FDA Approves New Indication for INVANZ(R) (ertapenem) for the Prevention of Surgical Site Infections (SSI) following Elective Colorectal Surgery in Adults

Merck & Co., Inc. announced today that the U.S. Food and Drug Administration (FDA) recently approved INVANZ® (ertapenem), a once-daily injectable antibiotic, for the prophylaxis of surgical site infection (SSI) following elective colorectal surgery in adults. This approval was based upon the results of the landmark PREVENT trial, the largest prospective, randomized double-blind, comparative clinical trial ever conducted in antibiotic prophylaxis for elective colorectal surgery (N=1002). Results from the study were presented today in the New England Journal of Medicine. "Given the high incidence of SSI, Merck is very pleased to be able to offer a new alternative with clinically demonstrated efficacy,” said Murray A. Abramson, M.D., M.P.H., senior medical director, Merck Research Labs, Infectious Diseases, Merck & Co. Inc. In the PREVENT study, a statistically significant difference favoring INVANZ over cefotetan with respect to the primary endpoint has been observed. A second adequate and well-controlled study to confirm these findings has not been conducted; therefore, the clinical superiority of ertapenem over cefotetan has not been demonstrated. INVANZ provides proven prophylaxis for elective colorectal surgery in a single 1 g dose given within one hour prior to surgical incision. The primary endpoint in the PREVENT study was the test of prophylaxis, which was defined as no evidence of SSI, post-operative anastomotic leak, or unexplained antibiotic use through four weeks post-surgery in the clinically evaluable and MITT populations. The rates of successful prophylaxis at 4 weeks posttreatment in the clinically evaluable patients were 70.5 percent (244/346) for ertapenem and 57.2 percent (194/339) for cefotetan. In the MITT analysis, the prophylactic success rates at 4 weeks posttreatment were 58.3 percent (263/451) for ertapenem and 48.9 percent (220/450) for cefotetan (difference 9.4 percent, [95 percent CI, 2.9, 15.9], p=0.002). Prophylaxis failure due to SSI, including superficial incisional, deep incisional or organ space infections, occurred in 18.2 percent (63/346) of ertapenem patients and 31 percent (105/339) of cefotetan patients. Post-operative anastomotic leak occurred in 2.9 percent (10/346) of ertapenem patients and 4.1 percent (14/339) of cefotetan patients. Unexplained antibiotic use occurred in 8.4 percent (29/346) and 7.7 percent (26/339) of ertapenem and cefotetan patients, respectively. INVANZ is now indicated in adults for the prophylaxis of surgical site infection following elective colorectal surgery. Elective colorectal (gastrointestinal) surgery is performed to repair or remove diseased portions of the lower intestinal tract (including the colon, rectum and anus) sometimes due to cancer or diverticulosis. The incidence of surgical site infection has become a focus of the National Surgical Infection Prevention Project implemented by the Centers for Medicare and Medicaid Services in collaboration with the Centers for Disease Control and Prevention to promote the proper use of prophylactic antibiotics. INVANZ is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams. Due to the use of lidocaine HCl as a diluent, INVANZ administered intramuscularly is contraindicated in patients with known hypersensitivity to local anesthetics of the amide type. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. New indication based on the PREVENT study, the largest prospective clinical trial to date of antibiotic prophylaxis for elective colorectal surgery. The PREVENT study, a randomized, double-blind, multi-center comparative trial conducted in 1,002 adult patients, compared INVANZ to cefotetan in the prophylaxis of surgical site infection following elective colorectal surgery. Patients received a single dose of either INVANZ 1 g (n=346) or cefotetan 2 g (n=339) in a 30-minute intravenous infusion started within 1 hour prior to surgical incision. All patients received one of two standard bowel preparations (sodium phosphate or polyethylene glycol) prior to surgery. Patients were evaluated during hospitalization, at discharge, and four weeks after surgery for signs or symptoms of infection at the surgical site and to determine that no further anti-microbial therapy or surgery was necessary. The modified intent-to-treat (MITT) population consisted of 451 ertapenem patients and 450 cefotetan patients and included all patients who were randomized, treated, and underwent elective colorectal surgery with adequate bowel preparation. The clinically evaluable population (346 ertapenem patients and 339 cefotetan patients) was a subset of the MITT population and consisted of patients who received a complete dose of study therapy no more than two hours prior to surgical incision and no more than six hours before surgical closure, and who had sufficient information and no confounding factors that interfered with determining outcome at the 4-week follow-up assessment. The adverse experiences associated with INVANZ in this study were generally comparable to those found in other clinical trials for INVANZ. During clinical trials, the most common side effects in adults related to treatment with INVANZ were diarrhea (5.5 percent), infused vein complication (3.7 percent), nausea (3.1 percent), headache (2.2 percent), vaginitis in females (2.1 percent), phlebitis/thrombophlebitis (1.3 percent), and vomiting (1.1 percent). Pseudomembranous colitis has been reported with nearly all antibacterial agents, including INVANZ, and may range in severity from mild to life threatening. For additional information, please refer to the prescribing information. About INVANZ INVANZ, a carbapenem related to the class of antibiotics known as beta-lactams, is generally given to adults as a 1-gram dose, once-a-day, by intravenous infusion or intramuscular injection. Dosage adjustment of INVANZ is required in patients with reduced renal function (creatinine clearance = 30 mL/min/1.73m2). In addition to the new indication, INVANZ is also indicated for the treatment of adults and pediatric patients over three months of age for the following moderate to severe infections caused by susceptible isolates of the designated pathogens: Complicated intra-abdominal infections: Due to Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis. Complicated skin and skin structure infections including diabetic foot infections without osteomyelitis: Due to Staphylococcus aureus (methicillin susceptible isolates only), Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis, Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotella bivia. Invanz has not been studied in diabetic foot infections with concomitant osteomyelitis. Community-acquired pneumonia: Due to Streptococcus pneumoniae (penicillin susceptible isolates only) including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates only), or Moraxella catarrhalis. Complicated urinary tract infections, including pyelonephritis (kidney infections): Due to Escherichia coli, including cases with concurrent bacteremia, or Klebsiella pneumoniae. And acute pelvic infections, including postpartum endomyometritis, septic abortion and post-surgical gynecologic infections: Due to Streptococcus agalactiae, Escherichia coli, Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus species, or Prevotella bivia. Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to ertapenem. Therapy with INVANZ may be initiated empirically before results of these tests are known; once results become available, antimicrobial therapy should be adjusted accordingly. To reduce the development of drug-resistant bacteria and maintain the effectiveness of INVANZ and other antibacterial drugs, INVANZ 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. Seizures and other central nervous system (CNS) adverse experiences have been reported during treatment with INVANZ. During clinical investigations in adult patients treated with INVANZ (1 g once a day), seizures, irrespective of drug relationship, occurred in 0.5 percent of patients during study therapy plus 14-day follow-up period. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function. Close adherence to the recommended dosage regimen is urged, especially in patients with known factors that predispose to convulsive activity. About Merck Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also published unbiased health information as a not-for-profit service. For more information, visit www.merck.com. Forward-looking statement This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference. Full prescribing information for INVANZ is attached. INVANZ is a registered trademark of Merck & Co., Inc. INVANZ(R) 9709701(ERTAPENEM FOR INJECTION) To reduce the development of drug-resistant bacteria and maintainthe effectiveness of INVANZ and other antibacterial drugs, INVANZshould be used only to treat or prevent infections that are proven orstrongly suspected to be caused by bacteria. For Intravenous or Intramuscular Use DESCRIPTION INVANZ** (Ertapenem for Injection) is a sterile, synthetic,parenteral, 1-(beta) methyl-carbapenem that is structurally related tobeta-lactam antibiotics. Chemically, INVANZ is described as(4R-(3(3S*,5S*),4(alpha),5(beta),6(beta)(R*)))-3-((5-(((3-carboxyphenyl)amino)carbonyl)-3-pyrrolidinyl)thio)-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylicacid monosodium salt. Its molecular weight is 497.50. The empiricalformula is C22H24N3O7SNa, and its structural formula is: (GRAPHIC OMITTED) Ertapenem sodium is a white to off-white hygroscopic, weaklycrystalline powder. It is soluble in water and 0.9% sodium chloridesolution, practically insoluble in ethanol, and insoluble in isopropylacetate and tetrahydrofuran. INVANZ is supplied as sterile lyophilized powder for intravenousinfusion after reconstitution with appropriate diluent (see DOSAGE ANDADMINISTRATION, PREPARATION OF SOLUTION) and transfer to 50 mL 0.9%Sodium Chloride Injection or for intramuscular injection followingreconstitution with 1% lidocaine hydrochloride. Each vial contains1.046 grams ertapenem sodium, equivalent to 1 gram ertapenem. Thesodium content is approximately 137 mg (approximately 6.0 mEq). Each vial of INVANZ contains the following inactive ingredients:175 mg sodium bicarbonate and sodium hydroxide to adjust pH to 7.5. CLINICAL PHARMACOLOGY Pharmacokinetics Average plasma concentrations (mcg/mL) of ertapenem following asingle 30-minute infusion of a 1 g intravenous (IV) dose andadministration of a single 1 g intramuscular (IM) dose in healthyyoung adults are presented in Table 1. Table 1 Plasma Concentrations of Ertapenem in Adults After Single Dose Administration---------------------------------------------------------------------- Average Plasma Concentrations (mcg/mL)Dose/Route 0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 18 hr 24 hr---------------------------------------------------------------------- 1 g IV* 155 115 83 48 31 20 9 3 1 1 g IM 33 53 67 57 40 27 13 4 2----------------------------------------------------------------------*Infused at a constant rate over 30 minutes---------------------------------------------------------------------- The area under the plasma concentration-time curve (AUC) ofertapenem in adults increased less-than dose-proportional based ontotal ertapenem concentrations over the 0.5 to 2 g dose range, whereasthe AUC increased greater-than dose proportional based on unboundertapenem concentrations. Ertapenem exhibits non-linearpharmacokinetics due to concentration-dependent plasma protein bindingat the proposed therapeutic dose. (See CLINICAL PHARMACOLOGY,Distribution.) There is no accumulation of ertapenem following multiple IV or IM1 g daily doses in healthy adults. Average plasma concentrations (mcg/mL) of ertapenem in pediatricpatients are presented in Table 2. Table 2Plasma Concentrations of Ertapenem in Pediatric Patients After Single IV* Dose Administration----------------------------------------------------------------------Age Group Dose Average Plasma Concentrations (mcg/mL)---------------------------------------------------------------------- 0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 24 hr----------------------------------------------------------------------3 to 23 months 15 mg/kg+ 103.8 57.3 43.6 23.7 13.5 8.2 2.5 - 20 mg/kg+ 126.8 87.6 58.7 28.4 - 12.0 3.4 0.4 40 mg/kg++ 199.1 144.1 95.7 58.0 - 20.2 7.7 0.6----------------------------------------------------------------------2 to 12 years 15 mg/kg+ 113.2 63.9 42.1 21.9 12.8 7.6 3.0 - 20 mg/kg+ 147.6 97.6 63.2 34.5 - 12.3 4.9 0.5 40 mg/kg++ 241.7 152.7 96.3 55.6 - 18.8 7.2 0.6----------------------------------------------------------------------13 to 17 years 20 mg/kg+ 170.4 98.3 67.8 40.4 - 16.0 7.0 1.1 1 g ss. 155.9 110.9 74.8 - 24.0 - 6.2 - 40 mg/kg++ 255.0 188.7 127.9 76.2 - 31.0 15.3 2.1----------------------------------------------------------------------* Infused at a constant rate over 30 minutes+ up to a maximum dose of 1 g/day++ up to a maximum dose of 2 g/dayss. Based on three patients receiving 1 g ertapenem who volunteered for pharmacokinetic assessment in one of the two safety and efficacy studies---------------------------------------------------------------------- Absorption Ertapenem, reconstituted with 1% lidocaine HCl injection, USP (insaline without epinephrine), is almost completely absorbed followingintramuscular (IM) administration at the recommended dose of 1 g. Themean bioavailability is approximately 90%. Following 1 g daily IMadministration, mean peak plasma concentrations (Cmax) are achieved inapproximately 2.3 hours (Tmax). Distribution Ertapenem is highly bound to human plasma proteins, primarilyalbumin. In healthy young adults, the protein binding of ertapenemdecreases as plasma concentrations increase, from approximately 95%bound at an approximate plasma concentration of lessthan 100 micrograms (mcg)/mL to approximately 85% bound at anapproximate plasma concentration of 300 mcg/mL. The apparent volume of distribution at steady state (Vss) ofertapenem in adults is approximately 0.12 liter/kg, approximately0.2 liter/kg in pediatric patients 3 months to 12 years of age andapproximately 0.16 liter/kg in pediatric patients 13 to 17 years ofage. The concentrations of ertapenem achieved in suction-induced skinblister fluid at each sampling point on the third day of 1 g oncedaily IV doses are presented in Table 3. The ratio of AUC0-24 in skinblister fluid/AUC0-24 in plasma is 0.61. Table 3Concentrations (mcg/mL) of Ertapenem in Adult Skin Blister Fluid at each Sampling Point on the Third Day of 1-g Once Daily IV Doses---------------------------------------------0.5 hr 1 hr 2 hr 4 hr 8 hr 12 hr 24 hr--------------------------------------------- 7 12 17 24 24 21 8 The concentration of ertapenem in breast milk from 5 lactatingwomen with pelvic infections (5 to 14 days postpartum) was measured atrandom time points daily for 5 consecutive days following the last 1 gdose of intravenous therapy (3-10 days of therapy). The concentrationof ertapenem in breast milk within 24 hours of the last dose oftherapy in all 5 women ranged from less than 0.13 (lower limit ofquantitation) to 0.38 mcg/mL; peak concentrations were not assessed.By day 5 after discontinuation of therapy, the level of ertapenem wasundetectable in the breast milk of 4 women and below the lower limitof quantitation (less than 0.13 mcg/mL) in 1 woman. Metabolism In healthy young adults, after infusion of 1 g IV radiolabeledertapenem, the plasma radioactivity consists predominantly (94%) ofertapenem. The major metabolite of ertapenem is the inactivering-opened derivative formed by hydrolysis of the beta-lactam ring. In vitro studies in human liver microsomes indicate that ertapenemdoes not inhibit metabolism mediated by any of the followingcytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. (SeeDRUG INTERACTIONS.) In vitro studies indicate that ertapenem does not inhibitP-glycoprotein-mediated transport of digoxin or vinblastine and thatertapenem is not a substrate for P-glycoprotein-mediated transport.