,4,5, and 6 of Escherichia coli and 1A, 1B, 2, 4, and 5 of Pseudomonas aeruginosa, with lethal effects attributed to its binding to PBP 2 and PBP 1B. It resists the action of beta-lactamases, both penicillinases and cephalosporinases, produced by gram-negative and gram-positive bacteria and it is also effective against a variety of bacteria. Cilastatin sodium, the sodium salt of a derivatized heptenoic acid, exhibits a synergistic effect with the antibiotic imipenem by preventing the renal enzyme dehydropeptidase I from breaking down imipenem.
    C) EPIDEMIOLOGY: Overdose is rare. No fatalities directly attributed to imipenem/cilastatin have been reported.
    D) WITH THERAPEUTIC USE
    1) Imipenem/cilastatin is usually well-tolerated. Since most patients receiving imipenem/cilastatin are severely ill, it is difficult to determine causal relationship of adverse effects to therapy of imipenem/cilastatin. Rash, pruritus, urticaria, seizures, hematologic abnormalities (eg, Leukopenia, granulocytopenia, and eosinophilia), hepatic enzyme abnormalities, and GI disturbances (eg, nausea, vomiting, diarrhea) have been observed following therapeutic use. These have usually resolved spontaneously following discontinuation of the drug. Hypotension, usually transient, and tachycardia were occasionally noted in clinical trials. Pseudomembranous colitis has rarely developed. Imipenem is a beta-lactam antibiotic, and allergic crossreactivity has been demonstrated with other beta-lactam agents such as penicillins or cephalosporins.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there are limited reports of overdose with imipenem/cilastatin. It is anticipated that overdose effects may be an extension of events reported with therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Imipenem/cilastatin has been classified as FDA pregnancy category C. There are no adequate and well-controlled studies of imipenem/cilastatin use during pregnancy. No evidence of teratogenicity has been noted in animals. The combination of imipenem/cilastatin should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. It is unknown whether imipenem/cilastatin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when imipenem/cilastatin is administered to a nursing mother.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential with platelet count and liver enzymes in symptomatic patients.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. HYPERSENSITIVITY REACTION: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. ANAPHYLAXIS: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be required following an overdose; however, aggressive airway management is indicated in patients that develop a significant hypersensitivity/anaphylactoid reaction.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Imipenem/cilastatin is cleared well by hemodialysis. Approximately 73% imipenem and 82% cilastatin are removed during a 4-hour hemodialysis procedure; however, as severe toxicity is highly unlikely, hemodialysis is almost never indicated.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Imipenem/cilastatin is generally only used in the hospital setting.
    2) OBSERVATION CRITERIA: Patients with more than mild symptoms should be evaluated in a healthcare facility. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, dehydration, persistent seizures, and severe allergic reaction.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PHARMACOKINETICS
    1) Tmax: Imipenem, IM: (with 1% lidocaine), 2 hours; cilastatin sodium, IM: (with 1% lidocaine), 1 hour. Bioavailability: Imipenem, (IM, with 1% lidocaine), approximately 75%. Cilastatin sodium: approximately 95%. Protein binding: imipenem, 20%; cilastatin, 40%. Vd: 0.14 to 0.23 L/kg. Metabolism: Kidney, extensive. Extensive metabolism by a dipeptidase (dehydropeptidase-1) in the brush border of the proximal renal tubular cells to an open- lactam metabolite. Elimination half-life: Imipenem: (IM), approximately 2 to 3 hours; (IV), approximately 1 hour. Cilastatin sodium: (IV), approximately 1 hour.
    I) DIFFERENTIAL DIAGNOSIS
    1) Overdose with other antibiotics.

