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CARBAPENEM ANTIBIOTICS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Carbapenem antibiotics are broad-spectrum bactericidal agents that act by inhibiting the synthesis of the bacterial cell wall.

Specific Substances

    A) DORIPENEM
    1) S-4661
    2) CAS 148016-81-3
    ERTAPENEM
    1) Ertapenem sodium
    2) L-749345
    3) MK-826
    4) CAS 153832-46-3 (ertapenem)
    5) CAS 153832-38-3 (ertapenem disodium)
    6) CAS 153773-82-1 (ertapenem sodium)
    MEROPENEM
    1) ICI-194660
    2) SM-7338
    3) CAS 96036-03-2 (meropenem)
    4) CAS 119478-56-7 (meropenem trihydrate)

    1.2.1) MOLECULAR FORMULA
    1) DORIPENEM - C15-H24-N4-O6-S2 (Sweetman, 2007)
    2) ERTAPENEM - C22-H24-N3-Na-O7-S (Sweetman, 2007)
    3) MEROPENEM - C17-H25-N3-O5-S (Sweetman, 2007)

Available Forms Sources

    A) FORMS
    1) DORIPENEM: 250 mg and 500 mg single use vials of powder for reconstitution to be used for intravenous infusion (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015)
    2) ERTAPENEM: 1 g powder for injection (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    3) MEROPENEM: 500 mg and 1 g powder for injection (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    B) USES
    1) DORIPENEM: Approved as single-agent therapy for the treatment of complicated intra-abdominal and urinary tract infections (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    2) ERTAPENEM: Approved for the treatment of complicated intra-abdominal, dermal, and urinary tract infections, as well as community acquired pneumonia and acute pelvic infections. Ertapenem is also indicated for the prophylaxis of surgical site infection following elective colorectal surgery (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    3) MEROPENEM: Approved as single-agent therapy for the treatment of complicated intra-abdominal and dermal infections, as well as bacterial meningitis in pediatric patients at least 3 months of age (Prod Info MERREM(R) I.V. intravenous injection, 2014).

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: Carbapenem antibiotics are generally indicated for treatment of complicated intra-abdominal, dermal, and urinary tract infections.
    B) PHARMACOLOGY: Broad-spectrum bactericidal agents that act by inhibiting the synthesis of the bacterial cell wall.
    C) EPIDEMIOLOGY: Limited data. Overdose is rare and rarely causes significant toxicity.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects with therapy are headache, nausea, diarrhea, rash, and phlebitis.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Diarrhea and transient dizziness were reported in an adult patient following inadvertent administration of 3 ertapenem doses of 1 g each in a 24-hour period. Nausea and vomiting are also possible.
    2) SEVERE TOXICITY: Based on limited data, severe toxicity has not been reported following overdose.
    0.2.20) REPRODUCTIVE
    A) Doripenem, ertapenem, and meropenem are classified as pregnancy category B.

Laboratory Monitoring

    A) Plasma levels of carbapenem antibiotics are not widely available or useful in guiding therapy after overdose.
    B) Monitor fluid and electrolyte status in patients with severe vomiting or diarrhea.
    C) No specific lab work (CBC, electrolytes, urinalysis) is needed in asymptomatic patients unless otherwise clinically indicated.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. There is no known antidote.
    C) DECONTAMINATION
    1) Decontamination is not indicated as an ingestion is unlikely; carbapenem antibiotics are administered parenterally.
    D) ANTIDOTE
    1) None.
    E) SEIZURES
    1) Administer intravenous benzodiazepines or barbiturates if seizures recur or persist.
    F) ENHANCED ELIMINATION
    1) Limited reports have suggested that doripenem, ertapenem, and meropenem are readily dialyzable following therapeutic administration; however, no information is available regarding the use of hemodialysis following overdose.
    G) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: These antibiotics are most often administered in an inpatient setting. If overdose occurs in a patient receiving outpatient antibiotic infusion, mild to moderately symptomatic patients should be sent to health care facility for evaluation and treated until symptoms resolve.
    2) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    3) CONSULT CRITERIA: Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) When managing a suspected carbapenem antibiotic overdose, the treating physician should be aware of the possibility of multi-drug involvement.
    I) PHARMACOKINETICS
    1) DORIPENEM: Plasma protein binding is 8.1%. Volume of distribution is 16.8 L and is widely distributed into several body fluids and tissues including peritoneal and retroperitoneal fluid. It is metabolized to an inactive metabolite, doripenem-M1, via dehydropeptidase-I, and is primarily renally excreted unchanged via glomerular filtration and active tubular secretion. Doripenem's mean plasma terminal elimination half-life is approximately 1 hour.
    2) ERTAPENEM: The mean bioavailability following intramuscular administration of 1 gram is 90%. Protein binding, primarily to albumin, was approximately 95% with ertapenem plasma concentration of less than 100 mcg/mL and 85% with plasma concentrations of 300 mcg/mL. The apparent volume of distribution in adults is approximately 0.12 L/kg. In pediatric patients 3 months to 12 years of age and 13 to 17 years of age, the volume of distribution is 0.2 L/kg and 0.16 L/kg, respectively. A ring-opened derivative is formed by hydrolysis of the beta-lactam ring. Following intravenous administration of 1 g radiolabeled ertapenem to healthy volunteers, approximately 80% excreted in urine, with approximately 38% excreted unchanged and approximately 37% excreted as the ring-opened metabolite. In adults, the plasma elimination half-life is approximately 4 hours. In pediatric patients 3 months to 12 years of age and 13 to 17 years of age, the plasma elimination half-lives are approximately 2.5 hours and approximately 4 hours, respectively.
    3) MEROPENEM: Plasma protein binding is approximately 2%. The volume of distribution is 12 to 20 L. Approximately 70% of a meropenem dose administered intravenously is recovered unchanged in the urine over 12 hours. In adults and pediatric patients age 2 years and older, the elimination half-life is approximately 1 hour. In pediatric patients age 3 months to 2 years, the elimination half-life was 1.5 hours following linear elimination over a dose range of 10 to 40 mg/kg.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established with these agents. ADULTS: Diarrhea and transient dizziness were reported in an adult patient following inadvertent administration of three 1-gram ertapenem doses in a 24-hour period. CHILDREN: During pediatric clinical trials, a single IV ertapenem dose of 40 mg/kg up to a maximum of 2 g was well-tolerated with no toxicity reported.
    B) THERAPEUTIC DOSE: DORIPENEM: ADULTS: 500 mg every 8 hours administered as an IV infusion over a 1-hour period. ERTAPENEM: ADULTS (13 years of age or older): 1 g once daily administered as an IV infusion over a 30-minute period or as an IM injection. CHILDREN (3 months to 12 years of age): 15 mg/kg twice daily (max 1 g/day) administered as an IV infusion over a 30-minute period or as an IM injection. MEROPENEM: ADULTS: 500 to 1 g every 8 hours administered as an IV infusion over a 15- to 30-minute period. CHILDREN (3 months of age or older): 10 to 40 mg/kg (max 500 mg to 2 g) every 8 hours administered as an IV infusion over a 15- to 30-minute period.

