Amoxycillin

AMOXYCILLIN IS A SEMISYNTHETIC ANTIBIOTIC, AN ANALOG OF AMPICILLIN WITH A BROAT SPECTRUM OF BACTERICIDAL ACTIVITY AGAINST MANY GRAM-POSITIVE AND GRAM-NEGATIVE MICROORGANISM. IT IS STABLE IN THE PRESENCE OF GASTRIC ACID AND MAY BE GIVEN WITHOUT REGARD TO MEALS.

Dose

ADULTS :- 250 MG TO 500 MG THREE TIMES A DAY. CHILDREN UP TO 10 YEARS 125 MG TO 250 MG EVERY 8 HOURLY. CHILDREN UNDER 20 KG OF BODY WT :- 20 TO 40 MG/KG DAILY. DOSES FOR GONORRHOEA, UNCOMPLICATED ACUTE U.T.I :- 1-3 GM 8 HOURLY. RESPIATORY TRACT INFECTION :- 3 GM TWICE DAILY. CHILDREN 3 TO 10 YEARS WITH OTITIS MEDIA :- 750 MG TWICE DAILY FOR 2 DAYS. AMOXYCILLIN IS ADMINISTERED BY I.M. OR SLOW I.V. INJECTION IN DOSES OF 500 MG EVERY 8 HOURS. SEVERE INFECTION :- 1 GM GIVEN EVERY 6 HOURS BY SLOW I.V. INJ OVER 3 TO 4 MINUTE OR BY INFUSION OVER 30 TO 60 MINUTES. CHILDREN :- 50-100 MG/KG/BODY WT. DAILY BY INJ IN DIVIDED DOSES. DOSES SHOULD BE REDUCED IN SEVERE ERNAL IMPAIRMENT.