Range Of Toxicity

    A) TOXICITY: The minimal toxic or lethal dose is not well established in the literature.
    B) THERAPEUTIC DOSES: adults: 1 gram to 4 grams IV; MAX: 50 mg/kg/day or 4 grams/day IV or 1500 mg/day IM. CHILDREN 12 YEARS OF AGE AND OLDER: 500 to 750 mg IM every 12 hours for mild to moderate infections. Maximum: 1500 mg/day. GREATER THAN 3 MONTHS OF AGE AND OLDER: 60 to 100 mg/kg/day IV divided every 6 hours. Maximum 500 mg/dose for fully susceptible organisms and maximum 1 g/dose for moderately susceptible organisms including P. aeruginosa. 4 WEEKS TO 3 MONTHS: 25 mg/kg/dose every 6 hours. 1 WEEK TO 4 WEEKS OF AGE: 25 mg/kg/dose every 8 hours. LESS THAN 1 WEEK OF AGE: 25 mg/kg/dose every 12 hours.

Clinical Effects

Summary Of Exposure

    A) USES: Imipenem/cilastatin is indicated in treating severe infections due to multiresistant organisms. It may be used for serious mixed infections including lower respiratory tract, intra-abdominal, and gynecologic infections.
    B) PHARMACOLOGY: Imipenem, a thienamycin antibiotic, inhibits bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs) 1A, 1B, 2,4,5, and 6 of Escherichia coli and 1A, 1B, 2, 4, and 5 of Pseudomonas aeruginosa, with lethal effects attributed to its binding to PBP 2 and PBP 1B. It resists the action of beta-lactamases, both penicillinases and cephalosporinases, produced by gram-negative and gram-positive bacteria and it is also effective against a variety of bacteria. Cilastatin sodium, the sodium salt of a derivatized heptenoic acid, exhibits a synergistic effect with the antibiotic imipenem by preventing the renal enzyme dehydropeptidase I from breaking down imipenem.
    C) EPIDEMIOLOGY: Overdose is rare. No fatalities directly attributed to imipenem/cilastatin have been reported.
    D) WITH THERAPEUTIC USE
    1) Imipenem/cilastatin is usually well-tolerated. Since most patients receiving imipenem/cilastatin are severely ill, it is difficult to determine causal relationship of adverse effects to therapy of imipenem/cilastatin. Rash, pruritus, urticaria, seizures, hematologic abnormalities (eg, Leukopenia, granulocytopenia, and eosinophilia), hepatic enzyme abnormalities, and GI disturbances (eg, nausea, vomiting, diarrhea) have been observed following therapeutic use. These have usually resolved spontaneously following discontinuation of the drug. Hypotension, usually transient, and tachycardia were occasionally noted in clinical trials. Pseudomembranous colitis has rarely developed. Imipenem is a beta-lactam antibiotic, and allergic crossreactivity has been demonstrated with other beta-lactam agents such as penicillins or cephalosporins.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there are limited reports of overdose with imipenem/cilastatin. It is anticipated that overdose effects may be an extension of events reported with therapeutic use.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Transient hypotension attributed to imipenem/cilastatin occurred in 6/3470 (0.2%) of patients receiving this drug in clinical trials (Calandra, 1986).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Tachycardia attributed to imipenem/cilastatin was noted in 2/3470 patients in these clinical trials (Calandra, 1986).

