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Vancomycin (Vancomycin Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Vancomycin Hydrochloride Capsules, USP for oral administration contain chromatographically purified vancomycin hydrochloride (a white to slightly red or slightly brown semi-solid matrix), a tricyclic glycopeptide antibiotic derived from Amycolatopsis orientalis (formerly Nocardia orientalis ); 500 mg of the base is equivalent to 0.34 mmol.

The 125 mg capsules contain vancomycin hydrochloride equivalent to 125 mg (0.08 mmol) vancomycin.  The inactive ingredients are polyethylene glycol, black iron oxide, titanium dioxide, yellow iron oxide, and gelatin.  The capsules are printed with ink containing shellac, propylene glycol, black iron oxide and potassium hydroxide.

The 250 mg capsules contain vancomycin hydrochloride equivalent to 250 mg (0.17 mmol) vancomycin.  The inactive ingredients are polyethylene glycol, yellow iron oxide, black iron oxide, FD&C Blue No. 2, titanium dioxide, and gelatin.  The capsules are printed with ink containing shellac, povidone, propylene glycol, titanium dioxide and sodium hydroxide.

Vancomycin hydrochloride is chemically designated as ( S a )-(3 S ,6 R, 7 R, 22 R, 23 S ,26 S ,36 R, 38a R )-44-[[2- O -(3-Amino-2,3,6-trideoxy-3- C -methyl-α-L- lyxo -hexopyranosyl)-β-D-glucopyranosyl]oxy]-3-(carbamoylmethyl)-10,19-dichloro-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-7,22,28,30,32-pentahydroxy-6-[(2 R )-4-methyl-2-(methylamino)]valeramido]-2,5,24,38,39-pentaoxo-22 H -8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-1 H ,16 H -[1,6,9]oxadiazacyclohexadecino[4,5- m ][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid, monohydrochloride and has the following structural formula:


 

C 66H 75Cl 2N 9O 24•HCl                        M.W. 1485.71

CLINICAL PHARMACOLOGY

Mechanism of Action

Vancomycin is an antibacterial drug [see Clinical Pharmacology, Microbiology ].

Pharmacokinetics

Vancomycin is poorly absorbed after oral administration.  During multiple dosing of 250 mg every 8 hours for 7 doses, fecal concentrations of vancomycin in volunteers exceeded 100 mg/kg in the majority of samples.  No blood concentrations were detected and urinary recovery did not exceed 0.76%.  In anephric subjects with no inflammatory bowel disease who received vancomycin oral solution 2 g for 16 days, blood concentrations of vancomycin were less than or equal to 0.66 mcg/mL in 2 of 5 subjects.  No measurable blood concentrations were attained in the other 3 subjects.  Following doses of 2 g daily, concentrations of drug were >3100 mg/kg in the feces and <1 mcg/mL in the serum of subjects with normal renal function who had C. difficile -associated diarrhea.  After multiple-dose oral administration of vancomycin, measurable serum concentrations may occur in patients with active C. difficile -associated diarrhea, and, in the presence of renal impairment, the possibility of accumulation exists.  It should be noted that the total systemic and renal clearances of vancomycin are reduced in the elderly [ see Use in Specific Populations, Geriatric Use (8.5 ) ] .

Microbiology

Mechanism of action

The bactericidal action of vancomycin against Staphylococcus aureus and the vegetative cells of Clostridium difficile results primarily from inhibition of cell-wall biosynthesis.  In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis.

Mechanism of resistance

             Staphylococcus aureus

            S.   aureus isolates with vancomycin minimal inhibitory concentrations (MICs) as high as 1024 mcg/mL have been reported.

           The exact mechanism of this resistance is not clear but is believed to be due to cell wall thickening and potentially the transfer of genetic material.

 

            Clostridium difficile

            Isolates of C.   difficile generally have vancomycin MICs of <1 mcg/mL, however vancomycin MICs ranging from 4 mcg/mL to 16 mcg/mL have been reported. The

            mechanism which mediates C.   difficile’s decreased susceptibility to vancomycin has not been fully elucidated.

 

Vancomycin has been shown to be active against susceptible isolates of the following bacteria in clinical infections as described in the Indications and Usage section.