(See PRECAUTIONS, Drug Interactions.) Elimination Ertapenem is eliminated primarily by the kidneys. The mean plasmahalf-life in healthy young adults is approximately 4 hours and theplasma clearance is approximately 1.8 L/hour. The mean plasmahalf-life in pediatric patients 13 to 17 years of age is approximately4 hours and approximately 2.5 hours in pediatric patients 3 months to12 years of age. Following the administration of 1 g IV radiolabeled ertapenem tohealthy young adults, approximately 80% is recovered in urine and 10%in feces. Of the 80% recovered in urine, approximately 38% is excretedas unchanged drug and approximately 37% as the ring-opened metabolite. In healthy young adults given a 1 g IV dose, the mean percentageof the administered dose excreted in urine was 17.4% during 0-2 hourspostdose, 5.4% during 4-6 hours postdose, and 2.4% during 12-24 hourspostdose. Special Populations Renal Insufficiency Total and unbound fractions of ertapenem pharmacokinetics wereinvestigated in 26 adult subjects (31 to 80 years of age) with varyingdegrees of renal impairment. Following a single 1 g IV dose ofertapenem, the unbound AUC increased 1.5-fold and 2.3-fold in subjectswith mild renal insufficiency (CLCR 60-90 mL/min/1.73 m2) and moderaterenal insufficiency (CLCR 31-59 mL/min/1.73 m2), respectively,compared with healthy young subjects (25 to 45 years of age). Nodosage adjustment is necessary in patients with CLCR (greaterthan=)31 mL/min/1.73 m2. The unbound AUC increased 4.4-fold and7.6-fold in subjects with advanced renal insufficiency (CLCR5-30 mL/min/1.73 m2) and end-stage renal insufficiency (CLCR lessthan 10 mL/min/1.73 m2), respectively, compared with healthy youngsubjects. The effects of renal insufficiency on AUC of total drug wereof smaller magnitude. The recommended dose of ertapenem in adultpatients with CLCR (less than=)30 mL/min/1.73 m2 is 0.5 grams every 24hours. Following a single 1 g IV dose given immediately prior to a 4hour hemodialysis session in 5 adult patients with end-stage renalinsufficiency, approximately 30% of the dose was recovered in thedialysate. A supplementary dose of 150 mg is recommended if ertapenemis administered within 6 hours prior to hemodialysis. (See DOSAGE ANDADMINISTRATION.) There are no data in pediatric patients with renalinsufficiency. Hepatic Insufficiency The pharmacokinetics of ertapenem in patients with hepaticinsufficiency have not been established. However, ertapenem does notappear to undergo hepatic metabolism based on in vitro studies andapproximately 10% of an administered dose is recovered in the feces.(See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) Gender The effect of gender on the pharmacokinetics of ertapenem wasevaluated in healthy male (n=8) and healthy female (n=8) subjects. Thedifferences observed could be attributed to body size when body weightwas taken into consideration. No dose adjustment is recommended basedon gender. Geriatric Patients The impact of age on the pharmacokinetics of ertapenem wasevaluated in healthy male (n=7) and healthy female (n=7) subjects(greater than=)65 years of age. The total and unbound AUC increased37% and 67%, respectively, in elderly adults relative to young adults.These changes were attributed to age-related changes in creatinineclearance. No dosage adjustment is necessary for elderly patients withnormal (for their age) renal function. Pediatric Patients Plasma concentrations of ertapenem are comparable in pediatricpatients 13 to 17 years of age and adults following a 1 g once dailyIV dose. Following the 20 mg/kg dose (up to a maximum dose of 1 g), thepharmacokinetic parameter values in patients 13 to 17 years of age(N=6) were generally comparable to those in healthy young adults. Plasma concentrations at the midpoint of the dosing intervalfollowing a single 15 mg/kg IV dose of ertapenem in patients 3 monthsto 12 years of age are comparable to plasma concentrations at themidpoint of the dosing interval following a 1 g once daily IV dose inadults (see Pharmacokinetics). The plasma clearance (mL/min/kg) ofertapenem in patients 3 months to 12 years of age is approximately2-fold higher as compared to that in adults. At the 15 mg/kg dose, theAUC value (doubled to model a twice daily dosing regimen, i.e., 30mg/kg/day exposure) in patients 3 months to 12 years of age wascomparable to the AUC value in young healthy adults receiving a 1 g IVdose of ertapenem. Microbiology Ertapenem has in vitro activity against gram-positive andgram-negative aerobic and anaerobic bacteria. The bactericidalactivity of ertapenem results from the inhibition of cell wallsynthesis and is mediated through ertapenem binding to penicillinbinding proteins (PBPs). In Escherichia coli, it has strong affinitytoward PBPs 1a, 1b, 2, 3, 4 and 5 with preference for PBPs 2 and 3.Ertapenem is stable against hydrolysis by a variety ofbeta-lactamases, including penicillinases, and cephalosporinases andextended spectrum beta-lactamases. Ertapenem is hydrolyzed bymetallo-beta-lactamases. Ertapenem has been shown to be active against most isolates of thefollowing microorganisms in vitro and in clinical infections. (SeeINDICATIONS AND USAGE): Aerobic and facultative gram-positive microorganisms: Staphylococcus aureus (methicillin susceptible isolates only) Streptococcus agalactiae Streptococcus pneumoniae (penicillin susceptible isolates only) Streptococcus pyogenes Note: Methicillin-resistant staphylococci and Enterococcus spp.are resistant to ertapenem. Aerobic and facultative gram-negative microorganisms: Escherichia coli Haemophilus influenzae (Beta-lactamase negative isolates only) Klebsiella pneumoniae Moraxella catarrhalis Proteus mirabilis Anaerobic microorganisms: Bacteroides fragilis Bacteroides distasonis Bacteroides ovatus Bacteroides thetaiotaomicron Bacteroides uniformis Clostridium clostridioforme Eubacterium lentum Peptostreptococcus species Porphyromonas asaccharolytica Prevotella bivia The following in vitro data are available, but their clinicalsignificance is unknown. At least 90% of the following microorganisms exhibit an in vitrominimum inhibitory concentration (MIC) less than or equal to thesusceptible breakpoint for ertapenem; however, the safety andeffectiveness of ertapenem in treating clinical infections due tothese microorganisms have not been established in adequate andwell-controlled clinical studies: Aerobic and facultative gram-positive microorganisms: Staphylococcus epidermidis (methicillin susceptible isolates only) Streptococcus pneumoniae (penicillin-intermediate isolates only) Aerobic and facultative gram-negative microorganisms: Citrobacter freundii Citrobacter koseri Enterobacter aerogenes Enterobacter cloacae Haemophilus influenzae (Beta-lactamase positive isolates) Haemophilus parainfluenzae Klebsiella oxytoca (excluding ESBL producing isolates) Morganella morganii Proteus vulgaris Providencia rettgeri Providencia stuartii Serratia marcescens Anaerobic microorganisms: Bacteroides vulgatus Clostridium perfringens Fusobacterium spp. Susceptibility Test Methods: When available, the results of in vitro susceptibility testsshould be provided to the physician as periodic reports which describethe susceptibility profile of nosocomial and community-acquiredpathogens. These reports should aid the physician in selecting themost effective antimicrobial. Dilution Techniques: Quantitative methods are used to determine antimicrobial minimuminhibitory concentrations (MICs). These MICs provide estimates of thesusceptibility of bacteria to antimicrobial compounds. The MICs shouldbe determined using a standardized procedure. Standardized proceduresare based on a broth dilution method(1,2) or equivalent withstandardized inoculum concentrations and standardized concentrationsof ertapenem powder. The MIC values should be interpreted according tocriteria provided in Table 4. Diffusion Techniques: Quantitative methods that require measurement of zone diametersalso provide reproducible estimates of the susceptibility of bacteriato antimicrobial compounds. One such standardized procedure(2,3)requires the use of standardized inoculum concentrations. Thisprocedure uses paper disks impregnated with 10-(mu)g ertapenem to testthe susceptibility of microorganisms to ertapenem. The disk diffusioninterpretive criteria should be interpreted according to criteriaprovided in Table 4. Anaerobic Techniques: For anaerobic bacteria, the susceptibility to ertapenem as MICscan be determined by standardized test methods(4). The MIC valuesobtained should be interpreted according to criteria provided in Table4. Table 4 Susceptibility Interpretive Criteria for Ertapenem----------------------------------------------------------------------Pathogen Minimum Inhibitory Disk Diffusion(a) Concentrations(a) Zone Diameter (mm) MIC ( (mu)g/mL)---------------------------------------------------------------------- S I R S I R----------------------------------------------------------------------Enterobacteriaceae (less (greater (greater (less and than=)2.0 than=)8.0 than=)19 than=)15Staphylococcus spp. 4.0 16-18----------------------------------------------------------------------Haemophilus spp. (less (greater than=)0.5 - - than=)19 - -----------------------------------------------------------------------Streptococcus (less (greater pneumoniae (b,c) than=)1.0 - - than=)19 - -----------------------------------------------------------------------Streptococcus spp. (less (greater other than than=)1.0 than=)19 Streptococcus pneumoniae(d,e) - - - -----------------------------------------------------------------------Anaerobes (less (greater than=)4.08.0 than=)16.0 - - -----------------------------------------------------------------------(a) The current absence of data in resistant isolates precludes defining any results other than "Susceptible". Isolates yielding MIC results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.