Heent

    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) TASTE ALTERATION: Taste alteration was noted in 3/3470 (0.1%) of patients receiving imipenem/cilastatin (Calandra, 1986).
    2) ORAL CANDIDIASIS: Oral candidiasis and hypertrophy of tongue papillae attributed to imipenem/cilastatin was noted in 14/3470 patients (0.4%) (Calandra, 1986).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension, usually transient, and tachycardia were occasionally noted in clinical trials (Calandra, 1986).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) It remains uncertain whether imipenem or one of its metabolites is the actual etiology of the seizure activity. The potential of imipenem itself to induce seizures is approximately equal to that of cefazolin (Drusano, 1986).
    b) CASE SERIES - Seizures (generalized major motor, focal motor, or myoclonic) have been reported in 1.8% (62/3470) of patients receiving imipenem/cilastatin. Only 16 patients' seizures (0.5%) were considered to be possibly, probably or definitely related to the imipenem/cilastatin. Twenty-two of these 62 patients had seizure disorders prior to ever receiving imipenem/cilastatin, and 19 others also had various pre-existing CNS disorders which were potential causes of seizure disorders (Calandra, 1986; Haruta, 1986; Meguro, 1986; Park & Parker, 1986; Solomkin, 1985).
    c) In one patient without previous risk factors for seizure activity, asterixis and encephalopathy persisted for 5 days following the discontinuation of imipenem/cilastatin (Park & Parker, 1986).
    d) CASE SERIES - However, 23/3470 patients in the imipenem/cilastatin trials did not have seizures on imipenem/cilastatin, but did have seizure activity on other antibiotics during the same admission in which they received imipenem/cilastatin.
    e) Seizure activity may be related to imipenem/cilastatin dose, possibly after adjustment for body weight and renal function (Barza, 1985; Calandra, 1986). Other factors predisposing patients to seizures include age and CNS dysfunction (Fitzsimmons et al, 1987).
    f) CASE SERIES - A retrospective study of 1754 patients receiving imipenem/cilastatin revealed 7% of patients who received a dose in excess of the manufacturer's recommendations seized while 1.6% of patients who were dosed by the recommendations seized. Of the patients who experienced seizures during treatment, 21% (10/48) had a creatinine clearance of less than 20 mL/minute, while only 3% of non-seizing patients had low clearance (Calandra et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES - A retrospective study of 1754 patients receiving imipenem/cilastatin revealed 7% of patients who received a dose in excess of the manufacturer's recommendations seized while 1.6% of patients who were dosed by the recommendations seized. Of the patients who experienced seizures during treatment, 21% (10/48) had a creatinine clearance of less than 20 mL/minute, while only 3% of non-seizing patients had low clearance (Calandra et al, 1988).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) A study of a small number of mice (n=20) showed that imipenem caused ataxia and seizure activity at blood levels of 1900 micromoles/mL. The same effects were seen with cefotaxime blood levels of 3400 micromoles/mL and penicillin levels of 5800 micromoles/mL, indicating a lower threshold for adverse effects due to imipenem (Eng et al, 1989).
    2) In animal studies, the administration of IV imipenem-cilastatin sodium in a 1:1 ratio (doses, 751 to 1359 mg/kg) to mice resulted in ataxia and clonic seizures in about 45 minutes. Death occurred in 4 to 56 minutes after all doses. In several rat studies, reduced activity, bradypnea, ataxia, tremors, ptosis, seizures, and death were observed following doses 550 to 1734 mg/kg of IV imipenem/cilastatin (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting were the most common adverse experiences noted with therapeutic doses of imipenem/cilastatin occurring in 2% of patients (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2012; Calandra, 1986). Nausea and vomiting were both more common in adult patients receiving doses exceeding 2 g/day.
