Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) Diatracin
2) Lyphocin
3) Vancor
4) CAS 1404-90-6 (vancomycin)
5) CAS 1404-93-9 (vancomycin hydrochloride)
6) Chemical Formula C66-H75-Cl2-H9-O24

1) CAS 171099-57-3

1) Telavancin hydrochloride
2) Chemical Formula: C80-H106-C12-N11-O24

1) Dalbavancina
2) CAS 171500-79-1

1.2.1) MOLECULAR FORMULA
1) DALBAVANCIN: B(0), C88H100N10O28Cl2.1.6HCl
2) ORITAVANCIN DIPHOSPHATE: C86H97N10O26Cl3.2H3PO4
3) TELAVANCIN HYDROCHLORIDE: C80H106C12N11O27P.xHCl (where x = 1 to 3)
4) VANCOMYCIN: C66H75Cl2N9O24
5) VANCOMYCIN HYDROCHLORIDE: C66H75Cl2N9O24.HCl

Available Forms Sources

A)

1) VANCOMYCIN

a) Intravenous powder for solution: 1 g, 5 g, 10 g, 500 mg, 750 mg (Prod Info vancomycin HCl IV injection, 2011)
b) Intravenous solution: 750 mg/150 mL (Prod Info vancomycin HCl IV injection, 2011)
c) Oral capsules: 125 mg, 250 mg (Prod Info VANCOCIN(R) oral capsules, 2011).

2) DALBAVANCIN

a) INTRAVENOUS: Available in single use vial of 500 mg dalbavancin for intravenous administration (Prod Info DALVANCE(TM) intravenous injection, 2014).

3) ORITAVANCIN

a) INTRAVENOUS: Available in single use vials of 400 mg for IV administration. Three vials are packaged in a carton to supply for a single 1200 mg dose treatment (Prod Info ORBACTIV(TM) intravenous injection lyophilized powder, 2014).

4) TELAVANCIN

a) INTRAVENOUS: Available in single use vials of 250 mg or 750 mg telavancin for intravenous administration (Prod Info VIBATIV IV injection, 2009).

B)

1) VANCOMYCIN

a) Vancomycin is a glycopeptide antibiotic that is used in the treatment of serious staphylococci, streptococci, and other gram-positive organisms. It is the drug of choice for infections due to methicillin-resistant staphylococci (MRSA) and multiply resistant strains of Streptococcus pneumoniae. It is also used to treat serious staphylococcal and streptococcal infections in patients with allergies to penicillin or beta-lactam antibiotics (Prod Info vancomycin HCl IV injection, 2011). The Infectious Diseases Society of America clinical practice guidelines recommend vancomycin as empiric therapy of MRSA in hospitalized adult patients with complicated skin and soft tissue infection, bacteremia, endocarditis, pneumonia, bone and joint infections, and CNS infections (Liu et al, 2011).
b) Oral vancomycin therapy is indicated for the treatment of Clostridium difficile-associated diarrhea and enterocolitis associated with Staphylococcus aureus, including methicillin-resistant strains; parenteral administration of vancomycin is not effective (Prod Info VANCOCIN(R) oral capsules, 2011).

2) DALBAVANCIN

a) Dalbavancin, a semisynthetic lipoglycopeptide, is an antibacterial used in the treatment of acute bacterial skin and skin structure infections caused by susceptible Gram-positive microorganisms (Prod Info DALVANCE(TM) intravenous injection, 2014).

3) ORITAVANCIN

a) Oritavancin is a semisynthetic lipoglycopeptide antibacterial used for the treatment of acute bacterial skin and skin structure infections caused by susceptible Gram-positive bacteria in adults (Prod Info ORBACTIV(TM) intravenous injection lyophilized powder, 2014).

4) TELAVANCIN

a) Telavancin is a lipoglycopeptide antibacterial used for the treatment of complicated skin and skin structure infections caused by susceptible Gram-positive bacteria in adults (Prod Info VIBATIV IV injection, 2009).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Vancomycin is a glycopeptide antibiotic that is used intravenously in the treatment of serious staphylococci, streptococci, and other gram-positive organisms. It is the drug of choice for infections due to methicillin-resistant staphylococci (MRSA) and multiply resistant strains of Streptococcus pneumoniae. Oral vancomycin therapy is indicated for the treatment of Clostridium difficile-associated diarrhea and enterocolitis associated with Staphylococcus aureus, including methicillin-resistant strains.
B) PHARMACOLOGY: Vancomycin inhibits cell wall synthesis, most likely by interference with glycopeptide polymerization.
C) TOXICOLOGY: The mechanism by which vancomycin causes nephrotoxicity is unclear. "Red man syndrome" is an anaphylactoid reaction in which mast cells and basophils undergo degranulation and release histamine. A direct myocardial depressant effect is seen in animal studies.
D) EPIDEMIOLOGY: Vancomycin overdose is rare and serious toxicity is uncommon.
E) WITH THERAPEUTIC USE

1) Nephrotoxicity is an infrequent adverse effect and is more likely to occur when combined with aminoglycosides, though reversible nephrotoxicity has occurred with excessive serum concentrations. Neutropenia, thrombocytopenia, phlebitis, severe lacrimation, conjunctivitis, fever, and chills have occurred with therapeutic use. Pruritus and various rashes, erythema multiforme, and exfoliative dermatitis are seen infrequently with therapeutic doses. Most cases of permanent hearing loss have been associated with the coadministration of an aminoglycoside.
2) Severe adverse effects include hypotension and cardiac arrest, which have been associated with rapid intravenous administration.
3) Red man syndrome (RMS), which includes the following collection of signs/symptoms: sudden and profound decreases in blood pressure, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body (red man), pain and muscle spasm of the chest and back has been described following therapeutic use. It most often occurs with rapid intravenous infusion. Reactions generally resolve within 20 minutes, but may persist for several hours.

F) WITH POISONING/EXPOSURE

1) OVERDOSE: Hypotension, bradycardia, flushing, and apnea have been described in neonates. Nephrotoxicity can occur after excessive doses of these agents. Reversible ototoxicity has occurred with excessive serum concentrations.

0.2.20)

A) Oral vancomycin is classified as FDA pregnancy category B, while oritavancin, IV telavancin, and vancomycin are classified as FDA pregnancy category C. Vancomycin crosses the placenta. One study showed no association with malformation when vancomycin was given during gestation. Intravenous vancomycin is excreted in human breast milk; however, its effect on the breastfeeding infant is unknown. It is not known whether dalbavancin, oritavancin, telavancin, or oral vancomycin are excreted in human breast milk.

Laboratory Monitoring

A)

B)

C)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Red Man Syndrome: Antihistamines can be used as pretreatment. Increasing the dilution of vancomycin and slowing the rate intravenous administration may also help.

C) DECONTAMINATION

1) PREHOSPITAL: Vancomycin is poorly absorbed orally and toxicity from ingestion is unlikely. Gastrointestinal decontamination is not indicated unless coingestants are involved.
2) HOSPITAL: Vancomycin is poorly absorbed orally; gastrointestinal decontamination is not indicated.

D) ANTIDOTE

1) None

E) ENHANCED ELIMINATION PROCEDURE

1) Enhanced elimination is generally only necessary in patients with severe renal insufficiency. Hemoperfusion, hemofiltration, high-flux hemodialysis, and hemodifiltration have been effective in reducing serum vancomycin concentrations when high-porosity hemofilters are used. Multiple dose activated charcoal (MDAC): May decrease the half-life of intravenously administered vancomycin, but has not been shown to affect outcome. It is not routinely recommended but can be considered for patients with large overdoses when the patient is expected to have prolonged clearance, if the potential benefits are felt to outweigh risks. MDAC should not be administered in patients who are at risk for the abrupt onset of seizures or mental status depression or who are not able to protect airway.

F) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with inadvertent oral overdose who are asymptomatic can be managed at home.
2) OBSERVATION CRITERIA: Most overdoses are iatrogenic errors of intravenously administered vancomycin and these patients should be monitored. Any patient with a deliberate oral overdose or with symptoms after oral overdose should be referred to a healthcare facility.
3) ADMISSION CRITERIA: All symptomatic patients should be admitted to the hospital.
4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with large overdose or significant symptoms.

G) PITFALLS

1) When managing a suspected vancomycin overdose, the possibility of multidrug involvement should be considered.

