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STREPTOGRAMINS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Streptogramins are antibacterial agents used in the treatment of infections by multidrug-resistant pathogens.

Specific Substances

    A) DALFOPRISTIN
    1) Dalfopristin Mesylate
    2) Dalfopristin Mesilate
    3) QUINUPRISTIN/DALFOPRISTIN
    4) RP-54476
    5) CAS 112362-50-2
    PRISTINAMYCIN
    1) Pyostacine
    2) VIRGINIAMYCIN
    3) CAS 11006-76-1
    4) RP-7293
    QUINUPRISTIN
    1) QUINUPRISTIN/DALFOPRISTIN
    2) Quinupristin Mesylate
    3) Quinupristin Mesilate
    4) RP-57669
    5) CAS 120138-50-3

Available Forms Sources

    A) FORMS
    1) Pristinamycin is a streptogramin produced by the growth of Streptomyces pristina spiralis, and acts similar to virginiamycin. It is an oral preparation (S Sweetman , 2001).
    2) Virginiamycin is primarily two antimicrobial substances (virginiamycin M(1), and virginiamycin S(1)) produced by the growth of Streptomyces virginiae. Its available orally or topically (S Sweetman , 2001).
    3) Quinupristin/dalfopristin is a semisynthetic streptogramin derivative of pristinamycin I and pristinamycin IIA, (in a ratio of 30:70), respectively. It is available for parenteral administration (Prod Info Synercid(R) I.V. Quinupristin and dalfopristin for injection, 1999; S Sweetman , 2001).
    B) USES
    1) Streptogramins are used in the treatment of multidrug-resistant pathogens. Some agents of this family (pristinamycin and virginiamycin) have been used as antistaphylococcal agents for over two decades in Europe. Individual agents are administered based on the particular organism cultured as noted below:
    a) QUINIPRISTIN/DALFOPRISTIN-
    1) It is active against a range of gram-positive and some gram-negative organisms, but is usually reserved for the treatment of severe infections by multi-drug resistant gram-positive bacteria, specifically multidrug-resistant Staphylococcus aureus and pneumococci and vancomycin-resistant Enterococcus faecium (VREF)(S Sweetman , 2001).
    2) It was approved for marketing in September 1999 by the USFDA, via its accelerated approval regulations, for the treatment of serious or life-threatening infections associated with VREF bacteremia (Anon, 1999). At the time of this review, there is some evidence that resistance to quinupristin/dalfopristin can occur (Dowzicky et al, 2000).
    b) GENERAL - Pristinamycin and virginiamycin are oral antistaphylococcal agents which have been used in France for over 20 years (Leclercq & Courvalin, 1998).
    1) VIRGINIAMYCIN-
    a) It is used for the treatment of infections due to gram-positive cocci and in animal feed stuffs as a growth promotor (S Sweetman , 2001).
    2) PRISTINAMYCIN-
    a) Pristinamycin has been used as an oral antistaphylococcal drug and against streptococci. Its usefulness in severe infection is limited by its poor solubility; therefore, a water-soluble derivatives of pristinamycins I and II -- quinupristin/dalfopristin has been developed (S Sweetman , 2001).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) OVERDOSE - Overdose of 3 to 4 times the recommended dose has not caused toxicity.
    B) ADVERSE EVENTS - Adverse events related to oral or parenteral streptogramin use are mild to moderate and are most often related to gastrointestinal disturbances, central nervous system reactions (e.g., dizziness, insomnia, anxiety, confusion), arthralgia/myalgia, injection site reaction, and rash. Allergic reaction has been reported infrequently.
    1) Hyponatremia has been reported in one patient receiving parenteral streptogramin therapy.
    C) In animal studies, dyspnea, emesis, tremor and ataxia were reported following overdose.
    0.2.6) RESPIRATORY
    A) Dyspnea and pleural effusion have been reported infrequently during therapeutic use.
    0.2.7) NEUROLOGIC
    A) Mild central nervous system adverse effects have been reported infrequently with streptogramin therapy.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting and diarrhea have been reported with therapeutic quinupristin/dalfopristin use.
    0.2.9) HEPATIC
    A) Elevations in hepatic enzymes have occurred following quinupristin/dalfopristin therapy, but clinically important hepatic dysfunction has been reported rarely.
    0.2.12) FLUID-ELECTROLYTE
    A) Hyponatremia was reported in one case following parenteral streptogramin administration.
    0.2.14) DERMATOLOGIC
    A) Contact dermatitis has been reported infrequently with topical administration of streptogramins. Rash has also developed with oral and parenteral streptogramin therapy.
    0.2.15) MUSCULOSKELETAL
    A) Arthralgia/myalgia has been a dose limiting effect in some patients receiving quinupristin/dalfopristin therapy.
    0.2.19) IMMUNOLOGIC
    A) Allergic reaction has occurred infrequently following therapeutic streptogramin use.
    0.2.20) REPRODUCTIVE
    A) The manufacturer has classified quinupristin/dalfopristin as FDA pregnancy category B. It is unknown whether quinupristin/dalfopristin is excreted in human milk. Quinupristin/dalfopristin is excreted in the milk of lactating rats.
    0.2.22) OTHER
    A) Infusion site events (inflammation, pain and edema) have been reported during therapeutic use of quinupristin/dalfopristin.