Monograph

AMOXYCILLIN DESCRIPTION: WYMOX (amoxicillin) is a semisynthetic antibiotic, an analog of ampicillin, with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Chemically it is (2S,5R,6R)-6-((R)-(-)-2-amino-2- (P-hydroxyphenyl)acetamido)-3,3-dimethyl-7-oxo- 4-thia-1-azabicyclo(3.2.0) heptane-2-carboxylic acid trihydrate. The amoxicillin molecular formula is C16H19N3O5S.3H2O, and the molecular weight is 419.45. ACTIONS/CLINICAL PHARMACOLOGY: Amoxicillin is stable in the presence of gastric acid and may be given without regard to meals. It is rapidly absorbed after oral administration. It diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. The half-life of amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged in the urine; its excretion can be delayed by concurrent administration of probenecid. Amoxicillin is not highly protein-bound. In blood serum, amoxicillin is approximately 20% protein-bound as compared to 60% for penicillin G. Orally administered doses of 250 mg and 500 mg amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 3.5 mcg/mL to 5.0 mcg/mL and 5.5 mcg/mL to 7.5 mcg/mL, respectively. Orally administered doses of amoxicillin suspension, 125 mg/5 mL and 250 mg/5 mL, result in average peak blood levels 1 to 2 hours after administration in the range of 1.5 mcg/mL to 3.0 mcg/mL and 3.5 mcg/mL to 5.0 mcg/mL, respectively. Amoxicillin chewable tablets, 125 mg and 250 mg, produced blood levels similar to those achieved with the corresponding doses of amoxicillin oral suspensions. Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Following a 1 gram dose and utilizing a special skin window technique to determine levels of the antibiotic, it was noted that therapeutic levels were found in the interstitial fluid. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours. MICROBIOLOGY Amoxicillin is similar to ampicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptide. Amoxicillin 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: Enterococcus Faecalis Staphylococcus spp. **/* (Beta-lactamase-negative strains only) Streptococcus Pneumoniae Streptococcus spp. (alpha- and beta-hemolytic strains only) **/* Staphylococci which are susceptible to amoxicillin but resistant to methicillin/oxacillin should be considered as resistant to amoxicillin. AEROBIC GRAM-NEGATIVE MICROORGANISMS: Escherichia Coli (Beta-lactamase-negative strains only) Haemophilus Influenzae (Beta-lactamase-negative strains only) Neisseria Gonorrhoeae (Beta-lactamase-negative strains only) Proteus Mirabilis (Beta-lactamase-negative strains only) HELICOBACTER: Helicobacter Pylori SUSCEPTIBILITY TESTS DILUTION TECHNIQUES: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (REF. 1) (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of AMPICILLIN powder. Ampicillin is sometimes used to predict susceptibility of Streptococcus Pneumoniae to amoxicillin; however, some intermediate strains have been shown to be susceptible to amoxicillin. Therefore, Streptococcus Pneumoniae susceptibility should be tested using amoxicillin powder. The MIC values should be interpreted according to the following criteria: FOR GRAM-POSITIVE AEROBES: Enterococcus MIC (MCG/ML) INTERPRETATION /= 16 Resistant (R) Staphylococcus(a) MIC (MCG/ML) INTERPRETATION /= 0.5 Resistant (R) Streptococcus (Except S. Pneumoniae) MIC (MCG/ML) INTERPRETATION /= 8 Resistant (R) S. Pneumoniae(b) (AMOXICILLIN powder should be used to determine susceptibility.) MIC (MCG/ML) INTERPRETATION /= 2 Resistant (R) FOR GRAM-NEGATIVE AEROBES: Enterobacteriaceae MIC (MCG/ML) INTERPRETATION /= 32 Resistant (R) H. Influenzae(c) MIC (MCG/ML) INTERPRETATION /= 4 Resistant (R) ____________________________________________________________________________________________________________ a. Staphylococci which are susceptible to amoxicillin but resistant to methicillin/oxacillin should be considered as resistant to amoxicillin. ____________________________________________________________________________________________________________ b. These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood. ____________________________________________________________________________________________________________ c. These interpretive standards are applicable only to broth microdilution test with Haemophilus Influenzae using Haemophilus Test Medium (HTM). (REF. 1) ____________________________________________________________________________________________________________ A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganisms is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard AMPICILLIN powder should provide the following MIC values: ____________________________________________________________________________________________________________ MICROORGANISM MIC (MCG/ML) E. Coli ATCC 25922 2 to 8 E. Faecalis ATCC 29212 0.5 to 2 H. Influenzae ATCC 49247(d) 2 to 8 S. Aureus ATCC 29213 0.25 to 1 Using AMOXICILLIN to determine susceptibility: MICROORGANISM MIC RANGE (MCG/ML) S. Pneumoniae ATCC 49619(e) 0.03 to 0.12 ____________________________________________________________________________________________________________ d. This quality control range is applicable to only H. Influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM). (REF. 1) ____________________________________________________________________________________________________________ e. This quality control range is applicable to only S. Pneumoniae ATCC 49619 tested by the broth microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood. ____________________________________________________________________________________________________________ DIFFUSION TECHNIQUES: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure (REF. 2) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10 mcg ampicillin to test the susceptibility of microorganisms, except S. Pneumoniae, to amoxicillin. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for AMPICILLIN. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-mcg ampicillin disk should be interpreted according to the following criteria: FOR GRAM-POSITIVE AEROBES: Enterococcus ____________________________________________________________________________________________________________ ZONE DIAMETER (MM) INTERPRETATION >/= 17 Susceptible (S) /= 29 Susceptible (S) /= 26 Susceptible (S) 19 to 25 Intermediate (I) /= 20 mm are susceptible to amoxicillin. An amoxicillin MIC should be determined on isolates of S. Pneumoniae with oxacillin zone sizes of /= 17 Susceptible (S) 14 to 16 Intermediate (I) /= 22 Susceptible (S) 19 to 21 Intermediate (I) 3 MONTHS** ------------------------------------------------------------------------------------------------------------------------ Ear/nose/throat 250 mg every 8 20 mg/kg/day in hours divided doses every 8 hours Lower respiratory 500 mg every 8 40 mg/kg/day in tract hours divided doses every 8 hours Skin/skin 250 mg every 8 20 mg/kg/day in structure hours divided doses every 8 hours Genitourinary 250 mg every 8 20 mg/kg/day in tract hours divided doses every 8 hours Gonorrhea; 3 grams as single PREPUBERTAL acute, oral dose children: 50 mg/kg uncomplicated WYMOX, combined ano-genital and with 25 mg/kg urethral probenecid as a infections in single dose. males and NOTE: SINCE females PROBENECID IS CONTRAINDICATED IN CHILDREN UNDER 2 YEARS, DO NOT USE THIS REGIMEN IN THESE CASES. ---------------------------------------------------------------------------------------------------------------------------------- ** Children weighing 40 kg or more should be dosed according to the adult recommendations. In severe ear, nose, throat, genitourinary, skin and skin structure infections, or those caused by less susceptible organisms: Adults: 500 mg every 8 hours Children: 40 mg/kg/day in divided doses every 8 hours All patients with gonorrhea should be evaluated for syphilis. (See PRECAUTIONS - Laboratory Tests.) Larger doses may be required for stubborn or severe infections. H. PYLORI ERADICATION TO REDUCE THE RISK OF DUODENAL ULCER RECURRENCE Triple Therapy: WYMOX/Clarithromycin/Lansoprazole The recommended adult oral dose is 1 gram WYMOX, 500 mg clarithromycin, and 30 mg lansoprazole, all given twice daily (q12h) for 14 days. (See INDICATIONS AND USAGE.) Dual Therapy: WYMOX/Lansoprazole The recommended adult oral dose is 1 gram WYMOX and 30 mg lansoprazole, each given three times daily (q8h) for 14 days. (See INDICATIONS AND USAGE.) Please refer to clarithromycin and lansoprazole full prescribing information for CONTRAINDICATIONS and WARNINGS, and for information regarding dosing in elderly and renally impaired patients. GENERAL: The children's dosage is intended for individuals whose weight will not cause a dosage to be calculated greater than that recommended for adults. It should be recognized that in the treatment of chronic urinary tract infections, frequent bacteriological and clinical appraisals are necessary. Smaller doses than those recommended above should not be used. Even higher doses may be needed at times. In stubborn infections, therapy may be required for several weeks. It may be necessary to continue clinical and/or bacteriological follow-up for several months after cessation of therapy. Except for gonorrhea, treatment should be continued for a minimum of 48 to 72 hours beyond the time that the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. It is recommended that there be at least 10 days' treatment for any infection caused by Streptococcus Pyogenes to prevent the occurrence of acute rheumatic fever. After reconstitution, the required amount of suspension should be placed directly on the child's tongue for swallowing. Alternate means of administration are to add the required amount of suspension to formula, milk, fruit juice, water, ginger ale, or cold drinks. These preparations should then be taken immediately. To be certain the child is