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Glycopeptides

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Glycopeptides

Vancomycin (Vancocin®) --

Lipoglycopeptides

Dalbavancin (Dalvance™) Oritavancin (Orbactiv™)
Telavancin (Vibativ®) Infectious Disease -ALL Agents (INDEX)

Dalbavancin (Dalvance™) top of page

IV dilution monograph.

Mechanism of Action
Dalbavancin, a semisynthetic lipoglycopeptide, interferes with cell wall synthesis by binding to the D-alanyl-D-alanine terminus of the stem pentapeptide in nascent cell wall peptidoglycan, thus preventing cross-linking. Dalbavancin is bactericidal in vitro against Staphylococcus aureus and Streptococcus pyogenes at concentrations similar to those sustained throughout treatment in humans treated according to the recommended dosage regimen.

INDICATIONS AND USAGE
Acute Bacterial Skin and Skin Structure Infections
DALVANCE™ (dalbavancin) for injection is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus).

Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of DALVANCE and other antibacterial agents, DALVANCE should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.


DOSAGE AND ADMINISTRATION
Recommended Dose Regimen
For treatment of adults with ABSSSI, the recommended two-dose regimen of DALVANCE is 1000 mg followed one week later by 500 mg. DALVANCE should be administered over 30 minutes by intravenous infusion.

Patients with Renal Impairment
In patients with renal impairment whose known creatinine clearance is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended two-dose regimen of DALVANCE is 750 mg followed one week later by 375 mg. No dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and DALVANCE can be administered without regard to the timing of hemodialysis.

Preparation and Administration
DALVANCE(dalbavancin) for injection must be reconstituted with Sterile Water for Injection, USP, and subsequently diluted only with 5% Dextrose Injection, USP, to a final concentration of 1 mg/mL to 5 mg/mL.

Reconstitution: DALVANCE must be reconstituted under aseptic conditions, using 25 mL of Sterile Water for Injection, USP, for each 500 mg vial. To avoid foaming, alternate between gentle swirling and inversion of the vial until its contents are completely dissolved. Do not shake. The reconstituted vial contains 20 mg/mL dalbavancin as a clear, colorless to yellow solution.

Reconstituted vials may be stored either refrigerated at 2 to 8 °C (36 to 46 °F), or at controlled room temperature 20 to 25 °C (68 to 77 °F). Do not freeze.

Dilution: Aseptically transfer the required dose of reconstituted dalbavancin solution from the vial(s) to an intravenous bag or bottle containing 5% Dextrose Injection, USP. The diluted solution must have a final dalbavancin concentration of 1 mg/mL to 5 mg/mL. Discard any unused portion of the reconstituted solution.

Once diluted into an intravenous bag or bottle as described above, DALVANCE may be stored either refrigerated at 2 to 8 °C (36 to 46 °F) or at a controlled room temperature of 20 to 25 °C (68 to 77 °F). Do not freeze.

Stability
The total time from reconstitution to dilution to administration should not exceed 48 hours.

Like all parenteral drug products, diluted DALVANCE should be inspected visually for particulate matter prior to infusion. If particulate matter is identified, do not use.

After reconstitution and dilution, DALVANCE is to be administered via intravenous infusion, using a total infusion time of 30 minutes.

Do not co-infuse DALVANCE with other medications or electrolytes. Saline-based infusion solutions may cause precipitation and should not be used. The compatibility of reconstituted DALVANCE with intravenous medications, additives, or substances other than 5% Dextrose Injection, USP has not been established.

If a common intravenous line is being used to administer other drugs in addition to DALVANCE, the line should be flushed before and after each DALVANCE infusion with 5% Dextrose Injection, USP.

DOSAGE FORMS AND STRENGTHS
DALVANCE is supplied in single-use, clear glass vials containing sterile powder (white/off-white to pale yellow) equivalent to 500 mg of anhydrous dalbavancin.

CONTRAINDICATIONS
DALVANCE is contraindicated in patients with known hypersensitivity to dalbavancin. No data are available on cross-reactivity between dalbavancin and other glycopeptides, including vancomycin.