    1) The nausea was sometimes related to a relatively rapid rate of infusion, and was reduced in severity by slowing the infusion rate (Wang, 1985).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea related to imipenem/cilastatin has occurred in 1% to 2% of patients receiving imipenem/cilastatin (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2012; Calandra, 1986).
    C) ANTIBIOTIC ENTEROCOLITIS
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Pseudomembranous colitis has occurred with imipenem/cilastatin therapy. Four (n=2516; 0.16%) patients treated in a large series experienced diagnostic colonoscopy findings with or without isolation of C. difficile (Calandra, 1985).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Icterus and liver enzyme elevations necessitating discontinuation of imipenem/cilastatin developed in 0.1% (3/3470) of patients. These changes resolved without further adverse effects following drug termination (Calandra, 1986).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) KIDNEY FINDING
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Renal function remained normal in 25 subjects with serious infections given imipenem/cilastatin, 1 gram intravenously every 6 hours, for a duration of 5 to 56 days (Zajac et al, 1985).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia and granulocytopenia developed in about 1% of patients receiving imipenem/cilastatin in therapeutic doses; about 70% of these were felt to be probably or possibly drug-related (Calandra et al, 1985; Calandra et al, 1983).
    B) EOSINOPHIL COUNT RAISED
    1) WITH THERAPEUTIC USE
    a) Eosinophilia, probably or possibly attributed to the imipenem/cilastatin, was observed in 3% of patients, but did not result in clinical manifestations in the studied patients (Calandra et al, 1985; Calandra et al, 1983).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytosis (1.6% of patients) and thrombocytopenia (0.3% of patients) were both noted to be probably or possibly drug-related, but clinical effects were not observed (Calandra, 1986).
    D) DIRECT COOMBS TEST POSITIVE
    1) WITH THERAPEUTIC USE
    a) Positive direct antithrombin tests (positive direct Coomb's tests) were observed in 1.5% of study patients but were not related to hemolytic anemia in these individuals (Calandra, 1986).
    E) PROTHROMBIN TIME LOW
    1) WITH THERAPEUTIC USE
    a) Prolongation of prothrombin times probably or possibly secondary to imipenem/cilastatin occurred in 0.3% of patients, but did not result in clinical bleeding problems (Calandra, 1986).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Rashes, pruritus, and urticaria developed in 2.4% of patients receiving imipenem/cilastatin, which were felt to be probably or possibly drug-related. Some but not all patients who had developed rashes following the use of other beta-lactam antibiotics also developed rashes following imipenem/cilastatin use (Calandra, 1986).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Imipenem/cilastatin is a beta-lactam derivative and has been demonstrated to extensively cross-react immunologically with penicillins (Saxon, 1987). However, in one case report of IgE-mediated anaphylactic reaction to imipenem, skin prick tests were negative to penicillin (Chen et al, 2000).
    b) Allergic reactions (including drug fever , pruritus, skin rash and urticaria) occurred in 2.7% of 2516 patients in one report (Calandra et al, 1985).
    c) IgE-mediated anaphylactic reaction to imipenem has been reported in a 52-year-old man. He developed severe arterial hypotension with consequent cardiac arrest approximately 10 minutes after the beginning of the infusion. The patient had received 2 previous courses of topical imipenem, with the second course being associated with an application-related generalized skin rash, approximately 8 weeks prior to the anaphylactic event. Autoinhibition assays revealed dose-related inhibition of IgE binding up to 90% by pre-incubating serum with imipenem (Chen et al, 2000).