Laboratory Monitoring

    A) Monitor hepatic enzymes following significant exposure.
    B) Monitor fluid status and electrolytes in patients with significant GI loss.
    C) Obtain a baseline creatine phosphokinase level in patients experiencing arthralgia/myalgia.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) No overdose data reported with oral therapy. See PARENTERAL EXPOSURE for further treatment information.
    0.4.6) PARENTERAL EXPOSURE
    A) At the time of this review, there is no overdose data on streptogramins. Treatment is symptomatic and supportive.
    B) There have been infrequent reports of hypersensitivity following parenteral administration of streptogramins.
    1) ALLERGIC REACTION: MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.

Range Of Toxicity

    A) There have been several reports of individuals receiving up to 3 times the recommended dose of 7.5 milligrams/kilogram of quinupristin/dalfopristin. No adverse events were attributable to the overdose.
    B) Possible signs of acute overdose following quinupristin/dalfopristin may include dyspnea, vomiting, tremors and ataxia. These effects have been reported in animals given doses of 50 milligrams/kilogram.

Clinical Effects

Summary Of Exposure

    A) OVERDOSE - Overdose of 3 to 4 times the recommended dose has not caused toxicity.
    B) ADVERSE EVENTS - Adverse events related to oral or parenteral streptogramin use are mild to moderate and are most often related to gastrointestinal disturbances, central nervous system reactions (e.g., dizziness, insomnia, anxiety, confusion), arthralgia/myalgia, injection site reaction, and rash. Allergic reaction has been reported infrequently.
    1) Hyponatremia has been reported in one patient receiving parenteral streptogramin therapy.
    C) In animal studies, dyspnea, emesis, tremor and ataxia were reported following overdose.

Respiratory

    3.6.1) SUMMARY
    A) Dyspnea and pleural effusion have been reported infrequently during therapeutic use.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) Dyspnea and pleural effusion have been reported at a rate of 1% or less during parenteral administration of quinupristin/dalfopristin (Prod Info SYNERCID(R) IV injection, 2003).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DYSPNEA
    a) OVERDOSE - Animals given doses of 50 mg/kg (normal = 7.5mg/kg) developed dyspnea (Prod Info SYNERCID(R) IV injection, 2003).