USE IN SPECIFIC POPULATIONS

Pregnancy: Category C
There have been no adequate and well-controlled studies with dalbavancin in pregnant women. DALVANCE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

No evidence of embryo or fetal toxicity was found in the rat or rabbit at a dose of 15 mg/kg/day (1.2 and 0.7 times the human dose on an exposure basis, respectively). Delayed fetal maturation was observed in the rat at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis).

In a rat prenatal and postnatal development study, increased embryo lethality and increased offspring deaths during the first week post-partum were observed at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis).

Nursing Mothers
Dalbavancin is excreted in the milk of lactating rats. It is not known whether dalbavancin or its metabolite is excreted in human milk; therefore, caution should be exercised when DALVANCE is administered to a nursing woman.

Pediatric Use
Safety and efficacy in pediatric patients have not been established.

Geriatric Use
Of the 1778 patients treated with DALVANCE in Phase 2 and 3 clinical trials, 313 patients (17.7%) were 65 years of age or older. The efficacy and tolerability of DALVANCE were similar to comparator regardless of age. The pharmacokinetics of dalbavancin were not significantly altered with age; therefore, no dosage adjustment is necessary based on age alone.

DALVANCE is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this age group.

Renal Impairment
In patients with renal impairment whose known creatinine clearance is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended two-dose regimen for DALVANCE is 750 mg followed one week later by 375 mg. No dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and DALVANCE can be administered without regard to the timing of hemodialysis.

Hepatic Impairment
No dosage adjustment of DALVANCE is recommended for patients with mild hepatic impairment (Child-Pugh Class A). Caution should be exercised when prescribing dalbavancin to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) as no data are available to determine the appropriate dosing in these patients.

Oritavancin (Orbactiv™)  top of page

See IV dilution monograph.

Drug:  ORBACTIV® (oritavancin) for injection, for intravenous use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2014


Mechanism of Action:
Oritavancin has three mechanisms of action: (i) inhibition of the transglycosylation (polymerization) step of cell wall biosynthesis by binding to the stem peptide of peptidoglycan precursors; (ii) inhibition of the transpeptidation (crosslinking) step of cell wall biosynthesis by binding to the peptide bridging segments of the cell wall; and (iii) disruption of bacterial membrane integrity, leading to depolarization, permeabilization, and cell death. These multiple mechanisms contribute to the concentration-dependent bactericidal activity of oritavancin.

INDICATIONS AND USAGE:

Acute Bacterial Skin and Skin Structure Infections
ORBACTIV™ (Oritavancin) for injection is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms:

Staphylococcus aureus (including methicillin-susceptible and methicillin–resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), and Enterococcus faecalis (vancomycin-susceptible isolates only).

Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ORBACTIV and other antibacterial drugs, ORBACTIV should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Contraindications:
Intravenous Unfractionated Heparin Sodium
Use of intravenous unfractionated heparin sodium is contraindicated for 48 hours after ORBACTIV administration because the activated partial thromboplastin time (aPTT) test results are expected to remain falsely elevated for approximately 48 hours after ORBACTIV administration.

Hypersensitivity
ORBACTIV is contraindicated in patients with known hypersensitivity to ORBACTIV.

DOSAGE AND ADMINISTRATION:

Recommended Dosage
The recommended dosing for ORBACTIV is a single 1200 mg dose administered by intravenous infusion over 3 hours in patients 18 years and older.

Preparation of ORBACTIV for Intravenous Infusion
ORBACTIV is intended for intravenous infusion, only after reconstitution and dilution.

Three ORBACTIV 400 mg vials need to be reconstituted and diluted to prepare a single 1200 mg intravenous dose.

Reconstitution: Aseptic technique should be used to reconstitute three ORBACTIV 400 mg vials.

Add 40 mL of sterile water for injection (WFI) to reconstitute each vial to provide a 10 mg/mL solution per vial.
For each vial, gently swirl to avoid foaming and ensure that all ORBACTIV powder is completely reconstituted in solution.  Each vial should be inspected visually for particulate matter after reconstitution and should appear to be clear, colorless to pale yellow solution.