receiving full dosage, such preparations should be consumed in entirety. DIRECTIONS FOR MIXING ORAL SUSPENSION Prepare suspension at time of dispensing as follows: Tap bottle until all powder flows freely. Add approximately 1/3 of the total amount of water for reconstitution (see table below) and shake vigorously to wet powder. Add remainder of the water and again shake vigorously. DIRECTIONS FOR MIXING PEDIATRIC DROPS Prepare pediatric drops at time of dispensing as follows: Add the required amount of water (see table below) to the bottle and shake vigorously. Each mL of suspension will then contain amoxicillin trihydrate equivalent to 50 mg amoxicillin. AMOUNT OF WATER BOTTLE SIZE REQUIRED FOR RECONSTITUTION 15 mL 12 mL 30 mL 23 mL NOTE: SHAKE BOTH ORAL SUSPENSION AND PEDIATRIC DROPS WELL BEFORE USING. Keep bottle tightly closed. Any unused portion of the reconstituted suspension must be discarded after 14 days. Refrigeration preferable, but not required. CLINICAL STUDIES: H. PYLORI ERADICATION TO REDUCE THE RISK OF DUODENAL ULCER RECURRENCE Randomized, double-blind clinical studies performed in the U.S. in patients with H. Pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) evaluated the efficacy of lansoprazole in combination with amoxicillin capsules and clarithromycin tablets as triple 14-day therapy, or in combination with amoxicillin capsules as dual 14-day therapy, for the eradication of H. Pylori. Based on the results of these studies, the safety and efficacy of two different eradication regimens were established: Triple Therapy: amoxicillin 1 gram b.i.d./clarithromycin 500 mg b.i.d./lansoprazole 30 mg b.i.d. Dual Therapy: amoxicillin 1 gram t.i.d./lansoprazole 30 mg t.i.d. All treatments were for 14 days. H. Pylori eradication was defined as two negative tests (culture and histology) at 4 to 6 weeks following the end of treatment. Triple therapy was shown to be more effective than all possible dual therapy combinations. Dual therapy was shown to be more effective than both monotherapies. Eradication of H. Pylori has been shown to reduce the risk of duodenal ulcer recurrence. H. PYLORI ERADICATION RATES - TRIPLE THERAPY (AMOXICILLIN/CLARITHROMYCIN/LANSOPRAZOLE) PERCENT OF PATIENTS CURED (95% CONFIDENCE INTERVAL) (NUMBER OF PATIENTS) --------------------------------------------------------------------------------------------------------------------- TRIPLE THERAPY TRIPLE THERAPY -------------------------------------------------------------------------------------------------------------------- STUDY EVALUABLE ANALYSIS(I) INTENT-TO-TREAT ANALYSIS(II) -------------------------------------------------------------------------------------------------------------------- Study 1 92(III) 86(I) (80.0-97.7) (73.3-93.5) (n=48) (n=55) ------------------------------------------------------------------------------------------------------------------- Study 2 86(**) 83(**) (75.7-93.6) (72.0-90.8) (n=66) (n=70) ------------------------------------------------------------------------------------------------------------------ (I) This analysis was based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. Pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest(R) (Delta West Ltd., Bentley, Australia), histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. (II) Patients were included in the analysis if they had documented H. Pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy. (III) (P<0.05) versus lansoprazole/amoxicillin and lansoprazole/clarithromycin dual therapy. (**) (P<0.05) versus clarithromycin/amoxicillin dual therapy. H. PYLORI ERADICATION RATES - DUAL THERAPY (AMOXICILLIN/LANSOPRAZOLE) PERCENT OF PATIENTS CURED (95% CONFIDENCE INTERVAL) (NUMBER OF PATIENTS) ------------------------------------------------------------------------------------------------------------------ DUAL THERAPY DUAL THERAPY ------------------------------------------------------------------------------------------------------------------ STUDY EVALUABLE ANALYSIS(##) INTENT-TO-TREAT ANALYSIS(#) ------------------------------------------------------------------------------------------------------------------ Study 1 77(###) 70(###) (62.5-87.2) (56.8-81.2) (n=51) (n=60) ----------------------------------------------------------------------------------------------------------------- Study 2 66(IIII) 61(IIII) (51.9-77.5) (48.5-72.9) (n=58) (n=67) ----------------------------------------------------------------------------------------------------------------- (#) This analysis was based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. Pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest(R), histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. (##) Patients were included in the analysis if they had documented H. Pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy. (###) (P<0.05) versus lansoprazole alone. (IIII) (P<0.05) versus lansoprazole alone or amoxicillin alone.