H) PHARMACOKINETICS

1) Absorption: Vancomycin is poorly absorbed orally. Protein binding: approximately 55% protein bound at vancomycin serum concentration of 10 to 100 mcg/mL. Vd: 0.2 to 1.25 L/kg. Metabolism: does not undergo metabolism. Excretion: In the first 24 hours, approximately 75% of an intravenous dose is excreted in the urine via glomerular filtration. Mean elimination half-life from plasma of 4 to 6 hours in healthy subjects with normal renal function. The half-life in children has ranged from 5 to 11 hours. Vancomycin half-life is prolonged in renal failure. In anephric patients, it may be prolonged up to 7.5 days. Premature infants: vancomycin clearance decreases as postconceptual age decreases; this may necessitate longer dosing intervals in these infants.

I) DIFFERENTIAL DIAGNOSIS

1) Includes other agents that cause hypotension, nephrotoxicity, or ototoxicity.

0.4.4)

A) Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) Remove decontaminated clothing and wash exposed area extremely thoroughly with soap and water. Seek healthcare if irritation and pain persist after washing.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) Nephrotoxicity is an infrequent adverse effect and is more likely to occur when combined with aminoglycosides, though reversible nephrotoxicity has occurred with excessive serum concentrations. Neutropenia, thrombocytopenia, phlebitis, severe lacrimation, conjunctivitis, fever, and chills have occurred with therapeutic use. Pruritus and various rashes, erythema multiforme, and exfoliative dermatitis are seen infrequently with therapeutic doses. Most cases of permanent hearing loss have been associated with the coadministration of an aminoglycoside.
2) Severe adverse effects include hypotension and cardiac arrest, which have been associated with rapid intravenous administration.
3) Red man syndrome (RMS), which includes the following collection of signs/symptoms: sudden and profound decreases in blood pressure, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body (red man), pain and muscle spasm of the chest and back has been described following therapeutic use. It most often occurs with rapid intravenous infusion. Reactions generally resolve within 20 minutes, but may persist for several hours.

F)

1) OVERDOSE: Hypotension, bradycardia, flushing, and apnea have been described in neonates. Nephrotoxicity can occur after excessive doses of these agents. Reversible ototoxicity has occurred with excessive serum concentrations.

Vital Signs

3.3.3)

A) WITH THERAPEUTIC USE

1) Fever was reported in 9% of patients who received oral vancomycin 125 mg 4 times/day for 10 days (n=260) in 2 randomized, controlled, phase 3 trials for the treatment of diarrhea associated with Clostridium difficile (Prod Info VANCOCIN(R) oral capsules, 2011).
2) Chills have been reported infrequently in patients receiving vancomycin (Prod Info vancomycin HCl IV injection, 2011).
3) CASE REPORT: A 51-year-old man developed a febrile episode, rigors, presumed interstitial nephritis, and a rash 4 weeks after beginning vancomycin (1.75 g IV daily) for streptococcus pneumoniae. The delayed hypersensitivity resolved with drug cessation and treatment with methylprednisolone (Marik & Ferris, 1997).

B) WITH POISONING/EXPOSURE

1) Numerous workers have reported chills and fever (Geraci, 1958) Spears and Koch, 1959-1960; Ehrenkranz, 1958-1959; Kirby, 1960). However, many of the dermatological and febrile type of adverse reactions may have been related to impurities in early batches of the antibiotics.

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) LACRIMATION: Profuse lacrimation and conjunctivitis were reported in a 49-year-old man treated with intravenous vancomycin for septic arthritis caused by Staphylococcus aureus. The reaction occurred after each dose of vancomycin, and recurred upon rechallenge. It was successfully treated with topical corticosteroids, and continued vancomycin therapy was possible. The authors felt that an allergic component was likely, since a marked eosinophilia was present (Temperley et al, 1987).
2) ANIMAL STUDIES: INTRAVITREAL INJECTION: Rabbits had vancomycin injected at doses of 1 to 5 mg. The eyes injected with 1 mg or less showed no toxic changes histologically. The 2 to 5 mg doses produced localized toxicity to the retina (Homer et al, 1975).

3.4.4)

A) WITH THERAPEUTIC USE

1) Transient or permanent ototoxicity has occurred in patients receiving vancomycin, particularly in those administered excessive IV doses, those who have kidney dysfunction or a underlying hearing loss, or who are receiving concomitant therapy with other ototoxic agents (Prod Info vancomycin HCl IV injection, 2011; Prod Info VANCOCIN(R) oral capsules, 2011).
2) Ototoxicity can occur with excessive serum levels, but is usually reversible upon discontinuation of the drug (Riley, 1970). It is unlikely if serum levels are under 80 mcg/mL (Farber, 1984).
3) Lindholm and Murray (1966) indicated that ototoxicity is the most serious effect of vancomycin and occurs as deafness in patients who have serum concentrations greater than 80 mcg/mL for more than several days (Lindholm & Murray, 1966).
4) INCIDENCE: In a large case series of 742 cancer patients who received vancomycin, 6% developed ototoxicity when given with another ototoxic agent and only 3% of patients receiving vancomycin monotherapy developed toxicity (Elting et al, 1998).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) SUMMARY: Hypotension has been reported with vancomycin therapy and is more likely to occur with rapid administration (Prod Info vancomycin HCl IV injection, 2011).
b) CASE REPORT: Two adult women, 19 and 29 years of age, became acutely hypotensive after receiving 1 and 0.5 g of IV vancomycin respectively over less than 10 minutes after induction of anesthesia. Blood pressure dropped to 50/30 mm Hg in 1 patient and 60 mm Hg in the other; both rapidly responded to the administration of IV fluid. The latter patient also developed an erythematous macular rash over her trunk and extremities. No permanent sequelae was reported (Newfield & Roizen, 1979).
c) CASE REPORT: Miller and Tausk (1977) reported the occurrence of hypotension (mean blood pressure equals 30 mmHg) and rash in a 63-year-old woman after receiving intravenous vancomycin intraoperatively. Postoperatively the patient produced a positive skin reaction to intradermal vancomycin. The patient also received cefazolin which may have increased the risk of developing significant hypotension. Symptoms resolved without permanent sequelae (Miller & Tausk, 1977).
d) RED MAN SYNDROME

1) Vancomycin has been associated with the Red man syndrome, characterized by sudden and/or profound hypotension during vancomycin IV infusion, with or without a maculopapular skin rash over the face, neck, chest, and extremities. The reaction may occur within a few minutes of starting the infusion or near its completion, and skin rash subsides several hours after completion of an IV infusion. The syndrome may be mistaken for an allergic or anaphylactoid reaction; hypotension from vancomycin has been associated with a rapid rate of IV administration. However, it has also been reported with slow administration of vancomycin (Odio et al, 1984; Davis et al, 1986; Pau & Khakoo, 1985). Red Man syndrome has also been associated with an intraperitoneal loading dose of vancomycin and in 2 cases with oral vancomycin therapy (Bergeron & Boucher, 1994); (Bailey et al, 1990)(Killian et al, 1991).

2) WITH POISONING/EXPOSURE

a) Three neonates developed hypotension, apnea, flushed skin and inflammation at the infusion site after receiving vancomycin infusions of 300 to 400 mg/kg (Barker et al, 2002).
b) RED MAN SYNDROME: Two premature twins developed signs and symptoms of Red man syndrome (ie, flushed face and trunk, peripheral cyanosis, apnea, hypoxemia, bradycardia, hypotension) a few minutes after inadvertently receiving an overdose of vancomycin (doses: 38 and 35 mg/kg, respectively) as a single 1-min IV injection. Laboratory results revealed metabolic acidosis (pH 7.29 and 7.24, a base excess of -10.5 and -10.9 mmol/L, respectively). Following supportive therapy for 30 minutes, both RMS and metabolic acidosis resolved. Vancomycin serum concentrations were 32 and 34.5 mg/L, respectively, 9 hours after administration. On day 19, all laboratory results were normal, except for a urinary protein electrophoresis revealing tubular proteinuria with elevated activity of the tubular enzyme N-acetyl-beta-D-glucosaminidase (NAG) in the urine. Both proteinuria and NAG excretion returned to normal values a week later (Muller et al, 1999).

B) PROLONGED QT INTERVAL

1) WITH THERAPEUTIC USE

a) TELAVANCIN: Doses of 7.5 and 15 mg/kg of telavancin prolonged the QTc interval in healthy volunteers. The manufacturer suggests cautious use of this agent in patients with a history of QTc prolongation, congenital long QT syndrome, uncompensated heart failure, or severe left ventricular hypertrophy (Prod Info VIBATIV IV injection, 2009).

C) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) NEONATES: A 6-day-old infant who was born with a solitary hypodysplastic left kidney, anuric renal failure, and pulmonary hypoplasia, was treated with nafcillin and cefotaxime for suspected sepsis after developing metabolic acidosis and hypotension. On day 8, his condition worsened and nafcillin was replaced with vancomycin. However, he was inadvertently administered 100 mg/kg of vancomycin instead of 10 mg/kg. At this time, his vancomycin serum concentration was 240 mcg/mL. He did not develop any adverse effects, except for brief episodes of bradycardia (70 beats/min). He was successfully treated with supportive care, including 41 hours of continuous venovenous hemodiafiltration (CVVHD) with a high-flux membrane (Goebel et al, 1999).
b) RED MAN SYNDROME: Two premature twins developed signs and symptoms of Red man syndrome (ie, flushed face and trunk, peripheral cyanosis, apnea, hypoxemia, bradycardia, hypotension) a few minutes after inadvertently receiving an overdose of vancomycin (doses: 38 and 35 mg/kg, respectively) as a single 1-min IV injection. Laboratory results revealed metabolic acidosis (pH 7.29 and 7.24, a base excess of -10.5 and -10.9 mmol/L, respectively). Following supportive therapy for 30 minutes, both RMS and metabolic acidosis resolved. Vancomycin serum concentrations were 32 and 34.5 mg/L, respectively, 9 hours after administration. On day 19, all laboratory results were normal, except for a urinary protein electrophoresis revealing tubular proteinuria with elevated activity of the tubular enzyme N-acetyl-beta-D-glucosaminidase (NAG) in the urine. Both proteinuria and NAG excretion returned to normal values a week later (Muller et al, 1999).

D) CARDIAC ARREST

1) WITH THERAPEUTIC USE

a) SUMMARY

1) Cardiac arrest has rarely been reported with rapid intravenous administration of vancomycin (Prod Info vancomycin HCl IV injection, 2011; Glicklich & Figura, 1984).

b) CASE REPORTS

1) ADULT: Cardiopulmonary arrest occurred in a 57-year-old diabetic woman undergoing peritoneal dialysis following vancomycin 1 g IV bolus over 2 minutes for the treatment of enterococcal peritonitis (Glicklich & Figura, 1984). The authors suggested that rapid IV infusion of vancomycin could result in neuromuscular blockade or ventricular dysrhythmias and recommended that manufacturer dose guidelines be followed.
2) PEDIATRIC: Intraoperative administration of 250 mg vancomycin resulted in severe hypotension and cardiac arrest in a 2-year-old child during kidney transplantation. Vancomycin was administered into a long IV line connected to a newly placed central Hickman catheter. The patient did not survive despite intensive resuscitation (Mayhew & Deutsch, 1985).
3) NEONATE: Cardiac arrest in a neonate has been associated with inadvertent and rapid intravenous administration of vancomycin 150 mg (S Sweetman , 2000).

E) PERIPHERAL EDEMA

1) WITH THERAPEUTIC USE

a) Peripheral edema was reported in 6% of patients who received oral vancomycin 125 mg 4 times/day (n=260) in 2 randomized, controlled, phase 3 trials for the treatment of Clostridium difficile associated diarrhea. Compared to younger subjects, peripheral edema occurred more often in patients older than 65 years of age (Prod Info VANCOCIN(R) oral capsules, 2011).

Respiratory

3.6.2)

A) APNEA

1) WITH POISONING/EXPOSURE

a) Three neonates developed hypotension, apnea, flushed skin and inflammation at the infusion site after receiving vancomycin infusions of 300 to 400 milligrams/kilogram (Barker et al, 2002).

Neurologic

3.7.2)

A) CLOUDED CONSCIOUSNESS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 56-year-old female diagnosed with D-lactic acidosis syndrome was admitted with mental confusion, disorientation, slurred speech and staggering gait after receiving vancomycin therapy for a severe intravenous line infection. The patient reported anorexia, diarrhea and a reduction in oral intake after beginning antibiotic therapy. The authors concluded that the underlying syndrome was probably precipitated by the use of vancomycin, because neurological symptoms were only present when the patient's nutritional status deteriorated (Gavazzi et al, 2001).

B) HEADACHE

1) WITH THERAPEUTIC USE

a) Headache was reported in 7% of patients who received oral vancomycin 125 mg 4 times/day for 10 days (n=260) in 2 randomized, controlled, phase 3 trials for the treatment of diarrhea associated with Clostridium difficile (Prod Info VANCOCIN(R) oral capsules, 2011).

Gastrointestinal

3.8.2)

A) NAUSEA

1) WITH THERAPEUTIC USE

a) Nausea was reported in 17% of patients who received oral vancomycin 125 mg 4 times/day for 10 days (n=260) in 2 randomized, controlled, phase 3 trials for the treatment of diarrhea associated with Clostridium difficile. Nausea was among the most common events leading to discontinuation, occurring in less than 1% of patients (Prod Info VANCOCIN(R) oral capsules, 2011). Nausea has also been reported infrequently in patients receiving IV vancomycin (Prod Info vancomycin HCl IV injection, 2011).

B) VOMITING

1) WITH THERAPEUTIC USE

a) Vomiting was reported in 9% of patients who received oral vancomycin 125 mg 4 times/day for 10 days (n=260) in 2 randomized, controlled, phase 3 trials for the treatment of diarrhea associated with Clostridium difficile (Prod Info VANCOCIN(R) oral capsules, 2011).

C) ABDOMINAL PAIN

1) WITH THERAPEUTIC USE

a) Abdominal pain was reported in 15% of patients who received oral vancomycin 125 mg 4 times/day for 10 days (n=260) in 2 randomized, controlled, phase 3 trials for the treatment of diarrhea associated with Clostridium difficile (Prod Info VANCOCIN(R) oral capsules, 2011).

D) DIARRHEA

1) WITH THERAPEUTIC USE

a) Diarrhea was reported in 9% of patients who received oral vancomycin 125 mg 4 times/day for 10 days (n=260) in 2 randomized, controlled, phase 3 trials for the treatment of diarrhea associated with Clostridium difficile (Prod Info VANCOCIN(R) oral capsules, 2011).

E) PSEUDOMEMBRANOUS ENTEROCOLITIS

1) WITH THERAPEUTIC USE

a) Pseudomembranous colitis due to Clostridium difficile has rarely been reported in patients receiving IV vancomycin. The onset of symptoms may occur during or after antibacterial treatment (Prod Info vancomycin HCl IV injection, 2011).

F) CHEMICAL PERITONITIS

1) WITH THERAPEUTIC USE

a) Over 50 cases of chemical peritonitis have been reported with the administration of vancomycin by intraperitoneal route during continuous ambulatory peritoneal dialysis. The peritonitis developed within 12 hours of administration in some patients and ranged in severity from cloudy dialysate alone to cloudy dialysate with fever and abdominal pain. All cases have been self-limiting and fluids were usually clear after discontinuation of vancomycin (Prod Info vancomycin HCl IV injection, 2011).

Genitourinary

3.10.2)

A) ABNORMAL RENAL FUNCTION

1) WITH THERAPEUTIC USE

a) SUMMARY

1) Nephrotoxicity may occur with the therapeutic use of these agents (Prod Info vancomycin hcl IV injection, 2009; Prod Info VIBATIV IV injection, 2009).
2) Nephrotoxicity can occur with excessive serum levels but is usually reversible upon discontinuation of the drug (Riley, 1970). Proteinuria, hematuria, and occasionally a rise in blood urea nitrogen have been described (Jawetz, 1968; Appel et al, 1986).

b) CASE SERIES

1) In 25 patients with renal failure, vancomycin did not increase BUN and return of renal function was not impaired by the drug (1:84).
2) Increases in serum creatinine occurred in 4 of 50 patients (8%) receiving IV vancomycin for bacterial infections. All of these patients were receiving concurrent aminoglycoside therapy. Proteinuria occurred in 1 of 50 patients treated (Sorrell & Collignon, 1985).
3) In a large case series of 726 cancer patients who received vancomycin, 17% (127 patients) of patients developed nephrotoxicity (Elting et al, 1998). The authors revealed that risk factors associated with increased risk included the coadministration of other nephrotoxic agents and advanced age. Nephrotoxicity was asymptomatic and self-limiting in all patients.

c) CASE REPORTS

1) ADULTS

a) A 54-year-old man developed acute renal failure after receiving 10 days of vancomycin at 1 gram every 4 hours intravenously (total dose 5.6 grams) for CSF S. epidermidis positive culture. Serum vancomycin concentration was 284 mcg/mL. Continuous arteriovenous hemofiltration (CAVH) over 5 days was associated with a rapid decline in serum concentrations (Walczyk et al, 1988).
b) A 51-year-old male developed presumed interstitial nephritis along with erythema multiforme and a febrile episode after 4 weeks of vancomycin therapy (1.75 g IV daily). The patient initially developed oliguria and renal function gradually declined (lowest level: creatinine 7.8 mg/dL and BUN 84 mg/dL). Symptoms improved with methylprednisolone (50 mg/day) and renal function gradually returned to normal (Marik & Ferris, 1997).
c) Acute interstitial nephritis was reported in a 64-year-old male who developed fever, maculopapular rash, acute renal failure, eosinophilia and eosinophiluria after receiving vancomycin for 1 month for a S. aureus infection (Wai et al, 1998). Biopsy results were consistent with an allergic drug reaction. A re-challenge one month later resulted in a rise in serum eosinophils and the urine tested positive for eosinophils, but the creatinine level remained stable.
d) A 70-year-old male receiving vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) developed acute tubulointerstitial nephritis (confirmed by biopsy), along with a fever and rash. The patient had been treated with vancomycin for approximately 28 days when peritoneal dialysis was started for the management of volume overload. Three days later, the patient was switched to hemodialysis. Due to a worsening rash, vancomycin was stopped. The rash progressed to erythema multiforme, then to toxic epidermal necrolysis in the setting of steroid taper and persistent serum vancomycin levels. The patient died on hospital day 25 of overwhelming polymicrobial sepsis. An autopsy was refused by the family (Hsu, 2001).