Neurologic

    3.7.1) SUMMARY
    A) Mild central nervous system adverse effects have been reported infrequently with streptogramin therapy.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) INCIDENCE
    a) The following central nervous system events occurred with a frequency of 1% or less during therapeutic use of quinupristin/dalfopristin in healthy adults and patients (n=1099): insomnia, anxiety, confusion, dizziness, hypertonia, and paresthesia (Prod Info SYNERCID(R) IV injection, 2003; Lamb et al, 1999).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ATAXIA
    a) OVERDOSE - Animals given doses of 50 mg/kg (normal = 7.5mg/kg) developed ataxia and tremors (Prod Info SYNERCID(R) IV injection, 2003).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting and diarrhea have been reported with therapeutic quinupristin/dalfopristin use.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) The following gastrointestinal events: nausea, vomiting and diarrhea have been reported during therapeutic use of quinupristin/dalfopristin (Lamb et al, 1999).
    2) INCIDENCE
    a) The following incidences have been reported during clinical studies (included healthy adults and patients {n=1099}): nausea developed in 4.6% of individuals and 2.7% each had vomiting or diarrhea (Prod Info SYNERCID(R) IV injection, 2003; Lamb et al, 1999).
    3) VIRGINIAMYCIN
    a) Diarrhea and vomiting have also been reported during therapeutic use of virginiamycin (S Sweetman , 2001).
    B) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) INCIDENCE
    a) The following gastrointestinal events occurred with a frequency of 1% or less during therapeutic use of quinupristin/dalfopristin in healthy adults and patients (n=1099): stomatitis, dyspepsia, constipation, pancreatitis, and pseudomembranous colitis (Prod Info SYNERCID(R) IV injection, 2003; Lamb et al, 1999).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) VOMITING
    a) OVERDOSE - Animals given doses of 50 mg/kg (normal = 7.5mg/kg) developed vomiting (Prod Info SYNERCID(R) IV injection, 2003).

Hepatic

    3.9.1) SUMMARY
    A) Elevations in hepatic enzymes have occurred following quinupristin/dalfopristin therapy, but clinically important hepatic dysfunction has been reported rarely.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) Elevations in hepatic aminotransferase or enzymes have been primarily reported at doses of greater than 10 milligrams/kilogram. Increases in conjugated bilirubin and total bilirubin levels have also been reported (Lamb et al, 1999).
    2) INCIDENCE - In comparative and noncomparative trials (n = approximately 2200 patients), elevations in liver enzymes were reported in 2% to 7% of patients, and increases in total and direct bilirubin of 1% to 5% (Allington & Rivey, 2001).
    B) LIVER ENZYMES ABNORMAL
    1) Hepatic dysfunction has been reported in several patients following quinupristin/dalfopristin therapy. At the time of this review, it is unknown if streptogramins induce hepatic toxicity directly. It has been suggested, however, that quinupristin/dalfopristin may interfere with the transport of bilirubin by competitive inhibition (Lamb et al, 1999; Delgado et al, 2000).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) DECREASED HEMOGLOBIN
    1) In comparative and noncomparative trials (n = approximately 2200 patients), a decrease in hemoglobin (less than 8 mg/dL) was reported in 2.6% of patients, along with thrombocytopenia occurring in 2% of patients (Allington & Rivey, 2001).

Dermatologic

    3.14.1) SUMMARY
    A) Contact dermatitis has been reported infrequently with topical administration of streptogramins. Rash has also developed with oral and parenteral streptogramin therapy.
    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) Contact dermatitis has been reported infrequently following topical application of a streptogramin (Michel et al, 1996).
    B) ERUPTION
    1) Rash and pruritus (e.g., maculopapular eruption) have been described infrequently following oral and parenteral administration of streptogramins (Prod Info SYNERCID(R) IV injection, 2003; Michel et al, 1996) .
    2) INCIDENCE
    a) Rash was reported in 2.5% of individuals (included healthy adults and patients {n=1099}) receiving quinupristin/dalfopristin (Prod Info SYNERCID(R) IV injection, 2003; Lamb et al, 1999).