Potassium Clavulanate

CLAVULANATE POT IS CONVERTED INTO CLAVULANIC ACID WHICH IS A BETA LACTUM STRUCTURALLY RELATED TO PENICILLINS, WHICH POSSESSES THE ABILITY TO INACTIVATE A WIDE RANGE OF BETA-LACTAMASE COMMOMNLY FOUND IN BACTERIA RESISTANT TO BETA LACTAM ANTIBIOTICS. THE FORMULATION OF AMOXICILLIN WITH CLAVULANIC ACID PROTECTS AMOXYCILIN FROM DEGRADATION BY BETA-LACTAMASE ENZYMES AND EFFECTIVELY EXTENDS THE ANTIBIOTIC SPECTRUM OF AMOXYCILLIN TO INCLUDE MANY BACTERIA RESISTANT TO AMOXYCILLIN AND OTHER BETA-LACTAM ANTIBIOTICS. ACTIVE BOTH AGAINST GRAM + AND GRAM - VE BACTERIAS.

Dose

ADULTS - 125 MG THREE TIMES FOR 7-10 DAYS. USED IN COMBINATION OF AMOXYCILLIN AND TICARCILLIN. CHILDREN - UPTO 40 KG OF WT. - 1.7 MG/KG THREE TIMES DAILY FOR 7-10 DAYS.