B) ACUTE TUBULAR NECROSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: An 8-year-old boy diagnosed with a ventriculoperitoneal shunt infection was started on vancomycin and cloxacillin therapy, and developed acute tubular necrosis. The patient was receiving a larger dose than usual of vancomycin (400 mg IV every 6 hours (60 mg/kg/day)) to treat his infection. After 7 doses (105 mg/kg total), creatinine was 215 micromol/L (2 mg/dL) with increasing oliguria and 6 hour though vancomycin concentration was 45.8 mg/L; vancomycin was stopped. Renal biopsy showed acute tubular necrosis and renal ultrasound displayed mildly enlarged hyperechoic kidneys without evidence of obstruction. Dialysis was performed on days 8, 10 and 12 for 4 hours. By day 15, urine output was improving and serum creatinine was beginning to decline; repeat ultrasound 4 months later was normal (Wicklow et al, 2006).

Hematologic

3.13.2)

A) NEUTROPENIA

1) WITH THERAPEUTIC USE

a) SUMMARY: Reversible neutropenia has been reported in several dozen patients receiving vancomycin. The neutropenia usually starts 1 week or more after the onset of therapy or after a total dosage of more than 25 grams, and appears to be promptly reversed after discontinuation of therapy (Prod Info VANCOCIN(R) oral capsules, 2011; Prod Info vancomycin HCl IV injection, 2011).
b) CASE REPORT: Borland and Farrar (1979) attributed one case of reversible neutropenia to vancomycin. On the 35th day of treatment, the neutrophil count was 500/mm(3) in this 10-year-old female. Other drugs were administered concurrently; however, the neutrophil count began to rise the day following discontinuance of vancomycin.
c) CASE REPORT: Vancomycin 250 mg IV Q12H for 17 days was associated with the occurrence of neutropenia in a 67-year-old woman with cellulitis and sepsis (S. aureus). Withdrawal of vancomycin resulted in increases in neutrophil count over the next 5 days (Mackett & Guay, 1985).

B) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) Thrombocytopenia has been reported rarely with vancomycin therapy (Prod Info vancomycin HCl IV injection, 2011). Thrombocytopenia has also been reported during postmarketing surveillance; however a causal relationship to product exposure has not been established (Prod Info VANCOCIN(R) oral capsules, 2011).
b) CASE REPORT: Severe thrombocytopenia occurred in a 48-year-old female who developed peritonitis secondary to peritoneal dialysis. Vancomycin 500 mg IV followed by 120 mg daily intraperitoneally in four divided doses was given. Six days later the patient developed spontaneous bruising, and bleeding of the tongue and gums; thrombocytopenia was present. Therapy was discontinued and the platelet count increased over the next few weeks. An autoimmune or immune-complex etiology was suggested as the cause of the thrombocytopenia (Walker & Heaton, 1985).
c) CASE REPORT: A 58-year-old male was being treated for resistant S. aureus with vancomycin and his platelet count decreased from 397 x 10(3)/mm(3) to 22 x 10(3)/mm(3) by hospital day 14. The platelet count rose with discontinuation of therapy, but dropped again upon rechallenge. Vancomycin was discontinued a second time with reports of a normal platelet count throughout the remainder of the hospital stay (Howard et al, 1997).

C) THROMBOPHLEBITIS

1) WITH THERAPEUTIC USE

a) CASE SERIES: In one series of patients, thrombophlebitis occurred in all 20 patients receiving vancomycin through peripheral venous cannulae. In 8 patients, therapy was restarted successfully through a central venous cannulae (Sorrell & Collignon, 1985).

Dermatologic

3.14.2)

A) SKIN FINDING

1) WITH THERAPEUTIC USE

a) Urticaria, pruritus and flushing has occurred as a result of rapid infusion of vancomycin resulting an anaphylactoid reaction. Symptoms usually resolve within 20 minutes but can persist for hours (Prod Info vancomycin HCl IV injection, 2011).
b) Infrequent reports of exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and rare cases of vasculitis have been associated with the use of vancomycin (Prod Info vancomycin HCl IV injection, 2011).

B) ERUPTION

1) WITH THERAPEUTIC USE

a) Rashes, including exfoliative dermatitis, have been reported infrequently with vancomycin therapy (Prod Info vancomycin HCl IV injection, 2011; Carpenter et al, 1992; Piketty et al, 1994).

1) However, many of the dermatological and febrile types of adverse reactions may have been related to impurities in early batches of the antibiotics (Alexander, 1974).

b) INCIDENCE/CASE SERIES: In a large case series of 726 cancer patients who received vancomycin, 11% of patients developed rashes (Elting et al, 1998). Most patients were also on concomitant beta-lactam antibiotic therapy.

2) WITH POISONING/EXPOSURE

a) Numerous workers have reported phlebitis, chills, fever (Geraci, 1958) Spears and Koch, 1959-1960; Ehrenkranz, 1958-1959; Kirby, 1960).

1) However, many of the dermatological and febrile types of adverse reactions may have been related to impurities in early batches of the antibiotics (Alexander, 1974).

C) ERYTHEMA MULTIFORME

1) WITH THERAPEUTIC USE

a) CASE REPORTS

1) ADULTS

a) Erythema multiforme progressing to exfoliative dermatitis was reported in a 29-year-old woman with end-stage renal disease receiving intraperitoneal vancomycin for a catheter infection. The serum vancomycin concentration measured the day after her last 1500 mg dose was 40.4 mcg/mL. Her condition improved over the next three weeks, and she recovered completely (Gutfeld et al, 1988).
b) Erythema multiforme, presumed interstitial nephritis and fever developed in a 51-year-old male after receiving vancomycin for 4 weeks for streptococcus pneumoniae. All symptoms resolved with drug cessation and therapy with methylprednisolone 50 mg/day IV (Marik & Ferris, 1997).
c) A 70-year-old male received vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) and developed a rash that progressed to erythema multiforme major after rechallenge with vancomycin. Symptoms progressed to toxic epidermal necrolysis in the setting of steroid taper and persistent serum vancomycin levels. The patient died on hospital day 25 of overwhelming polymicrobial sepsis. An autopsy was refused by the family (Hsu, 2001).

D) DRUG-INDUCED ERYTHRODERMA

1) WITH THERAPEUTIC USE

a) SUMMARY: Red man syndrome (RMS) which includes the following collection of signs/symptoms: sudden and profound decreases in blood pressure, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body (red man), pain and muscle spasm of the chest and back has been described following therapeutic use. Reactions generally resolve within 20 minutes, but may persist for several hours (Prod Info vancomycin HCl IV injection, 2011; Polk et al, 1988).
b) INTRAVENOUS ADMINISTRATION

1) The reaction may occur within a few minutes of starting the infusion or near its completion, and skin rash subsides several hours after completion of an IV infusion (Prod Info Vancocin(R), vancomycin, capsules, oral, and intravenous, 1998). It is suggested that vancomycin be administered slowly (over one hour) to avoid the Red Man syndrome and blood pressure monitoring should be undertaken during IV infusion (Garrelts & Peterie, 1985). However, slow infusion does NOT preclude the risk of the red-neck syndrome (Pau & Khakoo, 1985; Davis et al, 1986a).
2) The syndrome may be mistaken for an allergic or anaphylactoid reaction; hypotension from vancomycin has been associated with a rapid rate of IV administration.

c) INTRAPERITONEAL ADMINISTRATION

1) Intraperitoneal administration has also been associated with this syndrome (Bailie et al, 1990).

d) ORAL ADMINISTRATION

1) Oral administration of 500 milligrams via a nasogastric tube produced a red man-like syndrome in a 67-year-old with colitis (Killian et al, 1991a).

e) ETIOLOGY: The causes of the cardiovascular and cutaneous reactions to vancomycin are unknown. In isolated pharmacologic preparations, vancomycin has been shown to exert cardiac depressant and vasodilating actions (Cohen et al, 1970). Myocardial release of histamine may be involved in some cardiovascular events observed (Zavecz & Levi, 1977).