Dilution: Use ONLY 5% dextrose in sterile water (D5W) for dilution. Do NOT use Normal Saline for dilution as it is incompatible with ORBACTIV and may cause precipitation of the drug. Use aseptic technique to:

Withdraw and discard 120 mL from a 1000 mL intravenous bag of D5W.
Withdraw 40 mL from each of the three reconstituted vials and add to D5W intravenous bag to bring the bag volume to 1000 mL. This yields a concentration of 1.2 mg/mL.

Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparing the final intravenous solution.

Diluted intravenous solution in an infusion bag should be used within 6 hours when stored at room temperature, or used within 12 hours when refrigerated at 2 to 8°C (36 to 46°F). The combined storage time (reconstituted solution in the vial and diluted solution in the bag) and 3 hour infusion time should not exceed 6 hours at room temperature or 12 hours if refrigerated.

Incompatibilities
ORBACTIV is administered intravenously. ORBACTIV should only be diluted in D5W. Do NOT use normal saline for dilution as it is incompatible with ORBACTIV and may cause precipitation of the drug. Therefore other intravenous substances, additives or other medications mixed in normal saline should not be added to ORBACTIV single-use vials or infused simultaneously through the same IV line or through a common intravenous port. In addition, drugs formulated at a basic or neutral pH may be incompatible with ORBACTIV. ORBACTIV should not be administered simultaneously with commonly used intravenous drugs through a common intravenous port. If the same intravenous line is used for sequential infusion of additional medications, the line should be flushed before and after infusion of ORBACTIV with D5W.

DOSAGE FORMS AND STRENGTHS:
ORBACTIV is supplied as sterile, white to off-white lyophilized powder equivalent to 400 mg of oritavancin in a single use 50 mL clear glass vial.



 Telavancin (Vibativ®): top of page

WARNING: FETAL RISK
Women of childbearing potential should have a serum pregnancy test prior to administration of VIBATIV
Avoid use of VIBATIV during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus
Adverse developmental outcomes observed in 3 animal species at clinically relevant doses raise concerns about potential adverse developmental outcomes in humans [see PACKAGE INSERT FOR Warnings and Precautions (5.1), Use in Specific Populations (8.1)]

WARNINGS AND PRECAUTIONS
  • Nephrotoxicity: New onset or worsening renal impairment has occurred. Monitor renal function in all patients.
  • Decreased efficacy with moderate/severe baseline renal impairment: Consider these data when selecting antibacterial therapy for patients with baseline CrCl leq50 mL/min.
  • Infusion-related reactions: Administer VIBATIV over at least 60 minutes to minimize infusion-related reactions.
  • Clostridium difficile-associated disease: May range from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs.
  • QTc prolongation: Avoid use in patients at risk. Use with caution in patients taking drugs known to prolong the QT interval.
  • Coagulation test interference: Telavancin interferes with some laboratory coagulation tests, including prothrombin time, international normalized ratio, and activated partial thromboplastin time.
Microbiology:
Telavancin is a semisynthetic, lipoglycopeptide antibiotic. Telavancin exerts concentration-dependent, bactericidal activity against Gram-positive organisms in vitro, as demonstrated by time-kill assays and MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. In vitro studies demonstrated a telavancin post-antibiotic effect ranging from 1 to 6 hours against S. aureus and other Gram-positive pathogens.

Although telavancin is approximately 90% protein bound, the presence of human serum or human serum albumin has minimal impact on the in vitro activity of telavancin against staphylococci, streptococci, and vancomycin-susceptible enterococci.

Mechanism of Action
Telavancin inhibits bacterial cell wall synthesis by interfering with the polymerization and cross-linking of peptidoglycan. Telavancin binds to the bacterial membrane and disrupts membrane barrier function.

Interactions with Other Antibacterials
In vitro investigations demonstrated no antagonism between telavancin and amikacin, aztreonam, cefepime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, meropenem, oxacillin, piperacillin/tazobactam, rifampin, and trimethoprim/sulfamethoxazole, when tested in various combinations against telavancin susceptible staphylococci, streptococci, and enterococci. This information is not available for other bacteria.