Monograph

CLAVULANATE POTASSIUM DESCRIPTION: Augmentin is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C16H19N3 O5S.3H2O and the molecular weight is 419.46. Chemically, amoxicillin is (2S,5R,6R)-6-((R)-(-)-2-Amino-2-(P- hydroxyphenyl)acetamido)-3,3-dimethyl-7-oxo- 4-thia-1-azabicyclo (3.2.0)heptane- 2-carboxylic acid trihydrate. Clavulanic acid is produced by the fermentation of Streptomyces Clavuligerus. It is a beta-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of beta-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid mediated beta-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C8H8KNO5 and the molecular weight is 237.25. Chemically clavulanate potassium is potassium (Z)-(2R, 5R)-3-(2- hydroxyethylidene)-7-oxo-4-oxa- 1-azabicyclo(3.2.0)-heptane-2-carboxylate. INACTIVE INGREDIENTS: Colloidal silicon dioxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate and titanium dioxide. Each Augmentin tablet contains 0.63 mEq potassium. ACTIONS/CLINICAL PHARMACOLOGY: Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of Augmentin. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While Augmentin can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when Augmentin was dosed at 30 and 150 minutes after the start of a high fat breakfast. The safety and efficacy of Augmentin have been established in clinical trials where Augmentin was taken without regard to meals. Mean* amoxicillin and clavulanate potassium pharmacokinetic parameters are shown in the table below: Dose** and regimen AUC0-24 (mcgm.hr/mL) Cmax (mcgm/mL) ------------------------------------------------------------------------------ amoxicillin/ clavulanate clavulanate clavulanate amoxicillin potassium amoxicillin potassium potassium (+/- S.D.) (+/- S.D.) (+/- S.D.) (+/- S.D.) 250/125 mg q8h 26.7 +/- 4.56 12.6 +/- 3.25 3.3 +/- 1.12 1.5 +/- 0.70 500/125 mg q12h 33.4 +/- 6.76 8.6 +/- 1.95 6.5 +/- 1.41 1.8 +/- 0.61 500/125 mg q8h 53.4 +/- 8.87 15.7 +/- 3.86 7.2 +/- 2.26 2.4 +/- 0.83 875/125 mg q12h 53.5 +/- 12.31 10.2 +/- 11.6 +/- 2.78 2.2 +/- 0.99 3.04 --------------------------------------------------------------------------------------------------------------------------------------------------------------- * Mean values of 14 normal volunteers (n=15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose. ** Administered at the start of a light meal. Amoxicillin serum concentrations achieved with Augmentin are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. The half-life of amoxicillin after the oral administration of Augmentin is 1.3 hours and that of clavulanic acid is 1.0 hour. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single Augmentin 250 mg or 500 mg tablet. Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid. Neither component in Augmentin is highly protein- bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluids. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues. Microbiology: Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram- negative microorganisms. Amoxicillin is, however, susceptible to degradation by beta- lactamases and, therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of beta- lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid mediated beta-lactamases frequently responsible for transferred drug resistance. The formulation of amoxicillin and clavulanic acid in Augmentin protects amoxicillin from degradation by beta-lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other beta-lactam antibiotics. Thus Augmentin possesses the properties of a broad-spectrum antibiotic and a beta-lactamase inhibitor. Amoxicillin/clavulanic acid 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. GRAM-POSITIVE AEROBES Staphylococcus Aureus (beta-lactamase and non- beta-lactamase producing)*/* ---------- */* Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid. ---------- GRAM-NEGATIVE AEROBES Enterobacter species (Although most strains of Enterobacter species are resistant In Vitro, clinical efficacy has been demonstrated with Augmentin in urinary tract infections caused by these organisms.) Escherichia Coli (beta-lactamase and non-beta- lactamase producing) Haemophilus Influenzae (beta-lactamase and non- beta-lactamase producing) Klebsiella species (All known strains are beta- lactamase producing.) Moraxella Catarrhalis (beta-lactamase and non- beta-lactamase producing) The following In Vitro data are available, BUT THEIR CLINICAL SIGNIFICANCE IS UNKNOWN. Amoxicillin/clavulanic acid exhibits In Vitro minimal inhibitory concentrations (MICs) of 0.5 mcgm/mL or less against most (>/=90%) strains of Streptococcus Pneumoniae#; MICs of 0.06 mcgm/mL or less against most (>/=90%) strains of Neisseria Gonorrhoeae; MICs of 4 mcgm/mL or less against most (>/=90%) strains of staphylococci and anaerobic bacteria; and MICs of 8 mcgm/mL or less against most (>/=90%) strains of other listed organisms. However, with the exception of organisms shown to respond to amoxicillin alone, the safety and effectiveness of amoxicillin/clavulanic acid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. ---------- # Because amoxicillin has greater In Vitro activity against Streptococcus Pneumoniae than does ampicillin or penicillin, the majority of S. Pneumoniae strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin. ---------- GRAM-POSITIVE AEROBES Enterococcus Faecalis## Staphylococcus Epidermidis (beta-lactamase and non-beta-lactamase producing) Staphylococcus Saprophyticus (beta-lactamase and non-beta-lactamase producing) Streptococcus Pneumoniae## **/* Streptococcus Pyogenes## **/* viridans group Streptococcus## **/* GRAM-NEGATIVE AEROBES Eikenella Corrodens (beta-lactamase and non-beta- lactamase producing) Neisseria Gonorrhoeae## (beta-lactamase and non- beta-lactamase producing) Proteus Mirabilis## (beta-lactamase and non-beta- lactamase producing) ANAEROBIC BACTERIA Bacteroides species, including Bacteroides Fragilis (beta-lactamase and non- beta-lactamase producing) Fusobacterium species (beta-lactamase and non- beta-lactamase producing) Peptostreptococcus species**/* ---------- ## Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to these organisms. **/* These are non-beta-lactamase-producing organisms and, therefore, are susceptible to amoxicillin alone. ---------- SUSCEPTIBILITY TESTING DILUTION TECHNIQUES: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of amoxicillin/clavulanate potassium powder. The recommended dilution pattern utilizes a constant amoxicillin/clavulanate potassium ratio of 2 to 1 in all tubes with varying amounts of amoxicillin. MICs are expressed in terms of the amoxicillin concentration in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. The MIC values should be interpreted according to the following criteria: RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING For gram-negative enteric aerobes: MIC (mcgm/mL) Interpretation /=32/16 Resistant (R) For Staphylococcus*/** and Haemophilus species: MIC (mcgm/mL) Interpretation /=8/4 Resistant (R) ------------------------------------------------------------------------------------------------------------------------------------------------------ */** Staphylococci which are susceptible to amoxicillin/clavulanic acid but resistant to methicillin/oxacillin must be considered as resistant. For Streptococcus Pneumoniae: Isolates should be tested using amoxicillin/clavulanic acid and the following criteria should be used: MIC (mcgm/mL) Interpretation /=2/1 Resistant (R) A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard amoxicillin/clavulanate potassium powder should provide the following MIC values: Microorganism MIC Range (mcgm/mL)#/# Escherichia Coli ATCC 25922 2 to 8 Escherichia Coli ATCC 35218 4 to 16 Enterococcus Faecalis ATCC 29212 0.25 to 1.0 Haemophilus Influenzae ATCC 49247 2 to 16 Staphylococcus Aureus ATCC 29213 0.12 to 0.5 Streptococcus Pneumoniae ATCC 49619 0.03 to 0.12 ------------------------------------------------------------------------------ #/# Expressed as concentration of amoxicillin in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. DIFFUSION TECHNIQUES: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcgm of amoxicillin/clavulanate potassium (20 mcgm amoxicillin plus 10 mcgm clavulanate potassium) to test the susceptibility of microorganisms to amoxicillin/clavulanic acid. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcgm amoxicillin/clavulanate acid (20 mcgm amoxicillin plus 10 mcgm clavulanate potassium) disk should be interpreted according to the following criteria: RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING For Staphylococcus##/# species and H. Influenzae(a): Zone Diameter (mm) Interpretation >/=20 Susceptible (S) /=18 Susceptible (S) 14 to 17 Intermediate (I) /=20 mm are susceptible to amoxicillin/clavulanic acid. An amoxicillin/clavulanic acid MIC should be determined on isolates of S. Pneumoniae with oxacillin zone sizes of