(b) Streptococcus pneumoniae that are susceptible to penicillin (penicillin MIC (less than=)0.06 (mu)g/mL) can be considered susceptible to ertapenem. Testing of ertapenem against penicillin- intermediate or penicillin-resistant isolates is not recommended since reliable interpretive criteria for ertapenem are not available.(c) Streptococcus pneumoniae that are susceptible to penicillin (1- (mu)g oxacillin disk zone diameter (greater than=)20 mm), can be considered susceptible to ertapenem. Isolates with 1-(mu)g oxacillin zone diameter (less than=)19 mm should be tested against ertapenem using an MIC method.(d) Streptococcus spp. other than Streptococcus pneumoniae that are susceptible to penicillin (MIC (less than=)0.12 (mu)g/mL) can be considered susceptible to ertapenem. Testing of ertapenem against penicillin-intermediate or penicillin-resistant isolates is not recommended since reliable interpretive criteria for ertapenem are not available.(e) Streptococcus spp. other than Streptococcus pneumoniae that are susceptible to penicillin (10-units penicillin disk zone diameter (greater than=)24 mm), can be considered susceptible to ertapenem. Isolates with 10-units penicillin disk zone diameter less than 24 mm should be tested against ertapenem using an MIC method. Penicillin disk diffusion interpretive criteria are not available for viridans group streptococci and they should not be tested against ertapenem.---------------------------------------------------------------------- Note: Staphylococcus spp. can be considered susceptible toertapenem if the penicillin MIC is (less than=)0.12 (mu)g/mL. If thepenicillin MIC is greater than 0.12 (mu)g/mL, then test oxacillin.Staphylococcus aureus can be considered susceptible to ertapenem ifthe oxacillin MIC is (less than=)2.0 (mu)g/mL and resistant toertapenem if the oxacillin MIC is (greater than=)4.0 (mu)g/mL.Coagulase negative staphylococci can be considered susceptible toertapenem if the oxacillin MIC is (less than=)0.25 (mu)g/mL andresistant to ertapenem if the oxacillin MIC (greaterthan=)0.5 (mu)g/mL. Staphylococcus spp. can be considered susceptible to ertapenem ifthe penicillin (10 U disk) zone is (greater than=)29 mm. If thepenicillin zone is (less than=)28 mm, then test oxacillin by diskdiffusion (1 (mu)g disk). Staphylococcus aureus can be consideredsusceptible to ertapenem if the oxacillin (1 (mu)g disk) zone is(greater than=)13 mm and resistant to ertapenem if the oxacillin zoneis (less than=)10 mm. Coagulase negative staphylococci can beconsidered susceptible to ertapenem if the oxacillin zone is (greaterthan=)18 mm and resistant to ertapenem if the oxacillin (1 (mu)g disk)zone is (less than=)17 mm. A report of "Susceptible" indicates that the pathogen is likely tobe inhibited if the antimicrobial compound in blood reaches theconcentrations usually achievable. A report of "Intermediate"indicates that the result should be considered equivocal, and, if themicroorganism is not fully susceptible to alternative, clinicallyfeasible drugs, the test should be repeated. This category impliespossible clinical applicability in body sites where the drug isphysiologically concentrated or in situations where high dosage ofdrug can be used. This category also provides a buffer zone whichprevents small uncontrolled technical factors from causing majordiscrepancies in interpretation. A report of "Resistant" indicatesthat the pathogen is not likely to be inhibited if the antimicrobialcompound in the blood reaches the concentrations usually achievable;other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use oflaboratory control microorganisms to control the technical aspects ofthe laboratory procedures(1,2,3,4). Quality control microorganisms arespecific strains of organisms with intrinsic biological properties. QCstrains are very stable strains which will give a standard andrepeatable susceptibility pattern. The specific strains used formicrobiological quality control are not clinically significant.Standard ertapenem powder should provide the following range of valuesnoted in Table 5. Table 5 Acceptable Quality Control Ranges for Ertapenem----------------------------------------------------------------------Microorganism Minimum Disk Inhibitory Diffusion Concentrations Zone MIC Range Diameter ((mu)g/mL) (mm)----------------------------------------------------------------------Escherichia coli ATCC 25922 0.004-0.016 29-36----------------------------------------------------------------------Haemophilus influenzae ATCC 49766 0.016-0.06 27-33----------------------------------------------------------------------Staphylococcus aureus ATCC 29213 0.06-0.25 -----------------------------------------------------------------------Staphylococcus aureus ATCC 25923 - 24-31----------------------------------------------------------------------Streptococcus pneumoniae ATCC 49619 0.03-0.25 28-35----------------------------------------------------------------------Bacteroides fragilis ATCC 25285 0.06-0.5(f) 0.06-0.25(g) -----------------------------------------------------------------------Bacteroides thetaiotaomicron ATCC 29741 0.5-2.0(f) 0.25-1.0(g) -----------------------------------------------------------------------Eubacterium lentum ATCC 43055 0.5-4.0(f) 0.5-2.0(g) -----------------------------------------------------------------------(f) Quality control ranges for broth microdilution testing(g) Quality control ranges for agar microdilution testing---------------------------------------------------------------------- INDICATIONS AND USAGE Treatment INVANZ is indicated for the treatment of patients with thefollowing moderate to severe infections caused by susceptible isolatesof the designated microorganisms. (See DOSAGE AND ADMINISTRATION): Complicated Intra-abdominal Infections due to Escherichia coli,Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcusspecies, Bacteroides fragilis, Bacteroides distasonis, Bacteroidesovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis. Complicated Skin and Skin Structure Infections, including diabeticfoot infections without osteomyelitis due to Staphylococcus aureus(methicillin susceptible isolates only), Streptococcus agalactiae,Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae,Proteus mirabilis, Bacteroides fragilis, Peptostreptococcus species,Porphyromonas asaccharolytica, or Prevotella bivia. INVANZ has notbeen studied in diabetic foot infections with concomitantosteomyelitis (see CLINICAL STUDIES). Community Acquired Pneumonia due to Streptococcus pneumoniae(penicillin susceptible isolates only) including cases with concurrentbacteremia, Haemophilus influenzae (beta-lactamase negative isolatesonly), or Moraxella catarrhalis. Complicated Urinary Tract Infections including pyelonephritis dueto Escherichia coli, including cases with concurrent bacteremia, orKlebsiella pneumoniae. Acute Pelvic Infections including postpartum endomyometritis,septic abortion and post surgical gynecologic infections due toStreptococcus agalactiae, Escherichia coli, Bacteroides fragilis,Porphyromonas asaccharolytica, Peptostreptococcus species, orPrevotella bivia. Prevention INVANZ is indicated in adults for the prophylaxis of surgical siteinfection following elective colorectal surgery. Appropriate specimens for bacteriological examination should beobtained in order to isolate and identify the causative organisms andto determine their susceptibility to ertapenem. Therapy with INVANZ(ertapenem) may be initiated empirically before results of these testsare known; once results become available, antimicrobial therapy shouldbe adjusted accordingly. To reduce the development of drug-resistant bacteria and maintainthe effectiveness of INVANZ and other antibacterial drugs, INVANZshould be used only to treat or prevent infections that are proven orstrongly suspected to be caused by susceptible bacteria. When cultureand susceptibility information are available, they should beconsidered in selecting or modifying antibacterial therapy. In theabsence of such data, local epidemiology and susceptibility patternsmay contribute to the empiric selection of therapy. CONTRAINDICATIONS INVANZ is contraindicated in patients with known hypersensitivityto any component of this product or to other drugs in the same classor in patients who have demonstrated anaphylactic reactions tobeta-lactams. Due to the use of lidocaine HCl as a diluent, INVANZ administeredintramuscularly is contraindicated in patients with a knownhypersensitivity to local anesthetics of the amide type. (Refer to theprescribing information for lidocaine HCl.) WARNINGS SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC)REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITHBETA-LACTAMS. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALSWITH A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEENREPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITYWHO HAVE EXPERIENCED SEVERE HYPERSENSITIVITY REACTIONS WHEN TREATEDWITH ANOTHER BETA-LACTAM. BEFORE INITIATING THERAPY WITH INVANZ,CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITYREACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS AND OTHERALLERGENS. IF AN ALLERGIC REACTION TO INVANZ OCCURS, DISCONTINUE THEDRUG IMMEDIATELY. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATEEMERGENCY TREATMENT WITH EPINEPHRINE, OXYGEN, INTRAVENOUS STEROIDS,AND AIRWAY MANAGEMENT, INCLUDING INTUBATION. OTHER THERAPY MAY ALSO BEADMINISTERED AS INDICATED. Seizures and other CNS adverse experiences have been reportedduring treatment with INVANZ. (See PRECAUTIONS and ADVERSE REACTIONS.) Pseudomembranous colitis has been reported with nearly allantibacterial agents, including ertapenem, and may range in severityfrom mild to life-threatening. Therefore, it is important to considerthis diagnosis in patients who present with diarrhea subsequent to theadministration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of thecolon and may permit overgrowth of clostridia. Studies indicate that atoxin produced by Clostridium difficile is a primary cause of"antibiotic-associated colitis". After the diagnosis of pseudomembranous colitis has beenestablished, therapeutic measures should be initiated. Mild cases ofpseudomembranous colitis usually respond to drug discontinuationalone. In moderate to severe cases, consideration should be given tomanagement with fluids and electrolytes, protein supplementation andtreatment with an antibacterial drug clinically effective againstClostridium difficile colitis. Lidocaine HCl is the diluent for intramuscular administration ofINVANZ. Refer to the prescribing information for lidocaine HCl. PRECAUTIONS General During clinical investigations in adult patients treated withINVANZ (1 g once a day), seizures, irrespective of drug relationship,occurred in 0.5% of patients during study therapy plus 14-dayfollow-up period. (See ADVERSE REACTIONS.) These experiences haveoccurred most commonly in patients with CNS disorders (e.g., brainlesions or history of seizures) and/or compromised renal function.Close adherence to the recommended dosage regimen is urged, especiallyin patients with known factors that predispose to convulsive activity.Anticonvulsant therapy should be continued in patients with knownseizure disorders. If focal tremors, myoclonus, or seizures occur,patients should be evaluated neurologically, placed on anticonvulsanttherapy if not already instituted, and the dosage of INVANZre-examined to determine whether it should be decreased or theantibiotic discontinued. Dosage adjustment of INVANZ is recommended inpatients with reduced renal function. (See DOSAGE AND ADMINISTRATION.) As with other antibiotics, prolonged use of INVANZ may result inovergrowth of non-susceptible organisms. Repeated evaluation of thepatient's condition is essential. If superinfection occurs duringtherapy, appropriate measures should be taken. Prescribing INVANZ in the absence of a proven or stronglysuspected bacterial infection or a prophylactic indication is unlikelyto provide benefit to the patient and increases the risk of thedevelopment of drug-resistant bacteria. Caution should be taken when administering INVANZ intramuscularlyto avoid inadvertent injection into a blood vessel. (See DOSAGE ANDADMINISTRATION.) Lidocaine HCl is the diluent for intramuscular administration ofINVANZ. Refer to the prescribing information for lidocaine HCl foradditional precautions. Information for patients Patients should be counseled that antibacterial drugs includingINVANZ should only be used to treat bacterial infections. They do nottreat viral infections (e.g., the common cold). When INVANZ isprescribed to treat a bacterial infection, patients should be toldthat although it is common to feel better early in the course oftherapy, the medication should be taken exactly as directed. Skippingdoses or not completing the full course of therapy may (1) decreasethe effectiveness of the immediate treatment and (2) increase thelikelihood that bacteria will develop resistance and will not betreatable by INVANZ or other antibacterial drugs in the future. Laboratory Tests While INVANZ possesses toxicity similar to the beta-lactam groupof antibiotics, periodic assessment of organ system function,including renal, hepatic, and hematopoietic, is advisable duringprolonged therapy. Drug Interactions When ertapenem is co-administered with probenecid (500 mg p.o.every 6 hours), probenecid competes for active tubular secretion andreduces the renal clearance of ertapenem. Based on total ertapenemconcentrations, probenecid increased the AUC by 25% and reduced theplasma and renal clearances by 20% and 35%, respectively. Thehalf-life increased from 4.0 to 4.8 hours. Because of the small effecton half-life, the coadministration with probenecid to extend thehalf-life of ertapenem is not recommended. In vitro studies indicate that ertapenem does not inhibitP-glycoprotein-mediated transport of digoxin or vinblastine and thatertapenem is not a substrate for P-glycoprotein-mediated transport. Invitro studies in human liver microsomes indicate that ertapenem doesnot inhibit metabolism mediated by any of the following six cytochromep450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. Druginteractions caused by inhibition of P-glycoprotein-mediated drugclearance or CYP-mediated drug clearance with the listed isoforms areunlikely. (See CLINICAL PHARMACOLOGY, Distribution and Metabolism.) Other than with probenecid, no specific clinical drug interactionstudies have been conducted. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluatethe carcinogenic potential of ertapenem. Ertapenem was neither mutagenic nor genotoxic in the following invitro assays: alkaline elution/rat hepatocyte assay, chromosomalaberration assay in Chinese hamster ovary cells, and TK6 humanlymphoblastoid cell mutagenesis assay; and in the in vivo mousemicronucleus assay. In mice and rats, IV doses of up to 700 mg/kg/day (for mice,approximately 3 times the recommended human dose of 1 g based on bodysurface area and for rats, approximately 1.2 times the human exposureat the recommended dose of 1 g based on plasma AUCs) resulted in noeffects on mating performance, fecundity, fertility, or embryonicsurvival. Pregnancy: Teratogenic Effects Pregnancy Category B: In mice and rats given IV doses of up to700 mg/kg/day (for mice, approximately 3 times the recommended humandose of 1 g based on body surface area and for rats, approximately 1.2times the human exposure at the recommended dose of 1 g based onplasma AUCs), there was no evidence of developmental toxicity asassessed by external, visceral, and skeletal examination of thefetuses. However, in mice given 700 mg/kg/day, slight decreases inaverage fetal weights and an associated decrease in the average numberof ossified sacrocaudal vertebrae were observed. Ertapenem crosses theplacental barrier in rats. There are, however, no adequate and well-controlled studies inpregnant women. Because animal reproduction studies are not alwayspredictive of human response, this drug should be used duringpregnancy only if clearly needed. Nursing Mothers Ertapenem is excreted in human breast milk. (See CLINICALPHARMACOLOGY, Distribution.) Caution should be exercised when INVANZis administered to a nursing woman. INVANZ should be administered tonursing mothers only when the expected benefit outweighs the risk. Labor and delivery INVANZ has not been studied for use during labor and delivery. Pediatric Use Safety and effectiveness of INVANZ in pediatric patients 3 monthsto 17 years of age are supported by evidence from adequate andwell-controlled studies in adults, pharmacokinetic data in pediatricpatients, and additional data from comparator-controlled studies inpediatric patients 3 months to 17 years of age with the followinginfections (see INDICATIONS AND USAGE and CLINICAL STUDIES): -- Complicated Intra-abdominal Infections -- Complicated Skin and Skin Structure Infections -- Community Acquired Pneumonia -- Complicated Urinary Tract Infections -- Acute Pelvic Infections INVANZ is not recommended in infants under 3 months of age as nodata are available. INVANZ is not recommended in the treatment of meningitis in thepediatric population due to lack of sufficient CSF penetration. Geriatric Use Of the 1,835 patients in Phase IIb/III studies treated withINVANZ, approximately 26 percent were 65 and over, while approximately12 percent were 75 and over. No overall differences in safety oreffectiveness were observed between these patients and youngerpatients. Other reported clinical experience has not identifieddifferences in responses between the elderly and younger patients, butgreater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, andthe risk of toxic reactions to this drug may be greater in patientswith impaired renal function. Because elderly patients are more likelyto have decreased renal function, care should be taken in doseselection, and it may be useful to monitor renal function. (See DOSAGEAND ADMINISTRATION.) Hepatic Insufficiency The pharmacokinetics of ertapenem in patients with hepaticinsufficiency have not been established. Of the total number ofpatients in clinical studies, 37 patients receiving ertapenem 1 gdaily and 36 patients receiving comparator drugs were considered tohave Child-Pugh Class A, B, or C liver impairment. The incidence ofadverse experiences in patients with hepatic impairment was similarbetween the ertapenem group and the comparator groups. ANIMAL PHARMACOLOGY In repeat-dose studies in rats, treatment-related neutropeniaoccurred at every dose-level tested, including the lowest dose of2 mg/kg (approximately 2% of the human dose on a body surface areabasis). Studies in rabbits and Rhesus monkeys were inconclusive withregard to the effect on neutrophil counts. ADVERSE REACTIONS Adults Clinical studies enrolled 1954 patients treated with ertapenem; insome of the clinical studies, parenteral therapy was followed by aswitch to an appropriate oral antimicrobial. (See CLINICAL STUDIES.)Most adverse experiences reported in these clinical studies weredescribed as mild to moderate in severity. Ertapenem was discontinueddue to adverse experiences in 4.7% of patients. Table 6 shows theincidence of adverse experiences reported in (greater than=)1.0% ofpatients in these studies. The most common drug-related adverseexperiences in patients treated with INVANZ, including those who wereswitched to therapy with an oral antimicrobial, were diarrhea (5.5%),infused vein complication (3.7%), nausea (3.1%), headache (2.2%),vaginitis in females (2.1%), phlebitis/thrombophlebitis (1.3%), andvomiting (1.1%). Table 6 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in (greater than=)1.0% of Adult Patients Treated With INVANZ in Clinical Studies---------------------------------------------------------------------- Piperacillin/ INVANZ* Tazobactam* INVANZ+ Ceftriaxone+ 1 g 3.375 g q6h 1 g 1 or 2 g Adverse Events daily (N=774) daily daily (N=802) (N=1152) (N=942)----------------------------------------------------------------------Local: Extravasation 1.9 1.7 0.7 1.1 Infused vein complication 7.1 7.9 5.4 6.7 Phlebitis/thrombophlebitis 1.9 2.7 1.6 2.0----------------------------------------------------------------------Systemic: Asthenia/fatigue 1.2 0.9 1.2 1.1 Death 2.5 1.6 1.3 1.6 Edema/swelling 3.4 2.5 2.9 3.3 Fever 5.0 6.6 2.3 3.4 Abdominal pain 3.6 4.8 4.3 3.9 Chest pain 1.5 1.4 1.0 2.5 Hypertension 1.6 1.4 0.7 1.0 Hypotension 2.0 1.4 1.0 1.2 Tachycardia 1.6 1.3 1.3 0.7 Acid regurgitation 1.6 0.9 1.1 0.6 Oral candidiasis 0.1 1.3 1.4 1.9 Constipation 4.0 5.4 3.3 3.1 Diarrhea 10.3 12.1 9.2 9.8 Dyspepsia 1.1 0.6 1.0 1.6 Nausea 8.5 8.7 6.4 7.4 Vomiting 3.7 5.3 4.0 4.0 Leg pain 1.1 0.5 0.4 0.3 Anxiety 1.4 1.3 0.8 1.2 Altered mental status++ 5.1 3.4 3.3 2.5 Dizziness 2.1 3.0 1.5 2.1 Headache 5.6 5.4 6.8 6.9 Insomnia 3.2 5.2 3.0 4.1 Cough 1.6 1.7 1.3 0.5 Dyspnea 2.6 1.8 1.0 2.4 Pharyngitis 0.7 1.4 1.1 0.6 Rales/rhonchi 1.1 1.0 0.5 1.0 Respiratory distress 1.0 0.4 0.2 0.2 Erythema 1.6 1.7 1.2 1.2 Pruritus 2.0 2.6 1.0 1.9 Rash 2.5 3.1 2.3 1.5 Vaginitis 1.4 1.0 3.3 3.7----------------------------------------------------------------------* Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute pelvic infections studies+ Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa studies++ Includes agitation, confusion, disorientation, decreased mental acuity, changed mental status, somnolence, stupor---------------------------------------------------------------------- In patients treated for complicated intra-abdominal infections,death occurred in 4.7% (15/316) of patients receiving ertapenem and2.6% (8/307) of patients receiving comparator drug. These deathsoccurred in patients with significant co-morbidity and/or severebaseline infections. Deaths were considered unrelated to study drugsby investigators. In clinical studies, seizure was reported during study therapyplus 14-day follow-up period in 0.5% of patients treated withertapenem, 0.3% of patients treated with piperacillin/tazobactam and0% of patients treated with ceftriaxone. (See PRECAUTIONS.) Additional adverse experiences that were reported with INVANZ withan incidence greater than 0.1% within each body system are listedbelow: Body as a whole: abdominal distention, pain, chills, septicemia,septic shock, dehydration, gout, malaise, necrosis, candidiasis,weight loss, facial edema, injection site induration, injection sitepain, flank pain, and syncope; Cardiovascular System: heart failure, hematoma, cardiac arrest,bradycardia, arrhythmia, atrial fibrillation, heart murmur,ventricular tachycardia, asystole, and subdural hemorrhage; Digestive System: gastrointestinal hemorrhage, anorexia,flatulence, C. difficile associated diarrhea, stomatitis, dysphagia,hemorrhoids, ileus, cholelithiasis, duodenitis, esophagitis,gastritis, jaundice, mouth ulcer, pancreatitis, and pyloric stenosis; Nervous System & Psychiatric: nervousness, seizure (see WARNINGSand PRECAUTIONS), tremor, depression, hypesthesia, spasm, paresthesia,aggressive behavior, and vertigo; Respiratory System: pleural effusion, hypoxemia,bronchoconstriction, pharyngeal discomfort, epistaxis, pleuritic pain,asthma, hemoptysis, hiccups, and voice disturbance; Skin & Skin Appendage: sweating, dermatitis, desquamation,flushing, and urticaria; Special Senses: taste perversion; Urogenital System: renal insufficiency, oliguria/anuria, vaginalpruritus, hematuria, urinary retention, bladder dysfunction, vaginalcandidiasis, and vulvovaginitis. In a clinical trial for the treatment of diabetic foot infectionsin which 289 adult diabetic patients were treated with ertapenem, theadverse experience profile was generally similar to that seen inprevious clinical trials. In a clinical study in adults for the prophylaxis of surgical siteinfection following elective colorectal surgery in which 476 patientsreceived a 1 g dose of ertapenem 1 hour prior to surgery and were thenfollowed for safety 14 days post surgery, the overall adverseexperience profile was generally comparable to that observed forertapenem in previous clinical trials. Table 7 shows the incidence ofadverse experiences other than those previously described above forertapenem, regardless of causality, reported in (greater than=)1.0% ofpatients in this study. Table 7 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in (greater than=)1.0% of Adult Patients Treated With INVANZ for Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery---------------------------------------------------------------------- INVANZ Cefotetan 1 g 2 g Adverse Events (N= 476) (N= 476)----------------------------------------------------------------------Anemia 5.7 6.9Small intestinal obstruction 2.1 1.9Cellulitis 1.5 1.5C. difficile infection or colitis 1.7 0.6Pneumonia 2.1 4.0Postoperative infection 2.3 4.0Urinary tract infection 3.8 5.5Wound infection 6.5 12.4Anastomotic leak 1.5 1.3Seroma 1.3 1.9Wound complication 2.9 2.3Wound dehiscence 1.3 1.5Wound secretion 1.9 2.1Dysuria 1.1 1.3Atelectasis 3.4 