1) Administration of vancomycin 1 gram by intravenous infusion over 2 hours was associated with a lower incidence of "Red Man Syndrome", significantly lower peak concentration of histamine in plasma, and a lower total release of histamine than the 1-hour infusion in 10 subjects (Healy et al, 1990).

f) CASE REPORTS

1) A 55-year-old woman was administered vancomycin 1 g IV Q12H for cellulitis. During the infusion, the patient developed a hot and itchy feeling followed by a erythematous maculopapular rash over the face, neck, trunk, and extremities. Blood pressure was not recorded. The rash and urticaria subsided within three hours and no further reactions occurred when the dose was administered over at least one hour (Garrelts & Peterie, 1985).
2) Red-neck syndrome occurred secondary to a slow infusion of vancomycin in an adult. The patient received 1 g of vancomycin in 250 mL of D5W over 2 hours which resulted in dizziness, flushing, and a rash on the face and neck after 90 minutes of the infusion. Within the next 2 hours (after the withdrawal of the drug), the rash subsided (Pau & Khakoo, 1985).
3) PEDIATRIC: A histamine-like rash developed in 7 (35%) of 20 children given 15 mg/kg IV over 1 hour for surgical prophylaxis prior to cerebrospinal fluid shunt procedures. The reaction was accompanied by hypotension (blood pressure 40/25 mmHg) and hypothermia (rectal temperature 35 degrees C) in an 8-month-old infant. The reaction recurred upon readministration in one patient. The rash was characteristically maculopapular and localized to the face, neck, chest, and upper extremities and occurred approximately 25 minutes after beginning the infusion and persisted for 77 to 90 minutes (Odio et al, 1984a).

E) PHLEBITIS

1) WITH THERAPEUTIC USE

a) Phlebitis at the injection site has been reported with IV vancomycin (Prod Info vancomycin HCl IV injection, 2011).

Musculoskeletal

3.15.2)

A) MUSCLE PAIN

1) WITH THERAPEUTIC USE

a) Throbbing pain in the muscles of the back and neck have been reported. This can be minimized or avoided by slower administration (Prod Info vancomycin hcl IV injection, 2009).

Reproductive

3.20.1)

A) Oral vancomycin is classified as FDA pregnancy category B, while oritavancin, IV telavancin, and vancomycin are classified as FDA pregnancy category C. Vancomycin crosses the placenta. One study showed no association with malformation when vancomycin was given during gestation. Intravenous vancomycin is excreted in human breast milk; however, its effect on the breastfeeding infant is unknown. It is not known whether dalbavancin, oritavancin, telavancin, or oral vancomycin are excreted in human breast milk.

3.20.2)

A) LACK OF EFFECT

1) VANCOMYCIN

a) There was no evidence of teratogenicity in rats given vancomycin up to 200 mg/kg/day IV (1 times the maximum recommended human dose (MRHD) based on a mg/m(2) basis) or in rabbits given up to 120 mg/kg/day IV (1.1 times the MRHD based on a mg/m(2) basis). There was no effect on fetal weight or development with vancomycin administered the highest dose tested in rats or at 80 mg/kg/day (0.74 times the MRHD based on mg/m(2)) in rabbits (Prod Info VANCOCIN(R) PULVULES(R) oral capsules, 2005).
b) One study by MacCulloch (1981) showed no association with malformation when vancomycin was given during gestation. Vancomycin does cross the placenta (S Sweetman , 2000).

2) ORITAVANCIN

a) There is no evidence of fetal harm in rats or rabbits administered oritavancin at 30 mg/kg/day and 15 mg/kg/day, respectively (equivalent to a human dose of 300 mg or 25% of the clinical dose) (Prod Info ORBACTIV(TM) intravenous injection lyophilized powder, 2014).

B) ANIMAL STUDIES

1) DALBAVANCIN

a) There was no evidence of embryonic or fetal toxicity after the administration of dalbavancin at approximately 1.2 and 0.7 times the recommended human dose. Delayed fetal maturation as well as increased embryonic lethality, and offspring deaths during the first postpartum week were reported after dalbavancin administration at approximately 3.5 times the recommended human dose in pre- and postnatal development studies (Prod Info DALVANCE(R) intravenous injection, 2016).

2) TELAVANCIN

a) Reduced fetal weights and increased limb and skeletal malformations were reported in the offspring of rats, rabbits, and minipigs given IV telavancin doses up to 150, 45, or 75 mg/kg/day, respectively, during organogenesis. The telavancin AUC at the doses tested was 1 to 2 times that in humans receiving the maximum recommended human dose. Toxic effects observed at rates of less than 1% included adactyly (rabbits), brachymelia (rats, rabbits), polydactyly (minipigs), syndactyly (rats, minipigs), flexed front paw and absent ulna (rabbits), misshapen digits and deformed front leg (minipigs), and decreased fetal body weight and increased number of stillborn pups (rats); these effects were either absent or occurred at lower rates in historical or concurrent controls (Prod Info VIBATIV(R) intravenous injection, 2013).

3.20.3)

A) PREGNANCY CATEGORY

1) ORITAVANCIN is classified as FDA pregnancy category C (Prod Info ORBACTIV(TM) intravenous injection lyophilized powder, 2014)
2) TELAVANCIN is classified as FDA pregnancy category C (Prod Info VIBATIV(R) intravenous injection, 2013).
3) VANCOMYCIN is classified as FDA pregnancy category B (oral) (Prod Info VANCOCIN(R) PULVULES(R) oral capsules, 2005) and C (intravenous) (Prod Info vancomycin hcl IV injection, 2009).

B) DALBAVANCIN

1) There are no adequate or well controlled studies of dalbavancin use during human pregnancy. Dalbavancin should be used in pregnant women only if the potential maternal benefit outweighs the potential risk to the fetus (Prod Info DALVANCE(R) intravenous injection, 2016).

3.20.4)

A) LACK OF INFORMATION

1) DALBAVANCIN

a) Human lactation studies of dalbavancin have not been conducted; therefore, it is unknown whether dalbavancin is excreted in human breast milk. Due to the lack of human safety information, caution is advised when administering dalbavancin to breastfeeding women (Prod Info DALVANCE(R) intravenous injection, 2016).

2) TELAVANCIN

a) It is not known whether telavancin is excreted in human breast milk (Prod Info VIBATIV(R) intravenous injection, 2013).

B) ORITAVANCIN

1) Human lactation studies have not been conducted with oritavancin. It is unknown whether oritavancin is excreted in human breast milk. However, animal studies have shown excretion of oritavancin in the milk of lactating rats. Due to the lack of human safety information, caution is advised when administering oritavancin to nursing women (Prod Info ORBACTIV(TM) intravenous injection lyophilized powder, 2014).

C) VANCOMYCIN

1) Intravenous vancomycin is excreted into human breast milk; the effect on the nursing infant is unknown (Prod Info vancomycin hcl IV injection, 2009). It is not known if oral vancomycin appears in the breast milk of nursing women (Prod Info VANCOCIN(R) PULVULES(R) oral capsules, 2005).

D) ANIMAL STUDIES

1) DALBAVANCIN

a) Dalbavancin is excreted in the milk of lactating rats (Prod Info DALVANCE(R) intravenous injection, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs.
B) Monitor renal function, serum electrolytes, CBC, urine output, and serum vancomycin concentrations after an overdose. Therapeutic concentrations: Peak: 25 to 35 mcg/mL, trough: 10 to 15 mcg/mL.
C) Auditory function may also required monitoring.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) THERAPEUTIC LEVELS

a) Peak - 25 to 35 mcg/mL
b) Trough - 10 to 15 mcg/mL (Farber, 1984).

B) RENAL FUNCTION

1) Monitor renal function frequently in patients receiving these agents or following inadvertent exposure.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor the following in potentially toxic situations:

1) Renal function
2) Skin rash
3) Pain at infusion site
4) Hearing/serial audiometrics on patients with impaired renal function
5) Serum concentrations in patients with impaired renal function

Methods

A)

1) Polk et al (1981) described a radioimmunoassay for vancomycin and indicated that the results were significantly less variable than for a microbiological assay. A Monitor Science (Newport Beach, CA) kit was used for the RIA.
2) FLUORESCENCE POLARIZATION IMMUNOASSAY (FPIA)/FALSE POSITIVE - FPIA, used to commonly measure serum drug concentration, may be falsely elevated in individuals with end-stage renal disease (Kim et al, 1999). This overestimation may occur in 30% to 70% of hemodialysis patients and is believed to be due to the formation of a nontoxic nonmicrobiologically active by-product known as crystalline degradation product-1 (CDP-1) that accumulates secondary to delayed vancomycin elimination.

a) Bowhay & Timms (1997) reported that FPIA interference occurred in a patient with only mild renal dysfunction (calculated of renal function from serum creatinine was 48 mL/minute). The authors could not confirm that the interference was due to CDP-1.