Clinical Effects

Summary Of Exposure

    A) USES: Carbapenem antibiotics are generally indicated for treatment of complicated intra-abdominal, dermal, and urinary tract infections.
    B) PHARMACOLOGY: Broad-spectrum bactericidal agents that act by inhibiting the synthesis of the bacterial cell wall.
    C) EPIDEMIOLOGY: Limited data. Overdose is rare and rarely causes significant toxicity.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects with therapy are headache, nausea, diarrhea, rash, and phlebitis.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Diarrhea and transient dizziness were reported in an adult patient following inadvertent administration of 3 ertapenem doses of 1 g each in a 24-hour period. Nausea and vomiting are also possible.
    2) SEVERE TOXICITY: Based on limited data, severe toxicity has not been reported following overdose.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) ERTAPENEM
    a) CASE REPORT: Miosis was reported in a 79-year-old man approximately 1 week after beginning ertapenem therapy, 1 g daily, to treat sacral osteomyelitis. The miosis resolved following discontinuation of ertapenem. Rechallenge with the medication resulted in a recurrence of the miosis within 2 weeks. The miosis resolved within a week after discontinuation of therapy (Duquaine et al, 2011).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PHLEBITIS
    1) WITH THERAPEUTIC USE
    a) DORIPENEM
    1) In patients with complicated urinary tract infections (including pyelonephritis), phlebitis occurred in 4% of patients treated with doripenem 500 mg IV every 8 hours (n=376) during a phase 3 clinical trial (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    2) In patients with complicated intra-abdominal infections, phlebitis occurred in 8% of patients treated with doripenem 500 mg IV every 8 hours (n=477) during two phase 3 studies (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) DORIPENEM: During investigational use, pneumonitis was reported when doripenem was administered inhalationally (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) ERTAPENEM
    1) Seizures were reported in approximately 0.5% of patients in clinical trials during treatment and a 14-day follow-up period, primarily in those with renal insufficiency and/or central nervous system disorders, such as brain lesions or a history of seizures (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014). CASE REPORT: An 89-year-old woman experienced a generalized, tonic-clonic seizure lasting approximately 1 minute on day 10 of ertapenem therapy (1 gram every 24 hours). No antiseizure medication was required, and no sequelae were revealed on follow-up neurologic exam (Ortiz-Ruiz et al, 2002).
    2) CASE REPORTS: Seizures occurred in an 85-year-old man receiving ertapenem treatment for a urinary tract infection. The patient experienced 3 seizures on the fourth day of ertapenem (500 mg/day) treatment. Medical history included diabetes mellitus, hypertension, chronic renal failure, benign prostatic hypertrophy, and an old cerebral accident which was revealed by a brain computed tomography (CT) scan. The patient's antibiotic treatment was modified, and the seizures did not recur. A second patient, a 71-year-old man, also experienced seizures associated with ertapenem use. The patient was treated for a urinary tract infection with ertapenem (500 mg/day) and experienced 4 seizures on the fifth day of therapy, each accompanied by a loss of consciousness. Medical history included diabetes mellitus, hypertension, chronic ischemic heart disease, and an old cerebrovascular accident, also revealed by a brain CT scan. Antibiotic treatment was modified but seizures recurred the following day. The patient was treated with antiepileptic medications without further recurrence. The presence of underlying CNS disease in these two patients appeared to be a unique risk factor for the development of seizures associated with ertapenem use (Saidel-Odes et al, 2006).
    3) CASE REPORT: A 56-year-old man, with end-stage renal disease and on continuous peritoneal dialysis, experienced a generalized tonic-clonic seizure, lasting 3 minutes, 16 hours after receiving a second ertapenem dose of 500 mg intravenously. The patient had received his first ertapenem dose of 500 mg 23.25 hours previously. Laboratory data indicated hypocalcemia (ionized calcium 0.88 mEq/L {normal 1.16 to 1.32}). Speculating that the seizure was hypocalcemic-induced, the calcium concentration in the peritoneal dialysate was increased; however, approximately 3 hours after the first seizure, the patient experienced 2 more seizures occurring 15 minutes apart, with each seizure lasting 3 minutes. An ECG showed nonsustained ventricular tachycardia beginning 2 minutes after seizure onset. A CT scan of the head revealed mildly diffuse global atrophy without acute changes. After the CT scan, the patient experienced a fourth seizure and became apneic for 20 to 30 seconds. He spontaneously recovered, but experienced a fifth seizure approximately 15 minutes later, becoming apneic and pulseless. He was not resuscitated due to a "do not resuscitate" order. An autopsy revealed a dilated heart with severe coronary atherosclerosis, but his brain only showed small-vessel ischemia without structural abnormalities. Based on the Naranjo probability scale, it is believed that ertapenem may have been the causative agent (Seto et al, 2005).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) DORIPENEM
    1) In patients with complicated urinary tract infections (including pyelonephritis), headache occurred in 16% of patients treated with doripenem 500 mg IV every 8 hours (n=376) in a phase 3 study (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    2) In patients with complicated intra-abdominal infections, headache occurred in 4% of patients treated with doripenem 500 mg IV every 8 hours (n=477) during two phase 3 clinical trials (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    b) ERTAPENEM
    1) During clinical trials, the incidence of headaches in patients with complicated intra-abdominal infections, complicated skin and skin structure infections, and acute pelvic infections was 5.6% following administration of ertapenem 1 g daily (n=802) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    2) During clinical trials, the incidence of headaches in patients with community acquired pneumonia and complicated urinary tract infections was 6.8% following administration of ertapenem 1 g daily (n=1152) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    c) MEROPENEM
    1) Headaches occurred in 2.3% of adult immunocompetent patients (n=2904) treated with meropenem 500 or 1000 mg IV every 8 hours for non-CNS infections, during clinical trials. In a study of patients with complicated skin and skin structure infections, the incidence of headache was 7.8% (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    C) ALTERED MENTAL STATUS
    1) WITH THERAPEUTIC USE
    a) ERTAPENEM
    1) During clinical trials, the incidence of altered mental status (confusion, disorientation, somnolence, stupor) in patients with complicated intra-abdominal infections, complicated skin and skin structure infections, and acute pelvic infections was 5.1% following administration of ertapenem 1 g daily (n=802) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    2) During clinical trials, the incidence of altered mental status in patients with community acquired pneumonia and complicated urinary tract infections was 3.3% following administration of ertapenem 1 g daily (n=1152) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    3) CASE REPORTS: Two patients experienced mental status changes with ertapenem therapy. The first patient, a 79-year-old man, became incoherent with garbled speech approximately 1 week after beginning ertapenem therapy, 1 g daily, to treat sacral osteomyelitis. Two days after discontinuation of ertapenem therapy, the patient's mental status improved and returned to baseline 1 week later. Rechallenge with ertapenem resulted in a recurrence of altered mental status within 2 weeks. The patient's condition returned to baseline following discontinuation of the medication. The second patient, a 70-year-old man, experienced confusion and hallucinations approximately 1 week after beginning ertapenem therapy, 1 g daily. Over the next 2 days, the patient became obtunded with stridor and metabolic acidosis, necessitating intubation and mechanical ventilation. Following discontinuation of ertapenem therapy, the patient's condition improved and he was extubated 48 hours later (Duquaine et al, 2011).