Musculoskeletal

    3.15.1) SUMMARY
    A) Arthralgia/myalgia has been a dose limiting effect in some patients receiving quinupristin/dalfopristin therapy.
    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) INCIDENCE
    a) QUINUPRISTIN/DALFOPRISTIN - Severe arthralgia and myalgia have been reported in 7.8% of patients in one study (n=301) during therapeutic use (Prod Info SYNERCID(R) IV injection, 2003).
    1) Diffuse muscle pains and pains involving multiple joints of the upper and lower extremities were described in 8 of 24 patients receiving quinupristin/dalfopristin therapy. Pain was reversible in 2 to 3 days, and the authors suggested that pain may be dose-related. No symptoms were reported at doses of 5 mg/kg (normal = 7.5 mg/kg) every 8 hours (Winston et al, 2000).
    b) INCIDENCE - In one clinical study (n=396), arthralgia and myalgia were the most frequently reported adverse effect, with no evidence of articular pathology (Moellering et al, 1999). Arthralgia was reported in 9.1% of patients and 6.6% developed myalgia; all symptoms were reversible with discontinuation of therapy.
    c) SEVERITY - In one study, treatment of myalgia/arthralgia symptoms required narcotic pain relief (e.g., morphine, codeine) (Winston et al, 2000).
    d) ONSET - In one study, the median time to onset of symptoms was 6 days (range 4 to 10 days) after the start of therapy (Winston et al, 2000).

Immunologic

    3.19.1) SUMMARY
    A) Allergic reaction has occurred infrequently following therapeutic streptogramin use.
    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) Allergic reaction has been reported infrequently following oral and parenteral administration of streptogramins (Prod Info SYNERCID(R) IV injection, 2003; Michel et al, 1996; S Sweetman , 2001).

Reproductive

    3.20.1) SUMMARY
    A) The manufacturer has classified quinupristin/dalfopristin as FDA pregnancy category B. It is unknown whether quinupristin/dalfopristin is excreted in human milk. Quinupristin/dalfopristin is excreted in the milk of lactating rats.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified quinupristin/dalfopristin as FDA pregnancy category B (Prod Info Synercid(R) I.V. Quinupristin and dalfopristin for injection, 1999).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether quinupristin/dalfopristin is excreted in human milk (Prod Info Synercid(R) I.V. Quinupristin and dalfopristin for injection, 1999).
    B) ANIMAL STUDIES
    1) RATS - Quinupristin/dalfopristin is excreted in the milk of lactating rats (Prod Info Synercid(R) I.V. Quinupristin and dalfopristin for injection, 1999).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor hepatic enzymes following significant exposure.
    B) Monitor fluid status and electrolytes in patients with significant GI loss.
    C) Obtain a baseline creatine phosphokinase level in patients experiencing arthralgia/myalgia.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor hepatic enzymes following a significant exposure.
    2) Monitor fluid status and electrolytes as indicated in patients with significant GI loss.
    3) Obtain a baseline creatine phosphokinase level in patients experiencing arthralgias/myalgia and repeat as indicated.
    4) Serum sodium or serum osmolarity levels are indicated if clinical features of hyponatremia are present or suspected.
    4.1.3) URINE
    A) URINALYSIS
    1) Obtain urinalysis as indicated.

Methods

    A) HPLC
    1) A gradient high-performance liquid chromatographic method has been described to assay the streptogramin antibacterial quinupristin/dalfopristin (Vasselle et al, 1999).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor hepatic enzymes following significant exposure.
    B) Monitor fluid status and electrolytes in patients with significant GI loss.
    C) Obtain a baseline creatine phosphokinase level in patients experiencing arthralgia/myalgia.

Range Of Toxicity

Summary

    A) There have been several reports of individuals receiving up to 3 times the recommended dose of 7.5 milligrams/kilogram of quinupristin/dalfopristin. No adverse events were attributable to the overdose.
    B) Possible signs of acute overdose following quinupristin/dalfopristin may include dyspnea, vomiting, tremors and ataxia. These effects have been reported in animals given doses of 50 milligrams/kilogram.