B)

1) A method of of vancomycin determination in plasma via high-performance liquid chromatography has also been described. It reportedly has a detection limit of 0.01 mcg/mL (Hosotsubo, 1989).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All symptomatic patients should be admitted to the hospital.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients with inadvertent oral overdose who are asymptomatic can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist or poison center for patients with large overdose or significant symptoms.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Most overdoses are iatrogenic errors of intravenously administered vancomycin and these patients should be monitored. Any patient with a deliberate oral overdose or with symptoms after oral overdose should be referred to a healthcare facility.

Monitoring

A)

B)

C)

Oral Exposure

6.5.1)

A) Vancomycin is poorly absorbed orally and toxicity from ingestion is unlikely. Gastrointestinal decontamination is not indicated unless coingestants are involved.
B) OCULAR EXPOSURE: Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, the patient should be seen in a healthcare facility.
C) DERMAL EXPOSURE: Remove decontaminated clothing and wash exposed area extremely thoroughly with soap and water. Seek healthcare if irritation and pain persist after washing.

6.5.2)

A) SUMMARY

1) Vancomycin is poorly absorbed orally; gastrointestinal decontamination is not indicated.
2) Multiple dose activated charcoal may decrease the half-life of intravenously administered vancomycin, but has not been shown to affect outcome. It is not routinely recommended but can be considered for patients with large overdoses when the patient is expected to have prolonged clearance, if the potential benefits are felt to outweigh risks. MDAC should not be administered in patients who are at risk for the abrupt onset of seizures or mental status depression or who are not able to protect airway.

B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

3) Oral charcoal had no effect on the elimination of intravenous vancomycin in rabbits with induced renal failure (El-Sayed et al, 1993).

C) MULTIPLE DOSE ACTIVATED CHARCOAL

1) CASE REPORTS

a) Supratherapeutic vancomycin infusions of 300 to 400 milligrams/kilogram were inadvertently given to three premature neonates. Each infant became symptomatic (i.e., apnea, hypotension, flushed, inflamed infusion sites), and multiple dose activated charcoal was given. MDAC (1 gram/kilogram every 4 hours) was given for 24 hours to one infant (wt 3120 g), and for 48 hours to the other two infants (wt. 690 g and 1275 g, respectively). MDAC reduced the beta half-life in 2 of the 3 preterm neonates, with the reduction being the greatest in the infant that received the highest milligram/kilogram dose. The authors recommended the use of MDAC for the treatment of vancomycin toxicity (Barker et al, 2002).
b) Repeat and administration of activated charcoal 1 g/kg every 4 hours for 10 doses appeared to reduce the half-life of vancomycin in a 47-day-old premature male infant following an accidental intravenous vancomycin overdose. Before charcoal administration the half-life was 35 hours, during charcoal administration the half-life was 12 hours (Burkhart et al, 1992).
c) Kucukguclu et al (1996) reported a similar case in a 17-day-old female neonate given an inadvertent 500 mg bolus of vancomycin. The infant developed Red Man Syndrome within minutes of administration and had a serum vancomycin level of 165.7 micrograms/milliliter. Activated charcoal (1 g/kg) was given 5 hours after injection and continued every 4 hours for 12 doses. Half-life calculated during charcoal administration was 9.4 hours or less; normal is 13.4 to 33.l7 hours in neonates. Renal function remained normal; she was discharged to home on day 6 (Kucukguclu et al, 1996).

6.5.3)

A) SUPPORT

1) Monitor vital signs.
2) Monitor renal function, serum electrolytes, CBC, urine output, and serum vancomycin concentrations after an overdose. Therapeutic concentrations: Peak: 25 to 35 mcg/mL, trough: 10 to 15 mcg/mL.
3) Auditory function may also required monitoring.

B) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

4) CASE REPORT: A 2-year-old, 10 kilogram boy receiving 6.7 mg of vancomycin per 0.67 mL per minute by intravenous infusion during surgery for emergency ventriculoperitoneal (VP) shunt developed hypotension (50 mmHg systolic), decreased O2 saturation (from 98% to 85%), and increased peak inspiratory pressure (PIP) (3 minutes after a supplemental 0.25 milligram dose of vecuronium, followed by 5 milliliters of saline, was administered through an injection port of the tubing carrying the vancomycin). The authors suggested that the reaction seen was caused by an estimated dose of 25 mg of vancomycin given within 5 seconds, a dose rate of 300 mg/minute, that was in the tubing when the vecuronium was administered. Prompt improvement in PIP, BP, and O2 saturation was noted following administration of 12.5 mg of diphenhydramine intravenously (Lyon & Bruce, 1988). Additional studies are needed to confirm this observation.

Eye Exposure

6.8.1)

A) Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, the patient should be seen in a healthcare facility.

Dermal Exposure

6.9.1)

A) Remove decontaminated clothing and wash exposed area extremely thoroughly with soap and water. Seek healthcare if irritation and pain persist after washing.

Enhanced Elimination

A)

1) GENERAL: Vancomycin is poorly removed by hemodialysis (Prod Info VANCOCIN(R) PULVULES(R) oral capsules, 2005).
2) One study reported that 6 men on chronic hemodialysis were successfully treated with hemodialysis. Although clearance was not significantly affected using "traditional" cuprophane dialyzers, pharmacokinetic parameters were dramatically altered when Fresenius polysulfone F-80 dialyzers were used. The mean extent of vancomycin removal was 49.5%. Mean clearance was 85.2 milliliters/minute, and the mean intradialytic half-life was 4.5 hours (Lanese et al, 1989).
3) HIGH EFFICIENCY DIALYSIS: Two children (one with chronic renal insufficiency) were successfully treated with hemodialysis using high-efficiency dialysis membranes after inadvertent overdose with vancomycin. During 3 hour treatments, plasma vancomycin removal averaged 60%, with a calculated half-life of 2 hours. In both cases, repeat dialysis was required on a second day to treat a rebound in vancomycin levels. No sequelae was reported (Bunchman et al, 1999).

B)

1) CASE REPORT: A 9-year-old girl with cystic fibrosis developed non-oliguric renal failure and was successfully treated with high-flux large pore size membrane hemodialysis following toxic doses of vancomycin over 9 days. Pretreatment vancomycin serum level was 96 mg/L. A Gambro AK-100 hemodialysis machine was used with a high flux large pore-size polymethylmethacrylate dialysis membrane and the duration of treatment was 4 hours. The postdialysis vancomycin level was 26 mg/L which demonstrated a 73% intravascular vancomycin removal. A second session was completed 24 hours later resulted in a vancomycin level of 12 mg/L after 2 hours; renal function improved on admission day 3 with no permanent sequelae reported (Ulinski et al, 2005).

C)

1) GENERAL: Hemoperfusion with polysulfone resin has been reported to increase vancomycin clearance (Prod Info VANCOCIN(R) PULVULES(R) oral capsules, 2005).
2) Hemoperfusion using an Amberlite resin XAD-4 cartridge was effective in reducing serum vancomycin concentrations in a patient in renal failure who received a total of 2.5 grams of vancomycin intravenously (500 milligrams every six hours for five doses). Charcoal hemoperfusion was not effective (Ahmad et al, 1982).

D)

1) Nielsen et al (1979) have shown vancomycin to be cleared from the circulation by peritoneal dialysis. Eleven renal failure patients (creatinine clearance less than 2 milliliters/minute) received 1 gram of vancomycin intravenously over one-half hour just prior to dialysis with 2000 milliliters of dialysate every hour for 15 hours. Calculations were based on outlet samples of the dialysate at 5, 10, and 15 hours. The serum half-life was "about" 18 hours and clearance over the peritoneal membrane was calculated to be 6.1 milliliters/minute. Forty percent of the antibiotic was removed during the 15 hour dialysis. These workers recommend a dose of 0.5 gram intravenously twice weekly combined with 25 micrograms/milliliter of dialysate during chronic peritoneal dialysis after an initial dose of 1 gram intravenously (Nielsen, 1979).
2) Polk et al (1981) report peritoneal fluid levels of vancomycin nearly equal to corresponding serum levels after single intravenous doses of 1 gram. Both patients were receiving weekly peritoneal dialysis on a chronic basis. Peritoneal fluid levels were approximately 14 micrograms/milliliter on the 3rd day after administration for 1 patient and on the 7th day for the other. Only 1 peritoneal fluid level was reported for each patient. A serum T 1/2 of 9.8 days was reported for a third chronic renal failure patient (anuric) maintained on weekly peritoneal dialysis as a result of an infected bovine AV graft. The authors demonstrate that weekly 1 gram doses of vancomycin in chronic renal failure patients receiving either hemo- or peritoneal dialysis will cause the antibiotic to accumulate and that doses in such patients should be guided by serum levels rather than an arbitrary schedule (Polk, 1981).