    b) MEROPENEM
    1) CASE REPORT: A 100-year-old man developed confusion and agitation 2 days after beginning meropenem therapy, 1 gram IV initially followed by 500 mg IV every 12 hours, to treat a urinary tract infection (UTI). Following cessation of meropenem therapy, the patient recovered the next day. One month later, the patient again became confused 3 days after beginning meropenem therapy to treat another UTI. After discontinuation of meropenem therapy, the patient's confusion resolved the next day (Munoz-Gomez et al, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) DORIPENEM
    1) In patients with complicated urinary tract infections, nausea occurred in 4% of patients treated with doripenem 500 mg IV every 8 hours (n=376) during a phase 3 clinical trial (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    2) In patients with complicated intra-abdominal infections, nausea occurred in 12% of patients treated with doripenem 500 mg IV every 8 hours (n=477) during two phase 3 studies (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    b) ERTAPENEM
    1) During clinical trials, the incidence of nausea and vomiting in patients with complicated intra-abdominal infections, complicated skin and skin structure infections, and acute pelvic infections was 8.5% and 3.7%, respectively, following administration of ertapenem 1 g daily (n=802) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    2) During clinical trials, the incidence of nausea and vomiting in patients with community acquired pneumonia and complicated urinary tract infections was 6.4% and 4%, respectively, following administration of ertapenem 1 g daily (n=1152) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    3) In clinical studies in pediatric patients with complicated skin and skin structure infections, community acquired pneumonia, complicated urinary tract infections, acute pelvic infections, and complicated intra-abdominal infections, the incidence of vomiting was 10.2% for patients treated with ertapenem 15 mg/kg twice daily up to 1 g daily (n=384) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    c) MEROPENEM
    1) Nausea and vomiting occurred in 3.6% of adult immunocompetent patients (n=2904) treated with meropenem 500 or 1000 mg IV every 8 hours for non-CNS infections, during clinical trials. In a study of patients with complicated skin and skin structure infections, the incidence of nausea was 7.8% (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    2) In a study done in pediatric patients with serious bacterial infections ({n=515}, age 3 months to 12 years) receiving meropenem 10 to 20 mg/kg every 8 hours, the incidence of nausea and vomiting was 0.8% (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) DORIPENEM
    1) In patients with complicated urinary tract infections, diarrhea occurred in 6% of patients treated with doripenem 500 mg IV every 8 hours (n=376) during a phase 3 study (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    2) In patients with complicated intra-abdominal infections, diarrhea occurred in 11% of patients treated with doripenem 500 mg IV every 8 hours (n=477) during two phase 3 clinical trials (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    b) ERTAPENEM
    1) During clinical trials, the incidence of diarrhea in patients with complicated intra-abdominal infections, complicated skin and skin structure infections, and acute pelvic infections was 10.3% following administration of ertapenem 1 g daily (n=802) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    2) During clinical trials, the incidence of diarrhea in patients with community acquired pneumonia and complicated urinary tract infections was 9.2% following administration of ertapenem 1 g daily (n=1152) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    3) In clinical studies in pediatric patients with complicated skin and skin structure infections, community acquired pneumonia, complicated urinary tract infections, acute pelvic infections, and complicated intra-abdominal infections, the incidence of diarrhea was 11.7% for patients treated with ertapenem 15 mg/kg twice daily up to 1 g daily (n=384) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    c) MEROPENEM
    1) Diarrhea occurred in 4.8% of adult immunocompetent patients (n=2904) treated with meropenem 500 or 1000 mg IV every 8 hours for non-CNS infections, during clinical trials. In a study of patients with complicated skin and skin structure infections, the incidence of diarrhea was 7% (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    2) In 2 studies done in pediatric patients with either serious bacterial infections (n=515, age 3 months to 12 years) receiving meropenem 10 to 20 mg/kg every 8 hours, or treated for meningitis ((n=321), age 3 months to 16 years) receiving meropenem 40 mg/kg every 8 hours, the incidence of diarrhea was 3.5% and 4.7%, respectively (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    3) Diarrhea was the most commonly reported adverse drug-related event among 505 evaluable pediatric patients (aged 2 months to 12 years) receiving either meropenem (5.9%) or cefotaxime (4%) as initial empiric treatment of non-central nervous system infections (Snedden et al, 1999).
    2) WITH POISONING/EXPOSURE
    a) ERTAPENEM
    1) Diarrhea and transient dizziness were reported in an adult patient following inadvertent administration of three 1-gram ertapenem doses in a 24-hour period (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) ERTAPENEM
    1) During clinical trials, the incidence of abdominal pain in patients with complicated intra-abdominal infections, complicated skin and skin structure infections, and acute pelvic infections was 3.6% following administration of ertapenem 1 g daily (n=802) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    2) During clinical trials, the incidence of abdominal pain in patients with community acquired pneumonia and complicated urinary tract infections was 4.3% following administration of ertapenem 1 g daily (n=1152) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    3) In clinical studies in pediatric patients with complicated skin and skin structure infections, community acquired pneumonia, complicated urinary tract infections, acute pelvic infections, and complicated intra-abdominal infections, the incidence of abdominal pain was 4.7% for patients treated with ertapenem 15 mg/kg twice daily up to 1 g daily (n=384) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    D) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) ERTAPENEM/CASE REPORT: A 78-year-old man, without history of adverse drug reactions or chronic alcohol consumption, experienced acute pancreatitis during treatment with ertapenem following abdominal surgery for perforated sigmoid. Ertapenem (1 g every 24 hours) was initiated on day 2 of hospitalization. On day 8 of hospitalization, the patient was stable, renal function and transaminases were normal, a semi-solid diet was tolerated, and IV ertapenem was discontinued. On day 9, the patient experienced abdominal distension accompanied by epigastric pain. Blood tests from the sample taken on day 8 revealed elevated amylase (1823 units/L), lipase (8045 units/L), and C-reactive protein (16.09 mg/dL). Full blood count showed leukocytosis (12810 cells/microL) with an increase in neutrophils (9290 cells/microL), and eosinophils (850 cells/microL). Transaminases, bilirubin, and renal function remained normal. A diagnosis of postoperative acute pancreatitis was made and parenteral nutrition was re-initiated. The patient's clinical condition improved quickly and without complications. On day 9, the amylase had decreased to 486 units/L with a normal amylase by day 11 (73 units/L). On day 11, enteral diet was started and well tolerated. By day 16, leukocytosis and neutrophilia had resolved, and a CT revealed slight pancreatic edema compatible with a grade B of Baltazars acute pancreatitis scale. The patient experienced no further symptoms indicative of acute pancreatitis. In this patient, ertapenem use was likely the cause of the acute pancreatitis based on the Naranjo probability scale (5 points) (Martinez-Granados et al, 2008).
    E) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) ERTAPENEM
    1) During clinical trials, the incidence of constipation in patients with complicated intra-abdominal infections, complicated skin and skin structure infections, and acute pelvic infections was 4% following administration of ertapenem 1 g daily (n=802) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    2) During clinical trials, the incidence of constipation in patients with community acquired pneumonia and complicated urinary tract infections was 3.3% following administration of ertapenem 1 g daily (n=1152) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    3) In clinical studies in pediatric patients with complicated skin and skin structure infections, community acquired pneumonia, complicated urinary tract infections, acute pelvic infections, and complicated intra-abdominal infections, the incidence of constipation was 2.3% for patients treated with ertapenem 15 mg/kg twice daily up to 1 g daily (n=384) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) DORIPENEM
    1) In patients with complicated urinary tract infections, hepatic enzyme elevations, including increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), occurred in 2% of patients treated with doripenem 500 mg IV every 8 hours (n=376) during a phase 3 study (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    2) In patients with complicated intra-abdominal infections, hepatic enzyme elevations, including increased alanine aminotransferase and aspartate aminotransferase, occurred in 2% of patients treated with doripenem 500 mg IV every 8 hours (n=477) during two phase 3 clinical trials (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    b) ERTAPENEM
    1) During clinical trials, ALT and AST concentrations were elevated in 8.8% and 8.4% of patients (n=766), respectively, who received ertapenem 1 gram daily for treatment of complicated intra-abdominal infections, complicated skin and skin structure infections, and acute pelvic infections (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    2) During clinical trials, ALT and AST concentrations were elevated in 8.3% and 7.1% of patients (n=1122), respectively, who received ertapenem 1 gram daily for treatment of community acquired pneumonia and complicated urinary tract infections (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    3) In clinical studies in pediatric patients with complicated skin and skin structure infections, community acquired pneumonia, complicated urinary tract infections, acute pelvic infections, and complicated intra-abdominal infections, ALT and AST concentrations were elevated in 3.8% of patients (n=379) (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    c) MEROPENEM
    1) Abnormalities of liver function tests have occasionally been associated with meropenem therapy (Lami et al, 1991).
    2) Cholestatic jaundice occurred in 0.1% to 1% of adult immunocompetent patients (n=2904) treated with meropenem 500 or 1000 mg IV every 8 hours for non-CNS infections, during clinical trials (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    3) Transient elevation of serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) occurred in 11% and 6% of meropenem-treated patients, respectively, in a randomized, comparison trial with cefotaxime involving 190 children (aged 3 months to 14 years) with bacterial meningitis (Klugman & Dagan, 1995).
    4) CASE REPORT: Marked elevations in serum concentrations of alanine and aspartate transaminase (ALT and AST, respectively) developed in a 3-year-old boy after receiving meropenem 40 milligrams/kilogram (mg/kg) every 8 hours for 2 weeks followed by 100 mg/kg every 8 hours for 2 weeks to treat Morganella morgani meningitis. ALT measured at 310 International Units/liter , and AST measured at 684 international units/liter. Serum concentrations of both transaminases were reduced to within normal range 2 weeks after withdrawal of meropenem (Estella et al, 2000).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) MEROPENEM/CASE REPORT: Leukopenia with severe neutropenia, thrombocytopenia, and anemia developed in a 3-year-old boy after receiving meropenem 40 mg/kg every 8 hours for 2 weeks followed by 100 mg/kg every 8 hours for 2 weeks to treat Morganella morgani meningitis. Bone marrow biopsy revealed the presence of hypoplastic/hypocellular marrow. The patient also tested positive for direct Coombs antibody, and showed negative serology for all tested viral organisms. Despite the persistence of anemia, resolution of leukopenia and thrombocytopenia occurred within 2 weeks of discontinuing meropenem (Estella et al, 2000).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) DORIPENEM
    1) In patients with complicated urinary tract infections (including pyelonephritis), anemia occurred in 2% of patients treated with doripenem 500 mg IV every 8 hours (n=376) during a phase 3 study (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    2) In patients with complicated intra-abdominal infections anemia occurred in 10% of patients treated with doripenem 500 mg IV every 8 hours (n=477) during two phase 3 clinical trials (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    b) ERTAPENEM
    1) During a clinical study, anemia was reported in 5.7% of patients (n=476) who received 1 gram of ertapenem 1 hour prior to elective colorectal surgery for prophylaxis of surgical site infection (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) DORIPENEM
    1) In patients with complicated intra-abdominal infections, rash occurred in 4% of patients treated with doripenem 500 mg IV every 8 hours (n=477) during two phase 3 studies (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    b) MEROPENEM
    1) Rash occurred in 1.9% of adult immunocompetent patients (n=2904) treated with meropenem 500 or 1000 mg IV every 8 hours for non-CNS infections, during clinical trials (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    2) In 2 studies done in pediatric patients with either serious bacterial infections ({n=515}, age 3 months to 12 years) receiving meropenem 10 to 20 mg/kg every 8 hours, or treated for meningitis ({n=321}, age 3 months to 16 years) receiving meropenem 40 mg/kg every 8 hours, the incidence of rash was 1.6% and 3.1%, respectively. In the second study, rash was mostly diaper area moniliasis (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    3) Rash was reported in 2.4% of pediatric patients (aged 2 months to 12 years) receiving meropenem as initial empiric treatment of non-central nervous system infections (Snedden et al, 1999).
    B) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) MEROPENEM: Inflammation at the injection site occurred in 2.4% of adult immunocompetent patients (n=2904) treated with meropenem 500 or 1000 mg IV every 8 hours for non-CNS infections, during clinical trials (Prod Info MERREM(R) I.V. intravenous injection, 2014).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERLIPIDEMIA
    1) WITH THERAPEUTIC USE
    a) MEROPENEM/CASE REPORT: Significant triglyceridemia, accompanied by elevated liver enzymes, developed in a 3-year-old boy after receiving meropenem 40 mg/kg every 8 hours for 2 weeks, followed by a 2-week regimen of 100 mg/kg every 8 hours to treat Morganella morgani meningitis. Triglyceride concentration was measured at 8.37 millimoles/liter (mmol/L) prior to discontinuing meropenem; the triglyceride concentration declined to 0.99 mmol/L within 2 weeks of withdrawing the drug (Estella et al, 2000).