Cross-Resistance
Some vancomycin-resistant enterococci have a reduced susceptibility to telavancin. There is no known cross-resistance between telavancin and other classes of antibiotics.

Antibacterial Activity
Telavancin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections as described in the Indications and Usage section:

Facultative Gram-Positive Microorganisms
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus pyogenes
Enterococcus faecalis (vancomycin-susceptible isolates only)
Streptococcus agalactiae
Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)

Greater than 90% of the following microorganisms exhibit an in vitro MIC less than or equal to the telavancin-susceptible breakpoint for organisms of similar genus. The safety and effectiveness of telavancin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Facultative Gram-Positive Microorganisms
Enterococcus faecium (vancomycin-susceptible isolates only)
Staphylococcus haemolyticus
Streptococcus dysgalactaie subsp. equisimilis
Staphylococcus epidermidis


INDICATIONS AND USAGE:
To reduce the development of drug-resistant bacteria and maintain the effectiveness of VIBATIV and other antibacterial drugs, VIBATIV should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Complicated Skin and Skin Structure Infections
VIBATIV is indicated for the treatment of adult patients with complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), or Enterococcus faecalis (vancomycin-susceptible isolates only).

Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative organisms.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to telavancin. VIBATIV may be initiated as empiric therapy before results of these tests are known.

DOSAGE AND ADMINISTRATION:
Complicated Skin and Skin Structure Infections
The recommended dosing for VIBATIV is 10 mg/kg administered over a 60-minute period in patients =18 years of age by intravenous infusion once every 24 hours for 7 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress.


Renal Dosing:
Patients with Renal Impairment
Because telavancin is eliminated primarily by the kidney, a dosage adjustment is required for patients whose creatinine clearance is leq50 mL/min, as listed in Table 1.

Table 1: Dosage Adjustment in Adult Patients with Renal Impairment
Creatinine Clearance* (mL/min) VIBATIV Dosage Regimen
>50 10 mg/kg every 24 hours
30 - 50 7.5 mg/kg every 24 hours
10 - <30 10 mg/kg every 48 hours

* As calculated using the Cockcroft-Gault formula
There is insufficient information to make specific dosage adjustment recommendations for patients with end-stage renal disease (CrCl <10 mL/min), including patients undergoing hemodialysis.


Preparation and Administration
250 mg vial: Reconstitute the contents of a VIBATIV 250 mg vial with 15 mL of 5% Dextrose Injection, USP; Sterile Water for Injection, USP; or 0.9% Sodium Chloride Injection, USP. The resultant solution has a concentration of 15 mg/mL (total volume of approximately 17.0 mL).

750 mg vial: Reconstitute the contents of a VIBATIV 750 mg vial with 45 mL of 5% Dextrose Injection, USP; Sterile Water for Injection, USP; or 0.9% Sodium Chloride Injection, USP, The resultant solution has a concentration of 15 mg/mL (total volume of approximately 50.0 mL).

The following formula can be used to calculate the volume of reconstituted VIBATIV solution required to prepare a dose:

Telavancin dose (mg) = 10 mg/kg or 7.5 mg/kg x patient weight (in kg) (see Table 1)

Volume of reconstituted solution (mL) = Telavancin dose (mg) /15 mg/mL

For doses of 150 to 800 mg, the appropriate volume of reconstituted solution must be further diluted in 100 to 250 mL prior to infusion. Doses less than 150 mg or greater than 800 mg should be further diluted in a volume resulting in a final concentration of 0.6 to 8 mg/mL. Appropriate infusion solutions include: 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; or Lactated Ringer's Injection, USP. The dosing solution should be administered by intravenous infusion over a period of 60 minutes.

Reconstitution time is generally under 2 minutes, but can sometimes take up to 20 minutes. Mix thoroughly to reconstitute and check to see if the contents have dissolved completely. Parenteral drug products should be inspected visually for particulate matter prior to administration. Discard the vial if the vacuum did not pull the diluent into the vial.

Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparing the final intravenous solution. Studies have shown that the reconstituted solution in the vial should be used within 4 hours when stored at room temperature or within 72 hours under refrigeration at 2 to 8°C (36 to 46°F). The diluted (dosing) solution in the infusion bag should be used within 4 hours when stored at room temperature or used within 72 hours when stored under refrigeration at 2 to 8°C (36 to 46°F). However, the total time in the vial plus the time in the infusion bag should not exceed 4 hours at room temperature and 72 hours under refrigeration at 2 to 8°C (36 to 46°F).

VIBATIV is administered intravenously. Because only limited data are available on the compatibility of VIBATIV with other IV substances, additives or other medications should not be added to VIBATIV single-use vials or infused simultaneously through the same IV line. If the same intravenous line is used for sequential infusion of additional medications, the line should be flushed before and after infusion of VIBATIV with 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; or Lactated Ringer's Injection, USP.

SUPPLIED:
VIBATIV is supplied in single-use vials containing either 250 or 750 mg telavancin as a sterile, lyophilized powder.

SOURCE:
Package insert data:

 Vancomycin (Vancocin®): top of page

Microbiology:
The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin alters cell membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics. Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi.

Synergy
The combination of vancomycin and an aminoglycoside acts synergistically in vitro against many strains of Staphylococcus aureus, Streptococcus bovis, enterococci and the viridans group streptococci.

Vancomycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic gram-positive microorganisms
Diphtheroids
Enterococci (e.g., Enterococcus faecalis)
Staphylococci, including Staphylococcus aureus and Staphylococcus epidermidis (including heterogeneous methicillin-resistant strains)
Streptococcus bovis
Viridans group streptococci

The following in vitro data are available, but their clinical significance is unknown.
Vancomycin exhibits in vitro MIC’s of 1 mcg/mL or less against most (geq90%) strains of streptococci listed below and MIC’s of 4 mcg/mL or less against most (geq90%) strains of other listed microorganisms; however, the safety and effectiveness of vancomycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms
Listeria monocytogenes
Streptococcus pyogenes
Streptococcus pneumoniae (including penicillin-resistant strains)
Streptococcus agalactiae
Anaerobic gram-positive microorganisms
Actinomyces species
Lactobacillus species

INDICATIONS AND USAGE:
Vancomycin is indicated for the treatment of serious or severe infections caused by susceptible strains of methicillin-resistant (beta-lactam-resistant) staphylococci. It is indicated for penicillin-allergic patients, for patients who cannot receive or who have failed to respond to other drugs, including the penicillins or cephalosporins, and for infections caused by vancomycin-susceptible organisms that are resistant to other antimicrobial drugs. Vancomycin is indicated for initial therapy when methicillin-resistant staphylococci are suspected, but after susceptibility data are available, therapy should be adjusted accordingly.

Vancomycin hydrochloride is effective in the treatment of staphylococcal endocarditis. Its effectiveness has been documented in other infections due to staphylococci, including septicemia, bone infections, lower respiratory tract infections, and skin and skin-structure infections. When staphylococcal infections are localized and purulent, antibiotics are used as adjuncts to appropriate surgical measures.

Vancomycin hydrochloride has been reported to be effective alone or in combination with an aminoglycoside for endocarditis caused by S. viridans or S. bovis. For endocarditis caused by enterococci (e.g., E. faecalis), vancomycin hydrochloride has been reported to be effective only in combination with an aminoglycoside.

Vancomycin has been reported to be effective for the treatment of diphtheroid endocarditis. Vancomycin has been used successfully in combination with either rifampin, an aminoglycoside, or both in early-onset prosthetic valve endocarditis caused by S. epidermidis or diphtheroids.

Specimens for bacteriologic cultures should be obtained in order to isolate and identify causative organisms and to determine their susceptibilities to vancomycin.

The parenteral form of Sterile Vancomycin Hydrochloride may be administered orally for treatment of antibiotic-associated pseudomembranous colitis produced by C. difficile and for staphylococcal enterocolitis. Parenteral administration of vancomycin hydrochloride alone is of unproven benefit for these indications. Vancomycin is not effective by the oral route for other types of infection.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of vancomycin and other antibacterial drugs, vancomycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS
Vancomycin is contraindicated in patients with known hypersensitivity to this antibiotic.