Therapeutic Dose

    7.2.1) ADULT
    A) QUINUPRISTIN/DALFOPRISTIN
    1) COMPLICATED SKIN INFECTIONS: DOSE: 7.5 mg/kg every 12 hours IV; the minimum recommended treatment for complicated skin and skin structure infections is 7 days. Administer in 5% dextrose in water and infused over 60 minutes. An infusion pump or device should be used to control the rate of the infusion. If necessary a central venous access (eg, PICC line) can be used to reduce the incidence of venous irritation (Prod Info Synercid(R) IV injection, 2010).
    2) ENDOCARDITIS: The recommended dose of quinupristin/dalfopristin for the treatment of native or prosthetic valve endocarditis caused by Enterococcus faecium strains resistant to penicillin, aminoglycoside, and vancomycin is 7.5 milligrams/kilogram intravenously every 8 hours for a minimum of 8 weeks or greater (Baddour et al, 2005).
    7.2.2) PEDIATRIC
    A) QUINUPRISTIN/DALFOPRISTIN
    1) RESISTANT OR TREATMENT-REFRACTORY GRAM-POSITIVE INFECTION, INCLUDING VANCOMYCIN-RESISTANT E. FAECIUM (VREF): 7.5 mg/kg IV every 8 hours (Loeffler et al, 2002; Gray et al, 2000).
    2) COMPLICATED SKIN/SKIN STRUCTURE INFECTIONS: 12 years of age and older: 7.5 mg/kg IV every 12 hours (Prod Info Synercid(R) IV injection, 2010).
    3) INFECTIVE ENDOCARDITIS (E. FAECIUM STRAINS RESISTANT TO PENICILLIN, AMINOGLYCOSIDES, AND VANCOMYCIN): 7.5 mg/kg IV every 8 hours for a minimum of 8 weeks (Baddour et al, 2005).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.
    2) There have been several reports of individuals receiving up to 3 times the recommended dose of 7.5 milligrams/kilogram of quinupristin/dalfopristin. No adverse events were attributable to the overdose (Prod Info SYNERCID(R) IV injection, 2003).
    3) Possible signs of acute overdose following quinupristin/dalfopristin may include dyspnea, vomiting, tremors and ataxia. These effects have been reported in animals given doses of 50 milligrams/kilogram (Prod Info SYNERCID(R) IV injection, 2003).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) VIRGINIAMYCIN
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 450 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)MOUSE:
    a) 2100 mg/kg (RTECS, 2001)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 2500 mg/kg (RTECS, 2001)
    B) VIRGINIAMYCIN S1
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 350 mcg/kg (RTECS, 2001)
    2) LD50- (ORAL)MOUSE:
    a) 200 mg/kg (RTECS, 2001)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 200 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) In general, streptogramins were developed for the treatment of infections that are attributable to multidrug-resistant gram-positive bacteria (Lamb et al, 1999; S Sweetman , 2001).
    B) QUINUPRISTIN/DALFOPRISTIN - is a fixed 30:70 (w:w) mixture of 2 semisynthetic water soluble-derivatives of pristinamycin. The two agents act in synergy and have a broad spectrum of activity against most gram-positive bacteria (i.e., methicillin-resistant staphylococci, glycopeptide-resistant Enterococcus faecium, and penicillin-resistant Streptococcus pneumoniae, as well as some gram-negative cocci, some anaerobes and certain atypical pathogens) (Chevalier et al, 2000; MacConnachie, 1999).
    1) The two compounds act to inhibit the growth of susceptible organisms, and are reportedly 16 times more effective as a combined product. Bacteriocidal action is based on the drug's ability to inhibit bacterial protein synthesis (MacConnachie, 1999).
    2) The two compounds undergo nonenzymatic conversion; dalfopristin can convert to a primary active compound, pristinamycin IIa (Chevalier et al, 2000).
    3) Metabolites - Although quinupristin/dalfopristin are converted to several active major metabolites: two conjugated metabolites for quinupristin (one with glutathione and one with cysteine) and one non-conjugated metabolite for dalfopristin, the antimicrobial activity of the metabolites associated with this agent are several folds lower than the parent compound (Prod Info Synercid(R) I.V. Quinupristin and dalfopristin for injection, 1999; Chevalier et al, 2000).