Reproductive

    3.20.1) SUMMARY
    A) Doripenem, ertapenem, and meropenem are classified as pregnancy category B.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) DORIPENEM
    a) In studies in rats and rabbits, IV doses during organogenesis that resulted in at least 2.4 and 0.8 times the human exposure (following doses of 500 mg every 8 hours), respectively, were not teratogenic and did not have any effects on ossification, development, or fetal weight (Prod Info DORIBAX(R) IV injection, 2009).
    2) ERTAPENEM
    a) In mice and rats given IV doses of up to 700 mg/kg/day (approximately 3 times and 1.2 times the human exposure at the recommended dose of 1 gram based on plasma AUCs, respectively), there was no evidence of developmental toxicity as assessed by external, visceral, and skeletal examination of the fetuses (Prod Info INVANZ(R) IV, IM injection, 2008). However, in mice given 700 mg/kg/day, there were slight decreases in average fetal weights and an associated decrease in the average number of ossified sacrocaudal vertebrae observed.
    3) MEROPENEM
    a) Reproductive studies in rats at meropenem doses of up to 1000 mg/kg/day, and in cynomolgus monkeys at meropenem doses of up to 360 mg/kg/day (approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours) revealed no evidence of impaired fertility or harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of at least 250 mg/kg/day (0.4 times the human exposure at a dose of 1 g every 8 hours) in rats (Prod Info MERREM(R) I.V. intravenous injection, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Doripenem, ertapenem, and meropenem are classified as FDA pregnancy category B (Prod Info DORIBAX(R) IV injection, 2009; Prod Info INVANZ(R) IV, IM injection, 2008; Prod Info MERREM(R) I.V. intravenous injection, 2013).
    B) ANIMAL STUDIES
    1) PLACENTAL BARRIER
    a) ERTAPENEM
    1) Ertapenem crosses the placental barrier in rats (Prod Info INVANZ(R) IV, IM injection, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) DORIPENEM
    a) It is not known whether doripenem is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug are unknown (Prod Info DORIBAX(R) IV injection, 2009).
    B) BREAST MILK
    1) ERTAPENEM
    a) Ertapenem is excreted in human breast milk (Prod Info INVANZ(R) IV, IM injection, 2008).
    2) MEROPENEM
    a) Meropenem has been reported to be excreted in human breast milk (Prod Info MERREM(R) I.V. intravenous injection, 2013). A 7-day course of meropenem 1000 mg IV every 8 hours administered to a breastfeeding mother caused no dermatologic or gastrointestinal adverse effects in her exclusively breastfed neonate. Meropenem was prescribed postpartum to treat a urinary tract infection caused by an extended-spectrum beta-lactamase-producing strain of E. coli. Five breast milk samples collected over 48 hours during meropenem therapy yielded meropenem concentrations ranging from 0.246 to 0.644 mcg/mL (mean, 0.48 mcg/mL). Based on the sample concentrations, the infant's daily weight-adjusted meropenem exposure was calculated at 0.18% of the maternal dosage. No infant serum samples were collected during therapy (Sauberan et al, 2012).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) DORIPENEM
    a) There were no effects on the general fertility of treated male or female rats or on the reproductive performance of the offspring following intravenous administration of doripenem at doses up to 1 g/kg/day (1.5 times the exposure to humans at a dose of 500 mg every 8 hours) (Prod Info DORIBAX(R) IV injection, 2009).
    2) ERTAPENEM
    a) There were no effects on mating performance, fecundity, or fertility in mice and rats who were given intravenous ertapenem doses up to 700 mg/kg/day (3 times and 1.2 times, respectively, the recommended human dose of 1 gram) (Prod Info INVANZ(R) IV, IM injection, 2008).
    3) MEROPENEM
    a) No impairment of fertility was seen when meropenem was studied in rats at doses of up to 1000 mg/kg per day, and in cynomolgus monkeys at doses of up to 360 mg/kg per day. These doses are comparable to 1.8 and 3.7 times, respectively, the human exposure at the usual dose of 1 gram every 8 hours, based on area under the plasma concentration–time curve (AUC) (Prod Info MERREM(R) I.V. intravenous injection, 2013).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS148016-81-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS153832-46-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    C) IARC Carcinogenicity Ratings for CAS96036-03-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) Long-term carcinogenicity studies have not been performed in animals (Prod Info DORIBAX(R) IV injection, 2009; Prod Info INVANZ(R) IV, IM injection, 2008; Prod Info MERREM(R) IV injection, 2008).

Genotoxicity

    A) There was no evidence of mutagenicity following various in vitro and in vivo testing including the bacterial reverse mutation assay, the chromosomal aberration assay with Chinese hamster lung fibroblast cells, and the mouse bone marrow micronucleus assay (Prod Info DORIBAX(R) IV injection, 2009; Prod Info INVANZ(R) IV, IM injection, 2008; Prod Info MERREM(R) IV injection, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma levels of carbapenem antibiotics are not widely available or useful in guiding therapy after overdose.
    B) Monitor fluid and electrolyte status in patients with severe vomiting or diarrhea.
    C) No specific lab work (CBC, electrolytes, urinalysis) is needed in asymptomatic patients unless otherwise clinically indicated.

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 who remain symptomatic despite adequate treatment should be admitted.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) These antibiotics are most often administered in an inpatient setting. If overdose occurs in a patient receiving outpatient antibiotic infusion, mild to moderately symptomatic patients should be sent to health care facility for evaluation and treated until symptoms resolve.

Monitoring

    A) Plasma levels of carbapenem antibiotics are not widely available or useful in guiding therapy after overdose.
    B) Monitor fluid and electrolyte status in patients with severe vomiting or diarrhea.
    C) No specific lab work (CBC, electrolytes, urinalysis) is needed in asymptomatic patients unless otherwise clinically indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not indicated because an ingestion is unlikely; carbapenem antibiotics are administered parenterally.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) SUMMARY: Limited reports have suggested that doripenem, ertapenem, and meropenem are readily dialyzable following therapeutic administration; however, no information is available regarding the use of hemodialysis following overdose.
    2) DORIPENEM: The mean total recovery of doripenem and its inactive metabolite in the dialysate following a 4-hour hemodialysis session was 52% of the dose (a total of 259 mg) when 500 mg of doripenem was administered to patients with endstage renal disease (Prod Info DORIBAX(R) IV injection, 2009).
    3) ERTAPENEM: When a 4-hour hemodialysis session was performed in patients with endstage renal disease immediately following ertapenem administration, the plasma clearance of the total fraction of ertapenem was increased by 30% (Prod Info INVANZ(R) IV, IM injection, 2008).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established with these agents. ADULTS: Diarrhea and transient dizziness were reported in an adult patient following inadvertent administration of three 1-gram ertapenem doses in a 24-hour period. CHILDREN: During pediatric clinical trials, a single IV ertapenem dose of 40 mg/kg up to a maximum of 2 g was well-tolerated with no toxicity reported.
    B) THERAPEUTIC DOSE: DORIPENEM: ADULTS: 500 mg every 8 hours administered as an IV infusion over a 1-hour period. ERTAPENEM: ADULTS (13 years of age or older): 1 g once daily administered as an IV infusion over a 30-minute period or as an IM injection. CHILDREN (3 months to 12 years of age): 15 mg/kg twice daily (max 1 g/day) administered as an IV infusion over a 30-minute period or as an IM injection. MEROPENEM: ADULTS: 500 to 1 g every 8 hours administered as an IV infusion over a 15- to 30-minute period. CHILDREN (3 months of age or older): 10 to 40 mg/kg (max 500 mg to 2 g) every 8 hours administered as an IV infusion over a 15- to 30-minute period.