Reproductive

    3.20.1) SUMMARY
    A) Imipenem/cilastatin has been classified as FDA pregnancy category C. There are no adequate and well-controlled studies of imipenem/cilastatin use during pregnancy. No evidence of teratogenicity has been noted in animals. The combination of imipenem/cilastatin should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. It is unknown whether imipenem/cilastatin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when imipenem/cilastatin is administered to a nursing mother.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) RABBITS, RATS: In animal studies, there was no evidence of adverse effects on the fetus when rabbits were administered cilastatin IV at doses up to 1.9 times the maximum recommended human dose (MRHD) and rats were administered cilastatin subQ at doses up to 3.2 times the MRHD. No evidence of teratogenicity was observed in rabbits and rats given intravenous imipenem at doses of 15, 30 or 60 mg/kg/day (up to 0.4 times the MRHD) and 225, 450, or 900 mg/kg/day (up to 2.9 times the MRHD), respectively. There was no evidence of teratogenicity when pregnant rabbits and rats were exposed to imipenem/cilastatin sodium at IV doses up to 0.4 and 2.9 times, respectively, the MRHD (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2014).
    b) MICE, RATS: No teratogenicity was noted in the offspring of mice and rats exposed to imipenem/cilastatin during organogenesis at doses up to 0.5 times and approximately equal to the maximum recommended human dose, respectively (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2014).
    c) MONKEYS: There was no evidence of teratogenicity in the offspring of cynomolgus monkeys following IV administration of imipenem/cilastatin at human clinical infusion rates at exposures approximately 0.6 times the maximum recommended human dose of the IV formulation (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Imipenem/cilastatin is classified by the manufacturer as FDA pregnancy category C. There are no adequate and well-controlled studies of imipenem/cilastatin use during pregnancy. The combination of imipenem/cilastatin should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2014).
    B) ANIMAL STUDIES
    1) RATS: Slight decreases in live fetal body weights were noted with imipenem/cilastatin doses approximately equal to the highest recommended human dose of the IV formulation. When administered late in gestation, no adverse effects on the fetus were observed (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2014).
    2) MONKEYS: In pregnant cynomolgus monkeys given imipenem/cilastatin doses of 40 mg/kg/day (bolus IV injection) or 160 mg/kg/day (subcutaneous injection), maternal toxicity including emesis, inappetence, body weight loss, diarrhea, abortion, and in some cases, death, were observed. However, no significant toxicity was observed when non-pregnant cynomolgus monkeys were given subQ doses of imipenem/cilastatin up to 180 mg/kg/day. There was minimal maternal intolerance (occasional emesis) and no maternal deaths, but an increase in embryonic loss relative to control groups, when IV doses of imipenem/cilastatin sodium of approximately 0.6 times the maximum recommended human dose of the IV formulation were administered to pregnant cynomolgus monkeys at an IV infusion rate mimicking human clinical use (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2014).
    3) RABBITS: Weight loss, diarrhea, and maternal deaths were observed when subQ imipenem/cilastatin sodium was administered to pregnant rabbits at doses equivalent to the usual human dose of the intravenous formulation and higher. These adverse effects were also observed when comparable doses of imipenem/cilastatin were given to non-pregnant rabbits; this intolerance is similar to that observed with other beta-lactam antibiotics and is most likely due to alteration of gut flora (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether imipenem/cilastatin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when imipenem/cilastatin is administered to a nursing mother (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2014).
    B) ANIMAL STUDIES
    1) RATS: No adverse effects on lactation were observed when rats were given doses of imipenem/cilastatin approximately equal to the maximum recommended human dose late in gestation (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: No adverse effects on fertility or reproductive performance were noted when male and female rats were given imipenem/cilastatin at IV doses up to 80 mg/kg/day and at a subcutaneous dose of 320 mg/kg/day, approximately equal to the highest recommended human dose of the IV formulation (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential with platelet count and liver enzymes in symptomatic patients.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be admitted for severe vomiting, dehydration, persistent seizures, and severe allergic reaction.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) Imipenem/cilastatin is generally only used in the hospital setting.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with more than mild symptoms should be evaluated in a healthcare facility. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential with platelet count and liver enzymes in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Abstracts

Case Reports

    A) ADULT
    1) ACUTE EFFECTS
    a) Two patients with multiple organ system dysfunction (including renal) were dosed at 500 mg imipenem/cilastatin every 12 hours. The first patient developed tremor-like seizures on day 5 of treatment. After discontinuing imipenem/cilastatin, seizures did not resolve and he died 2 days later. The second patient developed facial and body tremors after 3 doses of imipenem/cilastatin and died a few hours later. The authors warn that decreasing the dose as recommended for renal dysfunction may not guard against severe neurologic reactions (Leo & Ballow, 1991).

Range Of Toxicity

Summary

    A) TOXICITY: The minimal toxic or lethal dose is not well established in the literature.
    B) THERAPEUTIC DOSES: adults: 1 gram to 4 grams IV; MAX: 50 mg/kg/day or 4 grams/day IV or 1500 mg/day IM. CHILDREN 12 YEARS OF AGE AND OLDER: 500 to 750 mg IM every 12 hours for mild to moderate infections. Maximum: 1500 mg/day. GREATER THAN 3 MONTHS OF AGE AND OLDER: 60 to 100 mg/kg/day IV divided every 6 hours. Maximum 500 mg/dose for fully susceptible organisms and maximum 1 g/dose for moderately susceptible organisms including P. aeruginosa. 4 WEEKS TO 3 MONTHS: 25 mg/kg/dose every 6 hours. 1 WEEK TO 4 WEEKS OF AGE: 25 mg/kg/dose every 8 hours. LESS THAN 1 WEEK OF AGE: 25 mg/kg/dose every 12 hours.