1.9---------------------------------------------------------------------- Additional adverse experiences that were reported in thisprophylaxis study with INVANZ, regardless of causality, with anincidence less than 1.0% and greater than 0.5% within each body systemare listed below: Gastrointestinal Disorders: dry mouth, hematochezia; General Disorders and Administration Site Condition: crepitations; Infections and Infestations: abdominal abscess, fungal rash,pelvic abscess; Injury, Poisoning and Procedural Complications: incision sitecomplication, incision site hemorrhage, intestinal stoma complication; Musculoskeletal and Connective Tissue Disorders: muscle spasms; Nervous System Disorders: cerebrovascular accident; Renal and Urinary Disorders: pollakiuria; Respiratory, Thoracic and Mediastinal Disorders: crackles lung,lung infiltration, pulmonary congestion, pulmonary embolism, wheezing. Pediatric Patients Clinical studies enrolled 384 patients treated with ertapenem; insome of the clinical studies, parenteral therapy was followed by aswitch to an appropriate oral antimicrobial. (See CLINICAL STUDIES.)The overall adverse experience profile in pediatric patients iscomparable to that in adult patients. Table 8 shows the incidence ofadverse experiences reported in (greater than=)1.0% of pediatricpatients in clinical studies. The most common drug-related adverseexperiences in pediatric patients treated with INVANZ, including thosewho were switched to therapy with an oral antimicrobial, were diarrhea(6.5%), infusion site pain (5.5%), infusion site erythema (2.6%),vomiting (2.1%). Table 8 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in (greater than=)1.0% of Pediatric Patients Treated With INVANZ in Clinical Studies---------------------------------------------------------------------- Ticarcillin/ INVANZ*+ Ceftriaxone* Clavulanate+Adverse Events (N=384) (N=100) (N=24)----------------------------------------------------------------------Local: Infusion Site Erythema 3.9 3.0 8.3 Infusion Site Induration 1.0 1.0 0.0 Infusion Site Pain 7.0 4.0 20.8 Infusion Site Phlebitis 1.8 3.0 0.0 Infusion Site Swelling 1.8 1.0 4.2 Infusion Site Warmth 1.3 1.0 4.2----------------------------------------------------------------------Systemic: Abdominal Pain 4.7 3.0 4.2 Upper Abdominal Pain 1.0 2.0 0.0 Constipation 2.3 0.0 0.0 Diarrhea 11.7 17.0 4.2 Loose Stools 2.1 0.0 0.0 Nausea 1.6 0.0 0.0 Vomiting 10.2 11.0 8.3 Pyrexia 4.9 6.0 8.3 Abdominal Abscess 1.0 0.0 4.2 Herpes Simplex 1.0 1.0 4.2 Nasopharyngitis 1.6 6.0 0.0 Upper Respiratory Tract Infection 2.3 3.0 0.0 Viral Pharyngitis 1.0 0.0 0.0 Hypothermia 1.6 1.0 0.0 Dizziness 1.6 0.0 0.0 Headache 4.4 4.0 0.0 Cough 4.4 3.0 0.0 Wheezing 1.0 0.0 0.0 Dermatitis 1.0 1.0 0.0 Pruritus 1.6 0.0 0.0 Diaper Dermatitis 4.7 4.0 0.0 Rash 2.9 2.0 8.3----------------------------------------------------------------------* Includes Phase IIb Complicated skin and skin structure infections, Community acquired pneumonia and Complicated urinary tract infections studies in which patients 3 months to 12 years of age received INVANZ 15 mg/kg IV twice daily up to a maximum of 1 g or ceftriaxone 50 mg/kg/day IV in two divided doses up to a maximum of 2 g, and patients 13 to 17 years of age received INVANZ 1 g IV daily or ceftriaxone 50 mg/kg/day IV in a single daily dose.+ Includes Phase IIb Acute pelvic infections and Complicated intra- abdominal infections studies in which patients 3 months to 12 years of age received INVANZ 15 mg/kg IV twice daily up to a maximum of 1 g and patients 13 to 17 years of age received INVANZ 1 g IV daily or ticarcillin/clavulanate 50 mg/kg for patients less than 60 kg or ticarcillin/clavulanate 3.0 g for patients greater than 60 kg, 4 or 6 times a day.---------------------------------------------------------------------- Additional adverse experiences that were reported with INVANZ withan incidence 1.0% and greater than 0.5% within each body system arelisted below: General Disorders and Administration Site Condition: chest pain,infusion site pruritus; Infections and Infestations: candidiasis, ear infection, oralcandidiasis; Metabolism and Nutrition Disorders: decreased appetite; Musculoskeletal and Connective Tissue Disorders: arthralgia; Nervous System Disorders: somnolence; Psychiatric Disorders: insomnia; Reproductive System and Breast Disorders: genital rash; Respiratory, Thoracic and Mediastinal Disorders: pleural effusion,rhinitis, rhinorrhea; Skin and Subcutaneous Tissue Disorders: dermatitis atopic, rasherythematous, skin lesion; Vascular Disorders: phlebitis. Post-Marketing Experience: The following post-marketing adverse experiences have beenreported: Immune System: anaphylaxis including anaphylactoid reactions Nervous System & Psychiatric: hallucinations Adverse Laboratory Changes Adults Laboratory adverse experiences that were reported during therapyin (greater than=)1.0% of adult patients treated with INVANZ inclinical studies are presented in Table 9. Drug-related laboratoryadverse experiences that were reported during therapy in 1.0% of adultpatients treated with INVANZ, including those who were switched totherapy with an oral antimicrobial, in clinical studies were ALTincreased (6.0%), AST increased (5.2%), serum alkaline phosphataseincreased (3.4%), platelet count increased (2.8%), and eosinophilsincreased (1.1%). Ertapenem was discontinued due to laboratory adverseexperiences in 0.3% of patients. Table 9 Incidence* (%) of Specific Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in (greater than=)1.0% of Adult Patients Treated With INVANZ in Clinical Studies---------------------------------------------------------------------- Piperacillin/ Adverse INVANZ++ Tazobactam++ INVANZ ss. Ceftriaxone ss. laboratory 1 g daily 3.375 g q6h 1 g daily 1 or 2 g daily experiences (n+=766) (n+=755) (n+=1122) (n+=920)----------------------------------------------------------------------ALT increased 8.8 7.3 8.3 6.9AST increased 8.4 8.3 7.1 6.5Serum albumin decreased 1.7 1.5 0.9 1.6Serum alkaline phosphatase increased 6.6 7.2 4.3 2.8Serum creatinine increased 1.1 2.7 0.9 1.2Serum glucose increased 1.2 2.3 1.7 2.0Serum potassium decreased 1.7 2.8 1.8 2.4Serum potassium increased 1.3 0.5 0.5 0.7Total serum bilirubin increased 1.7 1.4 0.6 1.1Eosinophils increased 1.1 1.1 2.1 1.8Hematocrit decreased 3.0 2.9 3.4 2.4Hemoglobin decreased 4.9 4.7 4.5 3.5Platelet count decreased 1.1 1.2 1.1 1.0Platelet count increased 6.5 6.3 4.3 3.5Segmented neutrophils decreased 1.0 0.3 1.5 0.8Prothrombin time increased 1.2 2.0 0.3 0.9WBC decreased 0.8 0.7 1.5 1.4Urine RBCs increased 2.5 2.9 1.1 1.0Urine WBCs increased 2.5 3.2 1.6 1.1----------------------------------------------------------------------* Number of patients with laboratory adverse experiences/Number of patients with the laboratory test+ Number of patients with one or more laboratory tests++ Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute pelvic infections studiesss. Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa studies---------------------------------------------------------------------- Additional laboratory adverse experiences that were reportedduring therapy in greater than 0.1% but less than 1.0% of patientstreated with INVANZ in clinical studies include: increases in BUN,direct and indirect serum bilirubin, serum sodium, monocytes, PTT,urine epithelial cells; decreases in serum bicarbonate. In a clinical trial for the treatment of diabetic foot infectionsin which 289 adult diabetic patients were treated with ertapenem, thelaboratory adverse experience profile was generally similar to thatseen in previous clinical trials. In a clinical study in adults for the prophylaxis of surgical siteinfection following elective colorectal surgery in which 476 patientsreceived a 1 g dose of ertapenem 1 hour prior to surgery and were thenfollowed for safety 14 days post surgery, the overall laboratoryadverse experience profile was generally comparable to that observedfor ertapenem in previous clinical trials. Additional laboratoryadverse experiences that were reported during therapy and the 14 dayspost surgery period in greater than 1.0% of patients, regardless ofcausality, include: white blood cell count increased and urine proteinpresent. Pediatric Patients Laboratory adverse experiences that were reported during therapyin (greater than=)1.0% of pediatric patients treated with INVANZ inclinical studies are presented in Table 10. Drug-related laboratoryadverse experiences that were reported during therapy in (greaterthan=)2.0% of