References

General Bibliography

    1) Allington DR & Rivey MP: Quinupristin/dalfopristin: A therapeutic review. Clin Therap 2001; 23:24-44.
    2) Anon: FDA approves quinupristin-dalfopristin for some vancomycin resistant infections. Am J Health-Syst Pharm 1999; 56:2174.
    3) Baddour LM, Wilson WR, Bayer AS, et al: Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005; 111(23):e394-e434.
    4) Bergeron M & Montay G: The pharmacokinetics of quinupristin/dalfopristin in laboratory animals and in humans. J Antimicrob Chemotherp 1997; 39 (suppl A):129-138.
    5) Chevalier P, Rey J, & Pasquier O: Pharmacokinetics of quinupristin/dalfopristin in patients with severe chronic renal insufficiency. Clin Pharmacokinet 2000; 39:77-84.
    6) Cole RP, Roberts WD, & Cheng MD: Hyponatremia associated with quinupristin/dalfopristin (letter). Ann Intern Med 2000; 133:485.
    7) Delgado G, Neuhauser MM, & Bearden DT: Quinupristin/Dalfopristin: an overview. Pharmacother 2000; 20:1469-1485.
    8) Dowzicky M, Talbot GH, & Feger C: Characterization of isolates associated with emerging resistance to quinupristin/dalfopristin (Synercid(R)) during a worldwide clinical program. Diag Microbiol Infect Dis 2000; 37:57-62.
    9) Gray JW, Darbyshire PJ, Beath SV, et al: Experience with quinupristin/dalfopristin in treating infections with vancomycin-resistant Enterococcus faecium in children. Pediatr Infect Dis J 2000; 19(3):234-238.
    10) Lamb HM, Figgitt DP, & Faulds D: Quinupristin/dalfopristin: A review of its use in the management of serious gram-positive infections. Drugs 1999; 58:1061-1097.
    11) Leclercq R & Courvalin P: Streptogramins: an answer to antibiotic resistance in gram-positive bacteria (letter). Lancet 1998; 352:591-592.
    12) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    13) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    14) Loeffler AM, Drew RH, Perfect JR, et al: Safety and efficacy of quinupristin/dalfopristin for treatment of invasive Gram-positive infections in pediatric patients. Pediatr Infect Dis J 2002; 21(10):950-956.
    15) MacConnachie AM: New antibiotics for gram positive infections: linezolid and combination quinupristin/dalfopristin. Inten & Crit Care Ns 1999; 15:239-241.
    16) Michel M, Dompmartin A, & Szczurko C: Eczematous-like drug eruption induced by synergistins. Contact Derm 1996; 34:86-87.
    17) Moellering RC, Linden PK, & Reinhardt J: The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant enterococcus faecium. J Antimicrob Chemother 1999; 44:251-261.
    18) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    19) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    20) Product Information: SYNERCID(R) IV injection, quinupristin, dalfopristin IV injection. Monarch Pharmaceuticals,Inc, Bristol, TN, 2003.
    21) Product Information: Synercid(R) I.V. Quinupristin and dalfopristin for injection. Rhone-Poulenc Rorer Pharmaceuticals, Inc, Collegeville, PA, 1999.
    22) Product Information: Synercid(R) IV injection, quinupristin and dalfopristin IV injection. Monarch Pharmaceuticals, Inc., Bristol, TN, 2010.
    23) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    24) RTECS: Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    25) S Sweetman : Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic version. The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    26) Vanden Hoek,TL; Morrison LJ; Shuster M et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    27) Vasselle B, Gousset G, & Bounine JP: Development and validation of a high performance liquid chromatographic stability-indicating method for the analysis of Synercid(R) in quality control, stability and compatibility studies. J Pharmaceut Biomed Anal 1999; 19:641-657.