E)

1) GENERAL: Hemofiltration has been reported to increase vancomycin clearance (Prod Info VANCOCIN(R) PULVULES(R) oral capsules, 2005).
2) CASE REPORT: A 17-year-old female weighing 38 kg (less than 3rd percentile for age) with ESRD secondary to chronic pyelonephritis for 5 years received an inadvertent massive overdose of vancomycin (40 mg/kg/day) for 8 days (or 320 mg/kg cumulative dose). A high flux hemodiafiltration (HDF) with a polysulfone membrane was started for 3 days to accelerate vancomycin removal. The first serum vancomycin level (101 mg/L) was obtained 12 hours after the last dose, and HDF was performed for 2 hours. Within 24 hours, the vancomycin level had decreased to 78 mg/L following the second 4-hour HDF therapy. After 48 hours, the level declined to 16.59 mg/L following the final last 4-hour HDF therapy. The patient developed no symptoms from this inadvertent exposure, and went on to have a successful kidney transplant 10 months later (Akil & Mir, 2001).
3) CASE REPORT: A 54-year-old man developed acute renal failure associated with 10 days of vancomycin 1 gram every 4 hours intravenously (total dose 5.6 grams) for CSF S. epidermidis positive culture. The resulting serum vancomycin concentration was 284 micrograms/milliliter. Continuous arteriovenous hemofiltration (CAVH) over 5 days was associated with a rapid decline in serum vancomycin concentrations. During CAVH procedure the estimated elimination half-life of vancomycin was 4.9 days. After discontinuation of CAVH the estimated elimination half-life was 10.9 days (Walczyk et al, 1988).
4) CASE REPORT: A 6-day-old infant who was born with a solitary hypodysplastic left kidney, anuric renal failure, and pulmonary hypoplasia, was treated with nafcillin and cefotaxime for suspected sepsis after developing metabolic acidosis and hypotension. On day 8, his condition worsened and nafcillin was replaced with vancomycin. However, he was inadvertently administered 100 mg/kg of vancomycin instead of 10 mg/kg. At this time, his vancomycin serum concentration was 240 mcg/mL. He did not develop any adverse effects, except for brief episodes of bradycardia (70 beats/min). He was successfully treated with supportive care, including 41 hours of continuous venovenous hemodiafiltration (CVVHD) with a high-flux membrane (Goebel et al, 1999).
5) Dupuis et al (1989) used CAVH to augment vancomycin elimination in a 48-year-old anuric male. Using a polysulfone (Amicon D-10) hemofilter, they demonstrated that CAVH reduced the serum half-life from 88 to 45 hours, and increased total body clearance from 7.6 milliliters/minute to 13.8 milliliters/minute (Dupuis et al, 1989).
6) Vancomycin elimination was measured in four anuric patients who were treated daily with arteriovenous hemofiltration using the Gambro HF 88 hemofilter. Vancomycin clearance ranged from 59 to 151 milliliters/minute, depending on blood and filtrate flow. The authors recommended hemofiltration as an effective treatment for vancomycin intoxication, but additional study is needed before this can be advocated (Rawer & Seim, 1989).
7) Using high-porosity polyacrylonitrile filters, one study found that continuous arteriovenous hemodiafiltration (CAVHD) was effective in clearing vancomycin from plasma in three patients with acute renal failure. While half-life and percentage of vancomycin removed were not specified, a mean clearance of 10.5 mL/minute (636 milliliters/hour) was reported. Although this appears to be an effective method to enhance vancomycin elimination, the clinical significance of this finding in relation to overdose remains uncertain (Bellomo et al, 1990).
8) ADVERSE EFFECTS

a) Two patients developed hypophosphatemia after undergoing high-flux hemodiafiltration for vancomycin toxicity. The first patient, a 26-year-old man with elevated vancomycin concentration of 140 mcg/mL, underwent 2 high-flux hemodiafiltration treatments for 12 and 4 hours, respectively. Despite intravenous phosphorous therapy, he developed hypophosphatemia. The second patient, a 70-year-old man with a history of congestive heart failure and coronary artery disease, had an elevated vancomycin concentration of 99 mcg/mL. He underwent a high-flux hemodiafiltration treatment for 4 hours, and then repeated the next day for 11 hours. He developed hypophosphatemia that was successfully treated with phosphorus therapy (Gatchalian et al, 2000).

F)

1) A 1.5 volume exchange transfusion had no effect on the plasma concentration of vancomycin in a 47-day-old premature male infant following an accidental intravenous vancomycin overdose. The vancomycin concentration was 230 mcg/mL before and after exchange transfusion (Burkhart et al, 1992).

G)

1) Charcoal hemoperfusion was successfully used to treat a 14-month-old female (8 kg) after an error in intravenous vancomycin dosing had occurred. The child had a history of bilateral renal dysplasia (baseline serum creatinine was 3.5 mg/dL). Initial serum vancomycin level was 337.6 mg/L following a total dose of 1.5 gram in 24 hours. Vancomycin half-life prior to hemoperfusion/hemodialysis was 61 to 145 hours. TREATMENT - Serum creatinine and vancomycin levels progressively increased and on day 5 treatment was begun using a pediatric charcoal unit along with a Mini-Minor dialysis cartridge allowing sequential hemoperfusion and dialysis. Two 4-hour sessions were done on consecutive days, using a single charcoal unit for each session. Hemoperfusion was most effective during the first hour with a 42% decline in vancomycin concentration. Half-life decreased to 12.5 and 11.1 hours during hemoperfusion/hemodialysis. Platelet replacement was required for treatment induced thrombocytopenia. Although charcoal hemoperfusion was effective in lowering serum levels rapidly, baseline renal function did not return and the patient became dialysis dependent (Panzarino et al, 1998).

H)

1) Plasma exchange transfusion appeared to remove vancomycin in an adult with sickle cell disease and normal renal function. Peak and trough vancomycin concentrations were 12.5 micrograms/mL and 3 micrograms/mL respectively on the day of plasma exchange transfusion, compared with 20.0 micrograms/mL and 8.4 micrograms/ml on another occasion when the same dose was used and renal function was unchanged(Foral & Heineman, 2001). This technique has not been used in overdose situations.

Abstracts

Case Reports

A)

1) INJECTION

a) A patient in renal failure was accidentally given a total dose of 2.5 grams of vancomycin intravenously (500 mg every 6 hours for five doses). Hemoperfusion using an Amberlite resin XAD-4 cartridge was effective in reducing serum vancomycin concentrations. Charcoal hemoperfusion was ineffective (Ahmad et al, 1982).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) DALBAVANCIN

1) The recommended dose is 1000 mg administered IV over 30 minutes followed by a 500 mg dose one week later (Prod Info DALVANCE(TM) intravenous injection, 2014).

B) VANCOMYCIN

1) ORAL

a) CAPSULES or SOLUTION: The usual recommended dose is 500 mg to 2 g administered orally in 3 or 4 divided doses (Prod Info VANCOCIN(R) oral capsules, 2011; Prod Info VANCOCIN(R) PULVULES(R) oral capsules, 2005).

2) INTRAVENOUS

a) PATIENTS WITH NORMAL RENAL FUNCTION

1) USUAL IV DOSE: 2 g/day divided either as 500 mg every 6 hours or 1 g every 12 hours. Administration should not exceed 10 mg/min or over a period of 60 minutes, whichever is longer. The dose may be modified as needed based on the patient's age or weight (Prod Info vancomycin HCl intravenous injection lyophilized powder for solution, 2012).

C) ORITAVANCIN

1) ACUTE BACTERIAL SKIN AND STRUCTURE INFECTIONS

a) Recommended dose: 1200 mg as a single dose administered by IV infusion over 3 hours in patients 18 years and older. Treatment is indicated for acute bacterial skin/skin structure infections caused by susceptible Gram-positive bacteria (Prod Info ORBACTIV(TM) intravenous injection lyophilized powder, 2014).

D) TELAVANCIN

1) COMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS

a) Recommended Dose: 10 mg/kg administered IV over a 60-min period every 24 hr in patients 18 years of age and older for 7 to 14 days. Treatment is indicated for complicated skin/skin structure infections caused by susceptible Gram-positive bacteria (Prod Info VIBATIV IV injection, 2009).