 

Gram-positive bacteria

            Staphylococcus aureus (including methicillin-resistant isolates) associated with enterocolitis

 

Anaerobic Gram-positive bacteria

            Clostridium difficile isolates associated with C.   difficile associated diarrhea


NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term carcinogenesis studies in animals have been conducted.

At concentrations up to 1000 mcg/mL, vancomycin had no mutagenic effect in vitro in the mouse lymphoma forward mutation assay or the primary rat hepatocyte unscheduled DNA synthesis assay.  The concentrations tested in vitro were above the peak plasma vancomycin concentrations of 20 to 40 mcg/mL usually achieved in humans after slow infusion of the maximum recommended dose of 1 g.  Vancomycin had no mutagenic effect in vivo in the Chinese hamster sister chromatid exchange assay (400 mg/kg IP) or the mouse micronucleus assay (800 mg/kg IP).

No definitive fertility studies have been conducted.

CLINICAL STUDIES

Diarrhea Associated with Clostridium difficile

In two trials, vancomycin  hydrochloride 125 mg orally four times daily for 10 days was evaluated in 266 adult subjects with C.   difficile -associated diarrhea (CDAD).  Enrolled subjects were 18 years of age or older and received no more than 48 hours of treatment with oral vancomycin hydrochloride or oral/intravenous metronidazole in the 5 days preceding enrollment.  CDAD was defined as ≥3 loose or watery bowel movements within the 24 hours preceding enrollment, and the presence of either C.   difficile toxin A or B, or pseudomembranes on endoscopy within the 72 hours preceding enrollment.  Subjects with fulminant C.   difficile disease, sepsis with hypotension, ileus, peritoneal signs or severe hepatic disease were excluded.

Efficacy analyses were performed on the Full Analysis Set (FAS), which included randomized subjects who received at least one dose of vancomycin hydrochloride and had any postdosing investigator evaluation data (N=259; 134 in Trial 1 and 125 in Trial 2).

The demographic profile and baseline CDAD characteristics of enrolled subjects were similar in the two trials.  Vancomycin hydrochloride-treated subjects had a median age of 67 years, were mainly white (93%), and male (52%).  CDAD was classified as severe (defined as 10 or more unformed bowel movements per day or WBC ≥15000/mm3) in 25% of subjects, and 47% were previously treated for CDAD.

Efficacy was assessed by using clinical success, defined as diarrhea resolution and the absence of severe abdominal discomfort due to CDAD, on Day 10.  An additional efficacy endpoint was the time to resolution of diarrhea, defined as the beginning of diarrhea resolution that was sustained through the end of the prescribed active treatment period.

The results for clinical success for vancomycin hydrochloride-treated subjects in both trials are shown in Table 2.

Table 2: Clinical Success Rates (Full Analysis Set)

          Clinical Success Rate

95% Confidence Interval

Vancomycin Hydrochloride % (N)

Trial 1

81.3 (134)

(74.4, 88.3)

Trial 2

80.8 (125)

(73.5, 88.1)

The median time to resolution of diarrhea was 5 days and 4 days in Trial 1 and Trial 2, respectively.  For subjects older than 65 years of age, the median time to resolution was 6 days and 4 days in Trial 1 and Trial 2, respectively. In subjects with diarrhea resolution at end-of-treatment with vancomycin hydrochloride, recurrence of CDAD during the following four weeks occurred in 25 of 107 (23%) and 18 of 102 (18%) in Trial 1 and Trial 2, respectively.

Restriction Endonuclease Analysis (REA) was used to identify C.   difficile baseline isolates in the BI group.  In Trial 1, the vancomycin hydrochloride-treated subjects were classified at baseline as follows 31 (23%) with BI strain, 69 (52%) with non-BI strain, and 34 (25%) with unknown strain.  Clinical success rates were 87% for BI strain, 81% for non-BI strain, and 76% for unknown strain.  In subjects with diarrhea resolution at end-of treatment with vancomycin hydrochloride, recurrence of CDAD during the following four weeks occurred in 7 of 26 subjects with BI strain, 12 of 56 subjects with non-BI strain, and 6 of 25 subjects with unknown strain.

 

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