WARNINGS
Rapid bolus administration (e.g., over several minutes) may be associated with exaggerated hypotension, including shock, and rarely, cardiac arrest. Vancomycin should be administered over a period of not less than 60 minutes to avoid rapid-infusion-related reactions. Stopping the infusion usually results in prompt cessation of these reactions.

Ototoxicity has occurred in patients receiving vancomycin. It may be transient or permanent. It has been reported mostly in patients who have been given excessive doses, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside. Vancomycin should be used with caution in patients with renal insufficiency because the risk of toxicity is appreciably increased by high, prolonged blood concentrations.

Dosage of vancomycin must be adjusted for patients with renal dysfunction.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Sterile Vancomycin Hydrochloride, USP and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.


DOSAGE AND ADMINISTRATION:
Review specialized reference(s) for specific dosing recommendation(s).

------------------------------------
Package insert:
------------------------------------

Infusion-related events are related to both the concentration and the rate of administration of vancomycin. Concentrations of no more than 5 mg/mL and rates of no more than 10 mg/min are recommended in adults (see also age-specific recommendations). In selected patients in need of fluid restriction, a concentration up to 10 mg/mL may be used; use of such higher concentrations may increase the risk of infusion-related events. An infusion rate of 10 mg/min or less is associated with fewer infusion-related events. Infusion-related events may occur, however, at any rate or concentration.

Patients with normal renal function
Adults

The usual daily intravenous dose is 2 g divided either as 500 mg every 6 hours or 1 g every 12 hours. Each dose should be administered at no more than 10 mg/min or over a period of at least 60 minutes, whichever is longer. Other patient factors, such as age or obesity, may call for modification of the usual intravenous daily dose.

Pediatric patients
The usual intravenous dosage of vancomycin is 10 mg/kg per dose given every 6 hours. Each dose should be administered over a period of at least 60 minutes. Close monitoring of serum concentrations of vancomycin may be warranted in these patients.

Neonates
In pediatric patients up to the age of 1 month, the total daily intravenous dosage may be lower. In neonates, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1st week of life and every 8 hours thereafter up to the age of 1 month. Each dose should be administered over 60 minutes. In premature infants, vancomycin clearance decreases as postconceptional age decreases. Therefore, longer dosing intervals may be necessary in premature infants. Close monitoring of serum concentrations of vancomycin is recommended in these patients.


Renal Dosing:
Dosage adjustment must be made in patients with impaired renal function. In the elderly, greater dosage reductions than expected may be necessary because of decreased renal function. Measurement of vancomycin serum concentrations can be helpful in optimizing therapy, especially in seriously ill patients with changing renal function. Vancomycin serum concentrations can be determined by use of microbiologic assay, radioimmunoassay, fluorescence polarization immunoassay, fluorescence immunoassay, or high-pressure liquid chromatography. If creatinine clearance can be measured or estimated accurately, the dosage for most patients with renal impairment can be calculated using the following table. The dosage of vancomycin per day in mg is about 15 times the glomerular filtration rate in mL/min:

DOSAGE TABLE FOR VANCOMYCIN IN PATIENTS WITH IMPAIRED RENAL FUNCTION
(Adapted from Meollering et al) 
Moellering RC, Krogstad DJ, Greenblatt DJ: Vancomycin therapy in patients with impaired renal function: A nomogram for dosage. Ann Inter Med 1981; 94:343.
Creatinine Clearance mL/min Vancomycin Dose mg/24 hr
100 1,545
90 1,390
80 1,235
70 1,080
60 925
50 770
40 620
30 465
20 310
10 155


SOURCE:
Package insert data:



Vancomycin - Target trough levels and monitoring??

Rybak M, Lomaestro B, Rotschafer JC, et al. (2009). "Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists". American Journal of Health-System Pharmacy 66 (1): 82-98.