Therapeutic Dose

    7.2.1) ADULT
    A) INTRAVENOUS
    1) 1 gram to 4 grams. MAX: 50 mg/kg/day or 4 grams/day, whichever is lower (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2012)
    2) Single doses of 125 mg, 250 mg, or 500 mg should be infused over at least 20 to 30 minutes; single doses of 750 mg or 1000 mg should be infused over at least 40 to 60 minutes (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2012).
    7.2.2) PEDIATRIC
    A) INTRAVENOUS
    1) LESS THAN 1 WEEK OF AGE: 25 mg/kg every 12 hours (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2012)
    2) 1 WEEK TO 4 WEEKS OF AGE: 25 mg/kg every 8 hours (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2012).
    3) 4 WEEKS TO 3 MONTHS: 25 mg/kg every 6 hours (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2012).
    4) 3 MONTHS OF AGE AND OLDER: Non-CNS infections, 15 to 25 mg/kg every 6 hours (Prod Info PRIMAXIN(R) I.V. intravenous injection, 2012); 60 to 100 mg/kg/day IV divided every 6 hours. Maximum 500 mg/dose for fully susceptible organisms and maximum 1 g/dose for moderately susceptible organisms including P. aeruginosa (Prod Info PRIMAXIN(R)IV IV injection, 2009; Uhari et al, 1992; Ahonkhai et al, 1989; Freij et al, 1987; Nalin et al, 1987; Alpert et al, 1985).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) IMIPENEM
    1) Plasma levels of imipenem antimicrobial activity decline to less than 1 microgram/milliliter in 4 to 6 hours following intravenous infusion of 250, 500, or 1000 milligrams of imipenem over 20 minutes (Prod Info Primaxin(R) IM, imipenem/cilastatin intramuscular, 1999).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) >5 gm/kg
    B) LD50- (ORAL)RAT:
    1) >5 gm/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Imipenem, a thienamycin antibiotic, inhibits bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs) 1A, 1B, 2,4,5, and 6 of Escherichia coli and 1A, 1B, 2, 4, and 5 of Pseudomonas aeruginosa, with lethal effects attributed to its binding to PBP 2 and PBP 1B. It resists the action of beta-lactamases, both penicillinases and cephalosporinases, produced by gram-negative and gram-positive bacteria and it is also effective against a variety of bacteria (Prod Info PRIMAXIN(R) intramuscular injection, 2003; Prod Info PRIMAXIN(R) intravenous injection, 2003).
    B) Cilastatin sodium, the sodium salt of a derivatized heptenoic acid, exhibits a synergistic effect with the antibiotic imipenem by preventing the renal enzyme dehydropeptidase I from breaking down imipenem (Prod Info PRIMAXIN(R) intramuscular injection, 2003; Prod Info PRIMAXIN(R) intravenous injection, 2003).

Physicochemical

Physical Characteristics

    A) Imipenem is off-white as a powder. Cilastatin is off-white to yellowish-white as a powder. In solution, the mixture ranges from colorless to yellow (Prod Info Primaxin(R) IM, imipenem/cilastatin intramuscular, 1999).

Ph

    A) The mixture of imipenem and cilastatin as supplied by the manufacturer is buffered to a pH of 6.5-7.5 (S Sweetman , 2001).

Molecular Weight

    A) IMIPENEM: 317.37 (Prod Info Primaxin(R) IM, imipenem/cilastatin intramuscular, 1999)
    B) CILASTATIN: 380.43 (Prod Info Primaxin(R) IM, imipenem/cilastatin intramuscular, 1999)

References

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