Therapeutic Dose

    7.2.1) ADULT
    A) DORIPENEM
    1) The recommended dosage is 500 mg administered every 8 hours as an intravenous infusion, given over 1 hour. The duration of therapy is 5 to 14 days, depending on the infection that is being treated (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    B) ERTAPENEM
    1) The recommended dosage is 1 gram administered once daily by intravenous infusion, given over a period of 30 minutes, or by intramuscular injection. The duration of therapy is up to 14 days when given by intravenous infusion or up to 7 days when given by intramuscular injection (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    C) MEROPENEM
    1) DERMAL INFECTIONS: The recommended dosage is 500 mg given every 8 hours; increase to 1 g IV every 8 hours for infections caused by Pseudomonas aeruginosa; administered as an IV infusion and given over approximately 15 to 30 minutes or as an IV bolus injection (5 to 20 mL) over 3 to 5 minutes (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    2) INTRA-ABDOMINAL INFECTIONS: The recommended dosage is 1 gram given every 8 hours, administered as an IV infusion over approximately 15 to 30 minutes, or as an IV bolus injection over approximately 3 to 5 minutes (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    7.2.2) PEDIATRIC
    A) DORIPENEM
    1) Safety and efficacy in pediatric patients have not been established (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    B) ERTAPENEM
    1) 13 YEARS OF AGE OR OLDER: The recommended dosage is 1 gram administered once daily by intravenous infusion, over a period of 30 minutes, or by intramuscular injection. The duration of therapy is up to 14 days when given by intravenous infusion or up to 7 days when given by intramuscular injection (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014)
    2) 3 MONTHS TO 12 YEARS OF AGE: The recommended dosage is 15 milligrams/kilogram twice daily, not to exceed 1 gram/day, administered as an intravenous infusion over 30 minutes, or as an intramuscular injection. The duration of therapy is up to 14 days when given by intravenous infusion or up to 7 days when given by intramuscular injection (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    C) MEROPENEM
    1) DERMAL INFECTIONS: In pediatric patients 3 months of age or older, the recommended dosage is 10 mg/kg; increase to 20 mg/kg (or 1 g for patients weighing over 50 kg) IV every 8 hours for infections caused by Pseudomonas aeruginosa; up to a maximum dose of 500 mg, given every 8 hours, administered as an IV infusion over a 15- to 30-minute period, or as an IV bolus injection over a period of 3 to 5 minutes (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    2) INTRA-ABDOMINAL INFECTIONS
    a) 3-MONTH-OLD AND OLDER: The recommended dosage is 20 mg/kg, up to a maximum of 1 g, given every 8 hours, administered as an IV infusion over a 15- to 30-minute period, or as an IV bolus injection over a period of 3 to 5 minutes (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    b) LESS THAN 3-MONTH-OLD: For infants less than 32 weeks gestational age (GA) and postnatal age (PNA) less than 2 weeks, the dose is 20 mg/kg every 12 hours, given as an IV infusion over 30 minutes. For infants less than 32 weeks GA and PNA 2 weeks and older or infants 32 weeks and older GA and PNA less than 2 weeks, the dose is 20 mg/kg every 8 hours, given as an IV infusion over 30 minutes. For infants 32 weeks and older GA and PNA 2 weeks and older, the dose is 30 mg/kg every 8 hours, given as an IV infusion over 30 minutes (Prod Info MERREM(R) I.V. intravenous injection, 2014).
    3) BACTERIAL MENINGITIS: In pediatric patients 3 months of age or older, the recommended dosage is 40 mg/kg, up to a maximum of 2 g, given every 8 hours, administered as an IV infusion over a 15- to 30-minute period, or as an IV bolus injection over a period of 3 to 5 minutes (Prod Info MERREM(R) I.V. intravenous injection, 2014). In patients older than 28 days, the recommended guideline dosing is 120 mg/kg/day IV divided every 8 hours; consider adding aminoglycoside for Pseudomonas aeruginosa (Tunkel et al, 2004).

Maximum Tolerated Exposure

    A) ERTAPENEM
    1) ADULTS: Diarrhea and transient dizziness were reported in an adult patient following inadvertent administration of three 1-g ertapenem doses in a 24-hour period (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).
    2) CHILDREN: During pediatric clinical trials, a single IV ertapenem dose of 40 mg/kg up to a maximum of 2 g was well-tolerated with no toxicity reported (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014).

Workplace Standards

    A) ACGIH TLV Values for CAS148016-81-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS153832-46-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) ACGIH TLV Values for CAS96036-03-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS148016-81-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) NIOSH REL and IDLH Values for CAS153832-46-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    F) NIOSH REL and IDLH Values for CAS96036-03-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    G) Carcinogenicity Ratings for CAS148016-81-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    H) Carcinogenicity Ratings for CAS153832-46-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    I) Carcinogenicity Ratings for CAS96036-03-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    J) OSHA PEL Values for CAS148016-81-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    K) OSHA PEL Values for CAS153832-46-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    L) OSHA PEL Values for CAS96036-03-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) MEROPENEM
    1) LD50- (ORAL)MOUSE:
    a) Greater than 5 g/kg (RTECS, 2006)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) Greater than 5 g/kg (RTECS, 2006)
    3) LD50- (ORAL)RAT:
    a) Greater than 5 g/kg (RTECS, 2006)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) Greater than 5 g/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) DORIPENEM: Doripenem, a carbapenem bactericidal antimicrobial inactivates essential penicillin-binding proteins in the cell wall inhibiting cell wall biosynthesis resulting in bacterial cell death. Doripenem is resistant to most beta-lactamases including penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria, but is not stable to hydrolysis by carbapenem beta-lactamases (Prod Info DORIBAX(R) intravenous injection powder for solution, 2015).
    B) ERTAPENEM: Ertapenem is a parenteral 1-beta-methyl carbapenem characterized by a relatively long plasma half-life, broad-spectrum antimicrobial activity, and enhanced stability against hydrolysis by renal dehydropeptidase-1 (DHP-1) (Sader & Gales, 2001; Gill et al, 1998; Jones, 2001). Ertapenem exhibits good stability against hydrolysis by various beta-lactamases, including cephalosporinases, penicillinases, and extended-spectrum beta-lactamases (ESBLs); the drug is hydrolyzed by metallo-beta-lactamases (Prod Info INVANZ(R) intravenous injection, intramuscular injection, 2014; Livermore et al, 2001a; Mouton et al, 2000; Lister & Black, 2001; Jones, 2001). A postantibiotic effect has been reported against gram-positive and some gram-negative pathogens (e.g., H. influenzae) (Sader & Gales, 2001).
    C) MEROPENEM: Meropenem exerts bactericidal activity by inhibiting cell wall synthesis by penetrating the cell wall of most gram-positive and gram-negative bacteria to reach penicillin-binding–protein (PBP) targets. Its strongest affinity is toward PBPs 2, 3, and 4 of Escherichia coli and Pseudomonas aeruginosa, and PBPs 1, 2, and 4 of Staphylococcus aureus. Bactericidal concentrations are typically one to two times the bacteriostatic concentrations; the exception is Listeria monocytogenes, against which lethal activity has not been observed (Prod Info MERREM(R) I.V. intravenous injection, 2014).

Physicochemical

Physical Characteristics

    A) DORIPENEM - A white to slightly yellowish off-white crystalline powder (Prod Info DORIBAX(R) IV injection, 2009).
    B) ERTAPENEM - A white to off-white hygroscopic, weakly crystalline powder soluble in water and 0.9% sodium chloride solution and insoluble in ethanol (Prod Info INVANZ(R) IV, IM injection, 2008).
    C) MEROPENEM - A white to pale yellow crystalline powder sparingly soluble in water and very slightly soluble in hydrated ethanol (Prod Info MERREM(R) IV injection, 2008).