2) HOSPITAL ACQUIRED AND VENTILATOR ASSOCIATED BACTERIAL PNEUMONIA

a) HABP/VABP: The recommended dose is 10 mg/kg administered IV over a 60 minute period every 24 hours for 7 to 21 days inpatients aged 18 years or older (Prod Info VIBATIV(R) intravenous injection, 2013).

7.2.2)

A) DALBAVANCIN

1) Safety and effectiveness has not been established in pediatric patients (Prod Info DALVANCE(TM) intravenous injection, 2014).

B) VANCOMYCIN

1) ORAL

a) The usual recommended dose is 40 mg/kg orally in 3 or 4 divided doses for 7 to 10 days. MAXIMUM DOSE: 2 g/day (Prod Info VANCOCIN(R) oral capsules, 2011).

2) INTRAVENOUS

a) INFANTS

1) INITIAL DOSE: Neonates and Young Infants: 15 mg/kg is suggested followed by 10 mg/kg every 12 hours for infants in the first week of life and every 8 hours thereafter up to the age of one month. Infuse over 60 minutes. Closely monitor serum vancomycin concentrations in these patients (Prod Info vancomycin HCl intravenous injection lyophilized powder for solution, 2012; Schaad et al, 1981).
2) BACTERIAL MENINGITIS (SUSPECTED OR DOCUMENTED NONSUSCEPTIBILITY TO PENICILLIN AND CEFOTAXIME): 29 days of age and older: 60 mg/kg/day IV divided every 6 hours; should NOT be used as single agent for treating bacterial meningitis; maintain serum trough concentrations of 15 to 20 mcg/mL (Chaudhuri et al, 2008; Tunkel et al, 2004; None Listed, 1997; Bradley et al, 1995; Schaad et al, 1981).
3) INFECTIVE ENDOCARDITIS (NON-MRSA): Infants 29 days and older: 40 mg/kg/day IV divided every 8 to 12 hours alone or in combination with appropriate antimicrobial therapy; adjust to obtain trough concentration of 10 to 15 mcg/mL (Baddour et al, 2005).
4) METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS, INVASIVE: Infants 29 days and older: 15 mg/kg IV every 6 hours for suspected or proven invasive MRSA disease (Liu et al, 2011). This dose would be expected to achieve an AUC/MIC ratio of greater than 400 (Frymoyer et al, 2009).
5) PNEUMOCOCCAL INFECTIONS, INVASIVE (NONMENINGEAL: SUSPECTED OR DOCUMENTED NONSUSCEPTIBILITY TO PENICILLIN AND CEFOTAXIME): Infants: 29 days of age and older: 40 to 60 mg/kg/day IV divided every 6 to 8 hours (None Listed, 1997).

b) PREMATURE INFANTS

1) Vancomycin clearance decreases as postconceptional age decreases, this may necessitate longer dosing intervals in these infants. Closely monitor serum vancomycin concentrations in these infants (Prod Info vancomycin HCl intravenous injection lyophilized powder for solution, 2012).

3) INTRAVENTRICULAR

a) Shunt infection: 5 to 20 mg intraventricularly once daily (preservative-free) (Tunkel et al, 2004; Swayne et al, 1987; Fan-Havard & Nahata, 1987; Pau et al, 1986). Generally, a 5 mg/dose for infants, 10 mg/dose for children, and 20 mg/dose for adolescents appears appropriate as the dose should be based on ventricular volume of distribution (Bafeltowska et al, 2004; Bayston et al, 1987; Swayne et al, 1987; Pau et al, 1986; Bayston et al, 1984). Consider monitoring CSF vancomycin levels during therapy to assess drug concentrations (goal: trough, 5 to 10 mcg/mL) and potential drug accumulation (Bafeltowska et al, 2004; Nagl et al, 1999; Pau et al, 1986).

C) ORITAVANCIN

1) The safety and effectiveness of oritavancin in pediatric patients has not been studied (Prod Info VIBATIV(R) intravenous injection, 2013).

D) TELAVANCIN

1) The safety and effectiveness of telavancin in pediatric patients has not been studied (Prod Info VIBATIV(R) intravenous injection, 2013).

Maximum Tolerated Exposure

A)

1) A single 2 gram intravenous injection caused increased urinary excretion of granular casts 4 to 8 hours later (Kirby & Divelbliss, 1956).
2) ADULT

a) Cardiopulmonary arrest occurred in a 57-year-old diabetic woman undergoing peritoneal dialysis following vancomycin 1 g IV bolus over 2 minutes for the treatment of enterococcal peritonitis. The authors suggested that rapid IV infusion of vancomycin could result in neuromuscular blockade or ventricular dysrhythmias and recommended that manufacturer dose guidelines be followed (Glicklich & Figura, 1984).

3) NEONATES

a) Three premature infants developed apnea, hypotension, flushed skin, and inflammation at the infusion site following inadvertent supratherapeutic administration of vancomycin (300 to 400 milligrams/kilogram). No permanent sequelae was reported following therapy with multiple dose activated charcoal (Barker et al, 2002).
b) Two premature infants with peak plasma vancomycin levels greater than 300 mcg/mL following accidental 10-fold overdoses did not experience any renal (except for one infant with a transient increase in serum creatinine to 1.4 mg/dL), auditory, or other toxicity symptoms. Specific interventions to clear vancomycin rapidly were not necessary. Both patients had normal hearing tests several months after discharge. The authors suggested that contemporary formulations of vancomycin appear to be less toxic than earlier formulation with high content of impurities (Miner & Faix, 2004).
c) A 6-day-old infant who was born with a solitary hypodysplastic left kidney, anuric renal failure, and pulmonary hypoplasia, was treated with nafcillin and cefotaxime for suspected sepsis after developing metabolic acidosis and hypotension. On day 8, his condition worsened and nafcillin was replaced with vancomycin. However, he was inadvertently administered 100 mg/kg of vancomycin instead of 10 mg/kg. At this time, his vancomycin serum concentration was 240 mcg/mL. He did not develop any adverse effects, except for brief episodes of bradycardia (70 beats/min). He was successfully treated with supportive care, including 41 hours of continuous venovenous hemodiafiltration (CVVHD) with a high-flux membrane (Goebel et al, 1999).
d) Two premature twins developed signs and symptoms of Red man syndrome (ie, flushed face and trunk, peripheral cyanosis, apnea, hypoxemia, bradycardia, hypotension) a few minutes after inadvertently receiving an overdose of vancomycin (doses: 38 and 35 mg/kg, respectively) as a single 1-min IV injection. Laboratory results revealed metabolic acidosis (pH 7.29 and 7.24, a base excess of -10.5 and -10.9 mmol/L, respectively). Following supportive therapy for 30 minutes, both RMS and metabolic acidosis resolved. Vancomycin serum concentrations were 32 and 34.5 mg/L, respectively, 9 hours after administration. On day 19, all laboratory results were normal, except for a urinary protein electrophoresis revealing tubular proteinuria with elevated activity of the tubular enzyme N-acetyl-beta-D-glucosaminidase (NAG) in the urine. Both proteinuria and NAG excretion returned to normal values a week later (Muller et al, 1999).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SUMMARY

a) Toxicity is reported at levels sustained above 80 to 100 mcg/mL (Farber, 1984).

2) CASE REPORTS

a) Two premature infants with peak plasma vancomycin levels greater than 300 mcg/mL following accidental 10-fold overdoses did not experience any renal (except for one infant with a transient increase in serum creatinine to 1.4 mg/dL), auditory, or other toxicity symptoms. Specific interventions to clear vancomycin rapidly were not necessary. Both patients had normal hearing tests several months after discharge (Miner & Faix, 2004).
b) A 6-day-old infant who was born with a solitary hypodysplastic left kidney, anuric renal failure, and pulmonary hypoplasia, was treated with nafcillin and cefotaxime for suspected sepsis after developing metabolic acidosis and hypotension. On day 8, his condition worsened and nafcillin was replaced with vancomycin. However, he was inadvertently administered 100 mg/kg of vancomycin instead of 10 mg/kg. At this time, his vancomycin serum concentration was 240 mcg/mL. He did not develop any adverse effects, except for brief episodes of bradycardia (70 beats/min). He was successfully treated with supportive care, including 41 hours of continuous venovenous hemodiafiltration (CVVHD) with a high-flux membrane (Goebel et al, 1999).

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 1734 mg/kg (RTECS , 2002)

2) LD50- (SUBCUTANEOUS)MOUSE:

a) 5 g/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

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Toxicologic Mechanism

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Physical Characteristics

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Animal Toxicology

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Classification | Detailed evidence-based information

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