Direct quotes from this reference (Rybak et al.):

"Further, data derived from more recent studies appear to suggest that vancomycin has little potential for nephrotoxicity or ototoxicity when used at conventional dosages (e.g., 1 g every 12 hours [15 mg/kg every 12 hours]), unless it is used concomitantly with known nephrotoxic drugs or at very high dosages."

Recommended TDM Parameters- Optimal monitoring parameter: "Trough serum vancomycin concentrations are the most accurate and practical method"

Timing of monitoring: "Troughs should be obtained just prior to the next dose at steady-state conditions (approximately after the fourth dose)."

Optimal trough concentration (see also Optimal trough concentration—complicated infections) : "Minimum serum vancomycin trough concentrations should always be maintained above 10 mg/L to avoid development of resistance. For a pathogen with an MIC of 1 mg/L, the minimum trough concentration would have to be at least 15 mg/L to generate the target AUC:MIC of 400."

Criteria for monitoring: "Data do not support using peak serum vancomycin concentrations to monitor for nephrotoxicity."

"Trough monitoring is recommended for patients receiving aggressive dosing (i.e., to achieve sustained trough levels of 15-20 mg/L) and all patients at high risk of nephrotoxicity (e.g., patients receiving concurrent nephrotoxins). Monitoring is also recommended for patients with unstable (i.e., deteriorating or significantly improving) renal function and those receiving prolonged courses of therapy (more than three to five days)."

Summary and recommendations
"Vancomycin dosages should be calculated on ABW. For obese patients, initial dosing can be based on ABW and then adjusted based on serum vancomycin concentrations to achieve therapeutic levels. Continuous infusion regimens are unlikely to substantially improve patient outcome when compared with intermittent dosing. (Level of evidence = II, grade of recommendation = A.)"

"Trough serum vancomycin concentrations are the most accurate and practical method for monitoring vancomycin effectiveness. Trough concentrations should be obtained just before the next dose at steadystate conditions. (Level of evidence = II, grade of recommendation = B.) (Note: Steady-state achievement is variable but occurs approximately after the fourth dose.)"

"Based on evidence suggesting that S. aureus exposure to trough serum vancomycin concentrations of <10 mg/L can produce strains with VISAlike characteristics, it is recommended that trough serum vancomycin concentrations always be maintained above 10 mg/L to avoid development of resistance. (Level of evidence = III, grade of recommendation = B.)"

"Based on the potential to improve penetration, increase the probability of optimal target serum vancomycin concentrations, and improve clinical outcomes for complicated infections such as bacteremia, endocarditis, osteomyelitis, meningitis, and hospital- acquired pneumonia caused by S. aureus, total trough serum vancomycin concentrations of 15-20 mg/L are recommended. Trough serum vancomycin concentrations in that range should achieve an AUC/MIC of geq400 in most patients if the MIC is leq1 mg/L. (Level of evidence = III, grade of recommendation = B.) In order to achieve rapid attainment of this target concentration for seriously ill patients, a loading dose of 25-30 mg/kg (based on ABW) can be considered. (Level of evidence = III, grade of recommendation = B.) A targeted AUC/MIC of geq 400 is not achievable with conventional dosing methods if the vancomycin MIC is geq2 mg/L in a patient with normal renal function (i.e., CLcr of 70-100 mL/min). Therefore, alternative therapies should be considered. Vancomycin dosages of 15-20 mg/kg (based on ABW) given every 8-12 hours are required for most patients with normal renal function to achieve the suggested serum concentrations when the MIC is leq1 mg/L. It should be noted that currently available nomograms were not developed to achieve these targeted endpoints. Individual pharmacokinetic adjustments and verification of serum target achievement are recommended. When individual doses exceed 1 g (i.e., 1.5 and 2 g), the infusion period should be extended to 1.5-2 hours. (Level of evidence = III, grade of recommendation = B.)"