Molecular Weight

    A) DORIPENEM - 438.52 (Prod Info DORIBAX(R) IV injection, 2009)
    B) ERTAPENEM - 497.50 (Prod Info INVANZ(R) IV, IM injection, 2008)
    C) MEROPENEM - 437.52 (Prod Info MERREM(R) IV injection, 2008)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    12) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    13) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    14) American Conference of Governmental Industrial Hygienists : ACGIH 2010 Threshold Limit Values (TLVs(R)) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs(R)), American Conference of Governmental Industrial Hygienists, Cincinnati, OH, 2010.
    15) Bax RP, Bastain W, Featherstone A, et al: The pharmacokinetics of meropenem in volunteers. J Antimicrob Chemother 1989; 24(Suppl A):311-320.
    16) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    17) Burman LA, Nilsson-Ehle I, Hutchison M, et al: Pharmacokinetics of meropenem and its metabolite ICI 213,689#in healthy subjects with known renal metabolism of imipenem. J Antimicrob Chemother 1991; 27:219-224.
    18) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    19) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    20) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    21) DFG: List of MAK and BAT Values 2002, Report No. 38, Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Wiley-VCH, Weinheim, Federal Republic of Germany, 2002.
    22) Duquaine S, Kitchell E, Tate T, et al: Central nervous system toxicity associated with ertapenem use. Ann Pharmacother 2011; 45(1):e6-e6.
    23) EPA: Search results for Toxic Substances Control Act (TSCA) Inventory Chemicals. US Environmental Protection Agency, Substance Registry System, U.S. EPA's Office of Pollution Prevention and Toxics. Washington, DC. 2005. Available from URL: http://www.epa.gov/srs/.
    24) Estella J, Villanueva J, Calvo M, et al: Bone marrow aplasia and meropenem in a paediatric patient. Br J Haematol 2000; 111:984-985.
    25) Gill CJ, Jackson JJ, Gerckens LS, et al: In vivo activity and pharmacokinetic evaluation of a novel long-acting carbapenem antibiotic, MK-826 (L-749,345). Antimicrob Agents Chemother 1998; 42(8):1996-2001.
    26) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    27) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    28) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: 1,3-Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide), 97, International Agency for Research on Cancer, Lyon, France, 2008.
    29) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxypropan-2-ol, 88, International Agency for Research on Cancer, Lyon, France, 2006.
    30) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Household Use of Solid Fuels and High-temperature Frying, 95, International Agency for Research on Cancer, Lyon, France, 2010a.
    31) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines, 89, International Agency for Research on Cancer, Lyon, France, 2007.
    32) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Some Non-heterocyclic Polycyclic Aromatic Hydrocarbons and Some Related Exposures, 92, International Agency for Research on Cancer, Lyon, France, 2010.
    33) IARC: List of all agents, mixtures and exposures evaluated to date - IARC Monographs: Overall Evaluations of Carcinogenicity to Humans, Volumes 1-88, 1972-PRESENT. World Health Organization, International Agency for Research on Cancer. Lyon, FranceAvailable from URL: http://monographs.iarc.fr/monoeval/crthall.html. As accessed Oct 07, 2004.
    34) International Agency for Research on Cancer (IARC): IARC monographs on the evaluation of carcinogenic risks to humans: list of classifications, volumes 1-116. International Agency for Research on Cancer (IARC). Lyon, France. 2016. Available from URL: http://monographs.iarc.fr/ENG/Classification/latest_classif.php. As accessed 2016-08-24.
    35) International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. Geneva, Switzerland. 2015. Available from URL: http://monographs.iarc.fr/ENG/Classification/. As accessed 2015-08-06.
    36) Jones RN: In vitro evaluation of ertapenem (MK-0826), a long-acting carbapenem, tested against selected resistant strains. J Chemother 2001; 13(4):363-376.
    37) Klugman KP & Dagan R: Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis. Meropenem Meningitis Study Group. Antimicrob Agents Chemother 1995; 39(5):1140-1146.
    38) Lami JL, Wilson SE, & Hopkins JA: Adjunctive antimicrobials in surgery of soft tissue infections: evaluation of cephalosporins and carbapenems. Am Surg 1991; 57:769-774.
    39) Lister PD & Black J: Pharmacodynamics of ertapenem, imipenem, cefepime and ceftriaxone against Escherichia coli and Klebsiella pneumoniae producing extended spectrum beta-lactamases (ESBL) and plasmid-encoded AmpC cephalosporinases (abstract). Abstracts of the IDSA 39th Annual Meeting. Clin Infect Dis 2001; 33(7):570.
    40) Livermore DM, Oakton KJ, Carter MW, et al: Activity of ertapenem (MK-0826) versus Enterobacteriaceae with potent beta-lactamases. Antimicrob Agents Chemother 2001a; 45(10):2831-2837.
    41) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    42) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    43) Martinez-Granados F, Navarro JN, Estrada JL, et al: Ertapenem-induced acute pancreatitis in a surgical elderly patient. Pharm World Sci 2008; 30(3):278-280.
    44) Mouton JW, Touw DJ, Horrevorts AM, et al: Comparative pharmacokinetics of the carbapenems: clinical implications. Clin Pharmacokinet 2000; 39(3):185-201.
    45) Munoz-Gomez S , Gran A , & Cunha BA : Meropenem delirium: a previously unrecognized neurologic side effect. J Chemother 2015; 27(2):120-121.
    46) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    47) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 1, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2001.
    48) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 2, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2002.
    49) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 3, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2003.
    50) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 4, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2004.
    51) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,3-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    52) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,4-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    53) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Butylene Oxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648083cdbb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    54) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Dibromoethane (Proposed). United States Environmental Protection Agency. Washington, DC. 2007g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802796db&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    55) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,3,5-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    56) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 2-Ethylhexyl Chloroformate (Proposed). United States Environmental Protection Agency. Washington, DC. 2007b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037904e&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    57) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Acrylonitrile (Proposed). United States Environmental Protection Agency. Washington, DC. 2007c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648028e6a3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    58) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Adamsite (Proposed). United States Environmental Protection Agency. Washington, DC. 2007h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    59) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Agent BZ (3-quinuclidinyl benzilate) (Proposed). United States Environmental Protection Agency. Washington, DC. 2007f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ad507&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    60) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Allyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039d9ee&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    61) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    62) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Arsenic Trioxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480220305&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    63) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Automotive Gasoline Unleaded (Proposed). United States Environmental Protection Agency. Washington, DC. 2009a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cc17&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    64) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Biphenyl (Proposed). United States Environmental Protection Agency. Washington, DC. 2005j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1b7&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    65) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bis-Chloromethyl Ether (BCME) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648022db11&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    66) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Boron Tribromide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae1d3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    67) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromine Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2007d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039732a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    68) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromoacetone (Proposed). United States Environmental Protection Agency. Washington, DC. 2008e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187bf&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    69) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Calcium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    70) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae328&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    71) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Sulfide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037ff26&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    72) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Chlorobenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803a52bb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    73) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Cyanogen (Proposed). United States Environmental Protection Agency. Washington, DC. 2008f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187fe&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    74) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Dimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbf3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    75) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Diphenylchloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    76) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091884e&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    77) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Phosphorodichloridate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480920347&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    78) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809203e7&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    79) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    80) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Germane (Proposed). United States Environmental Protection Agency. Washington, DC. 2008j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963906&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    81) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Hexafluoropropylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1f5&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    82) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ketene (Proposed). United States Environmental Protection Agency. Washington, DC. 2007. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ee7c&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    83) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    84) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    85) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Malathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2009k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809639df&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    86) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Mercury Vapor (Proposed). United States Environmental Protection Agency. Washington, DC. 2009b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a087&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    87) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Isothiocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a03&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    88) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a57&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    89) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl tertiary-butyl ether (Proposed). United States Environmental Protection Agency. Washington, DC. 2007a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802a4985&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    90) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methylchlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5f4&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    91) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    92) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c646&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    93) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN1 CAS Reg. No. 538-07-8) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    94) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN2 CAS Reg. No. 51-75-2) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    95) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN3 CAS Reg. No. 555-77-1) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    96) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Tetroxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091855b&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    97) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Trifluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e0c&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    98) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008o. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e32&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    99) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perchloryl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e268&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    100) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perfluoroisobutylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2009d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26a&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    101) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008p. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dd58&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    102) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2006d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020cc0c&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    103) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    104) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phorate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008q. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dcc8&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    105) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene (Draft-Revised). United States Environmental Protection Agency. Washington, DC. 2009e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a08a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    106) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene Oxime (Proposed). United States Environmental Protection Agency. Washington, DC. 2009f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26d&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    107) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    108) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    109) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Propargyl Alcohol (Proposed). United States Environmental Protection Agency. Washington, DC. 2006e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec91&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    110) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Selenium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec55&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    111) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Silane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d523&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    112) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    113) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    114) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Strontium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    115) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sulfuryl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec7a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    116) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tear Gas (Proposed). United States Environmental Protection Agency. Washington, DC. 2008s. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e551&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    117) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tellurium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e2a1&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    118) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tert-Octyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2008r. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5c7&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    119) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tetramethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-17.
    120) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    121) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7d608&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    122) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethylacetyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008t. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5cc&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    123) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Zinc Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    124) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for n-Butyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064808f9591&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    125) National Institute for Occupational Safety and Health: NIOSH Pocket Guide to Chemical Hazards, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Cincinnati, OH, 2007.
    126) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    127) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    128) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    129) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    130) Nilsson-Ehle I, Hutchison M, Haworth SJ, et al: Pharmacokinetics of meropenem compared to imipenem-cilastatin in young, healthy males. Eur J Clin Microbiol Infect Dis 1991; 10:85-88.
    131) Ortiz-Ruiz G , Caballero-Lopez J , Friedland IR , et al: A study evaluating the efficacy, safety, and tolerability of ertapenem versus ceftriaxone for the treatment of community-acquired pneumonia in adults. Clin Infect Dis 2002; 34(8):1076-1083.
    132) Product Information: DORIBAX(R) IV injection, doripenem IV injection. Ortho-NcNeil, Raritan, NJ, 2009.
    133) Product Information: DORIBAX(R) intravenous injection powder for solution, doripenem intravenous injection powder for solution. Shionogi Inc. (per FDA), Florham Park, NJ, 2015.
    134) Product Information: INVANZ(R) IV, IM injection, ertapenem IV, IM injection. Merck & Co,Inc, Whitehouse Station, NJ, 2008.
    135) Product Information: INVANZ(R) intravenous injection, intramuscular injection, ertapenem intravenous injection, intramuscular injection. Merck Sharp & Dohme Corp. (per manufacturer), Whitehouse Station, NJ, 2014.
    136) Product Information: MERREM(R) I.V. intravenous injection, meropenem intravenous injection. AstraZeneca Pharmaceuticals LP (per FDA), Wilmington, DE, 2013.
    137) Product Information: MERREM(R) I.V. intravenous injection, meropenem intravenous injection. AstraZeneca Pharmaceuticals LP (per FDA), Wilmington, DE, 2014.
    138) Product Information: MERREM(R) IV injection, meropenem IV injection. AstraZeneca Pharmaceuticals LP, Wilmington, DE, 2008.
    139) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    140) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    141) RTECS: Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2006; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    142) Sader HS & Gales AC: Emerging strategies in infectious diseases: new carbapenem and trinem antibacterial agents. Drugs 2001; 61(5):553-564.
    143) Saidel-Odes L, Borer A, Riesenberg K, et al: History of cerebrovascular events: a relative contraindication to ertapenem treatment. Clin Infect Dis 2006; 43(2):262-263.
    144) Sauberan JB, Bradley JS, Blumer J, et al: Transmission of meropenem in breast milk. Pediatr Infect Dis J 2012; 31(8):832-834.
    145) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    146) Seto AH , Song JC , & Guest SS : Ertapenem-associated seizures in a peritoneal dialysis patient. Ann Pharmacother 2005; 39(2):352-356.
    147) Snedden S, Rudoy R, Arrieta A, et al: Meropenem versus Cefotaxime-based therapy for initial treatment of infants and children hospitalised with non-cns infections. Clin Drug Invest 1999; 17(1):9-20.
    148) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    149) Sweetman, S: Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic Version, Thomson Healthcare. Greenwood Village, CO. 2007.
    150) Tegeder I, Neumann F, Bremer F, et al: Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration. Clin Pharmacol Ther 1999; 65:50-57.
    151) Tunkel AR, Hartman BJ, Kaplan SL, et al: Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39(9):1267-1284.
    152) U.S. Department of Energy, Office of Emergency Management: Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: Rev. 26 for chemicals of concern. U.S. Department of Energy, Office of Emergency Management. Washington, DC. 2010. Available from URL: http://www.hss.doe.gov/HealthSafety/WSHP/Chem_Safety/teel.html. As accessed 2011-06-27.
    153) U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project : 11th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Washington, DC. 2005. Available from URL: http://ntp.niehs.nih.gov/INDEXA5E1.HTM?objectid=32BA9724-F1F6-975E-7FCE50709CB4C932. As accessed 2011-06-27.
    154) U.S. Environmental Protection Agency: Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. Environmental Protection Agency's (EPA) Resource Conservation and Recovery Act (RCRA); List of hazardous substances and reportable quantities 2010b; 40CFR(261.33, e-f):77-.
    155) U.S. Environmental Protection Agency: Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency. Washington, DC. 2011. Available from URL: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showSubstanceList&list_type=date. As accessed 2011-06-21.
    156) U.S. Environmental Protection Agency: List of Radionuclides. U.S. Environmental Protection Agency. Washington, DC. 2010a. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    157) U.S. Environmental Protection Agency: List of hazardous substances and reportable quantities. U.S. Environmental Protection Agency. Washington, DC. 2010. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    158) U.S. Environmental Protection Agency: The list of extremely hazardous substances and their threshold planning quantities (CAS Number Order). U.S. Environmental Protection Agency. Washington, DC. 2010c. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-part355.pdf. As accessed 2011-06-17.
    159) U.S. Occupational Safety and Health Administration: Part 1910 - Occupational safety and health standards (continued) Occupational Safety, and Health Administration's (OSHA) list of highly hazardous chemicals, toxics and reactives. Subpart Z - toxic and hazardous substances. CFR 2010 2010; Vol6(SEC1910):7-.
    160) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    161) United States Environmental Protection Agency Office of Pollution Prevention and Toxics: Acute Exposure Guideline Levels (AEGLs) for Vinyl Acetate (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6af&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    162) van Enck JG, Touw DJ, & Lafeber HN: Pharmacokinetics of meropenem in preterm neonates. Ther Drug Monit 2001; 23:198-201.