"Available evidence does not support monitoring peak serum vancomycin concentrations to decrease the frequency of nephrotoxicity. (Level of evidence = I, grade of recommendation = A.) Monitoring of trough serum vancomycin concentrations to reduce nephrotoxicity is best suited to patients receiving aggressive dosing targeted to produce sustained trough drug concentrations of 15-20 mg/L or who are at high risk of toxicity, such as patients receiving concurrent nephrotoxins. (Level of evidence = III, grade of recommendation = B.) Monitoring is also recommended for patients with unstable renal function (either deteriorating or significantly improving) and those receiving prolonged courses of therapy (over three to five days). (Level of evidence = II, grade of recommendation = B.) All patients receiving prolonged courses of vancomycin should have at least one steady-state trough concentration obtained (approximately after the fourth dose). Frequent monitoring (more than a single trough concentration before the fourth dose) for short-course therapy (less than five days) or for lower-intensity dosing (targeted to attain trough serum vancomycin concentrations below 15 mg/L) is not recommended. (Level of evidence = II, grade of recommendation = B.)"

Summary

Variable Recommendation
Optimal monitoring parameter Serum trough concentration most practical.  (Level of evidence = II, grade of recommendation = B.)
Timing of troughs Troughs should be obtained at steady state: approximately prior to the fifth dose.  (Level of evidence = II, grade of recommendation = B.)
Optimal trough concentrations Should be >10 mg/l at a minimum to avoid development of resistanceFor a pathogen MIC of 1 mg/l, the trough should be at least 15 mg/l to attain an AUC/MIC of 400. (Level of evidence = III, grade of recommendation = B.)
Optimal trough concentrations: complicated infections (endocarditis, osteomyelitis, meningitis, hospital-acquired pneumonia caused by Staphylococcus aureus) Trough concentrations of 15-20 mg/l recommended to improve penetration, increase probability of target attainment and improve clinical outcomes.  (Level of evidence = III, grade of recommendation = B.)
Dosing regimen to achieve optimal trough Daily doses of 15-20 mg/kg (using actual bodyweight) given every 8-12 h recommended for most patients with normal renal function and when organism MIC is <1 mg/lTarget of AUC/MIC >400 is not possible with conventional dosing in patients with normal renal function when MIC is >2.0 mg/l. (Level of evidence = III, grade of recommendation = B.)
Loading doses: complicated infections In seriously ill patients, loading dose of 25-30 mg/kg (based on actual bodyweight) can be used to facilitate rapid attainment of target trough concentration.  (Level of evidence = III, grade of recommendation = B.)
Continuous versus intermittent administration Continuous infusion unlikely to improve patient outcome when compared with intermittent dosing.  (Level of evidence = II, grade of recommendation = B.)
Monitoring for nephrotoxicity A minimum of two or three consecutive documented increases in serum creatinine concentrations (0.5 mg/dl or >50% increase from baseline, whichever is greater) after several days of vancomycin therapy. (Level of evidence = II, grade of recommendation = B.)
Criteria for monitoring Data do not support serum peak concentration monitoring for nephrotoxicityTrough monitoring recommended when aggressive dosing (to achieve trough of 15-20 mg/l) and in patients at high risk (i.e., concurrent nephrotoxins)Monitoring recommended for patients with unstable renal function or prolonged treatment courses (>3-5 days). (Level of evidence = II, grade of recommendation = B.)
Frequency of monitoring Frequent monitoring (more than one trough before the fourth dose) for short course or lower intensity dosing (trough below 15 mg/l) is not recommendedPatients on prolonged courses of vancomycin (>3-5 days) should have at least one steady-state trough prior to the fifth dose and repeated as deemed clinically appropriateThere are limited data supporting the safety of sustained trough concentrations of 15-20 mg/lOnce-weekly monitoring of trough concentration is recommended in hemodynamically stable patientsMore frequent monitoring is recommended in hemodynamically unstable patients. (Level of evidence = II, grade of recommendation = B.)
Monitoring for ototoxicity Monitoring for ototoxicity is not recommended for patients receiving vancomycin monotherapyMonitoring should be considered for patients receiving concurrent ototoxins such as aminoglycosides.  (Level of evidence = III, grade of recommendation = B.
Rybak M, Lomaestro B, Rotschafer JC, et al. (2009). "Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists". American Journal of Health-System Pharmacy 66 (1): 82-98.

Direct quotes from this reference (Rybak et al.)

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Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
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