pediatric patients treated with INVANZ, including thosewho were switched to therapy with an oral antimicrobial, in clinicalstudies were neutrophil count decreased (3.0%), ALT increased (2.2%),and AST increased (2.1%). Table 10 Incidence* (%) of Specific Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in (greater than=)1.0% of Pediatric Patients Treated With INVANZ in Clinical Studies---------------------------------------------------------------------- Ticarcillin/ INVANZ Ceftriaxone Clavulanate Adverse laboratory experiences (n+=379) (n+=97) (n+=24)----------------------------------------------------------------------ALT Increased 3.8 1.1 4.3Alkaline Phosphatase Increased 1.1 0.0 0.0AST Increased 3.8 1.1 4.3Eosinophil Count Increased 1.1 2.1 0.0Neutrophil Count Decreased 5.8 3.1 0.0Platelet Count Increased 1.3 0.0 8.7----------------------------------------------------------------------* Number of patients with laboratory adverse experiences/Number of patients with the laboratory test; where at least 300 patients had the test+ Number of patients with one or more laboratory tests---------------------------------------------------------------------- Additional laboratory adverse experiences that were reportedduring therapy in greater than 0.5% but less than 1.0% of patientstreated with INVANZ in clinical studies include: white blood cellcount decreased and urine protein present. OVERDOSAGE No specific information is available on the treatment ofoverdosage with INVANZ. Intentional overdosing of INVANZ is unlikely.Intravenous administration of INVANZ at a dose of 2 g over 30 min or3 g over 1-2h in healthy adult volunteers resulted in an increasedincidence of nausea. In clinical studies in adults, inadvertentadministration of three 1 g doses of INVANZ in a 24 hour periodresulted in diarrhea and transient dizziness in one patient. Inpediatric clinical studies, a single IV dose of 40 mg/kg up to amaximum of 2 g did not result in toxicity. In the event of an overdose, INVANZ should be discontinued andgeneral supportive treatment given until renal elimination takesplace. INVANZ can be removed by hemodialysis; the plasma clearance of thetotal fraction of ertapenem was increased 30% in subjects withend-stage renal insufficiency when hemodialysis (4 hour session) wasperformed immediately following administration. However, noinformation is available on the use of hemodialysis to treatoverdosage. DOSAGE AND ADMINISTRATION The dose of INVANZ in patients 13 years of age and older is 1 gram(g) given once a day. The dose of INVANZ in patients 3 months to 12years of age is 15 mg/kg twice daily (not to exceed 1 g/day). INVANZmay be administered by intravenous infusion for up to 14 days orintramuscular injection for up to 7 days. When administeredintravenously, INVANZ should be infused over a period of 30 minutes. Intramuscular administration of INVANZ may be used as analternative to intravenous administration in the treatment of thoseinfections for which intramuscular therapy is appropriate. DO NOT MIX OR CO-INFUSE INVANZ WITH OTHER MEDICATIONS. DO NOT USEDILUENTS CONTAINING DEXTROSE ((alpha)-D-GLUCOSE). Table 11 presents treatment guidelines for INVANZ. Table 11 Treatment Guidelines for Adults and Pediatric Patients With Normal Renal Function* and Body Weight----------------------------------------------------------------------Infection+ Daily Dose Daily Recommended (IV or IM) Dose Duration of Adults and (IV or Total Pediatric IM) Antimicrobial Patients Pediatric Treatment 13 years Patients of age 3 months and older to 12 years of age---------------------------------------------------------------------- Complicated intra-abdominal 1 g 15 mg/kg 5 to 14 days infections twice dailyss. Complicated skin and skin structure 1 g 15 mg/kg 7 to 14 days| infections, including diabetic twice foot infections@ dailyss. Community acquired pneumonia 1 g 15 mg/kg 10 to 14 twice days++ dailyss. Complicated urinary tract 1 g 15 mg/kg 10 to 14 infections, including twice days++ pyelonephritis dailyss. Acute pelvic infections including 1 g 15 mg/kg 3 to 10 days postpartum endomyometritis, septic twice abortion and post surgical dailyss. gynecologic infections --------------* defined as creatinine clearance greater than 90 mL/min/1.73 m2+ due to the designated pathogens (see INDICATIONS AND USAGE)@ INVANZ has not been studied in diabetic foot infections with concomitant osteomyelitis (see CLINICAL STUDIES).| adult patients with diabetic foot infections received up to 28 days of treatment (parenteral or parenteral plus oral switch therapy)++ duration includes a possible switch to an appropriate oral therapy, after at least 3 days of parenteral therapy, once clinical improvement has been demonstrated.ss. not to exceed 1 g/day---------------------------------------------------------------------- Table 12 presents prophylaxis guidelines for INVANZ. Table 12 Prophylaxis Guidelines for Adults---------------------------------------------------------------------- Indication Daily Dose Recommended (IV) Duration of Adults Total Antimicrobial Treatment---------------------------------------------------------------------- Prophylaxis of surgical site infection 1 g Single following elective colorectal surgery intravenous dose given 1 hour prior to surgical incision---------------------------------------------------------------------- Patients with Renal Insufficiency: INVANZ may be used for thetreatment of infections in adult patients with renal insufficiency. Inpatients whose creatinine clearance is greater than 30 mL/min/1.73 m2,no dosage adjustment is necessary. Adult patients with advanced renalinsufficiency (creatinine clearance (less than=)30 mL/min/1.73 m2) andend-stage renal insufficiency (creatinine clearance (lessthan=)10 mL/min/1.73 m2) should receive 500 mg daily. There are nodata in pediatric patients with renal insufficiency. Patients on Hemodialysis: When adult patients on hemodialysis aregiven the recommended daily dose of 500 mg of INVANZ within 6 hoursprior to hemodialysis, a supplementary dose of 150 mg is recommendedfollowing the hemodialysis session. If INVANZ is given at least 6hours prior to hemodialysis, no supplementary dose is needed. Thereare no data in patients undergoing peritoneal dialysis orhemofiltration. There are no data in pediatric patients onhemodialysis. When only the serum creatinine is available, the followingformula** may be used to estimate creatinine clearance. The serumcreatinine should represent a steady state of renal function.Males: (weight in kg) x (140-age in years) (72) x serum creatinine (mg/100 mL) ----------------------------------------Females: (0.85) x (value calculated for males) Patients with Hepatic Insufficiency: No dose adjustmentrecommendations can be made in patients with impaired hepaticfunction. (See CLINICAL PHARMACOLOGY, Special Populations, HepaticInsufficiency and PRECAUTIONS.) No dosage adjustment is recommended based on age (13 years of ageand older) or gender. (See CLINICAL PHARMACOLOGY, SpecialPopulations.) PREPARATION OF SOLUTION Adults and pediatric patients 13 years of age and older Preparation for intravenous administration: DO NOT MIX OR CO-INFUSE INVANZ WITH OTHER MEDICATIONS. DO NOT USEDILUENTS CONTAINING DEXTROSE ((alpha)-D-GLUCOSE). INVANZ MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TOADMINISTRATION. 1. Reconstitute the contents of a 1 g vial of INVANZ with 10 mL ofone of the following: Water for Injection, 0.9% Sodium ChlorideInjection or Bacteriostatic Water for Injection. 2. Shake well to dissolve and immediately transfer contents of thereconstituted vial to 50 mL of 0.9% Sodium Chloride Injection. 3. Complete the infusion within 6 hours of reconstitution. Preparation for intramuscular administration: INVANZ MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION. 1. Reconstitute the contents of a 1 g vial of INVANZ with 3.2 mLof 1.0% lidocaine HCl injection*** (without epinephrine). Shake vialthoroughly to form solution. 2. Immediately withdraw the contents of the vial and administer bydeep intramuscular injection into a large muscle mass (such as thegluteal muscles or lateral part of the thigh). 3. The reconstituted IM solution should be used within 1 hourafter preparation. NOTE: THE RECONSTITUTED SOLUTION SHOULD NOT BEADMINISTERED INTRAVENOUSLY. Pediatric patients 3 months to 12 years of age: Preparation for intravenous administration: DO NOT MIX OR CO-INFUSE INVANZ WITH OTHER MEDICATIONS. DO NOT USEDILUENTS CONTAINING DEXTROSE ((alpha)-D-GLUCOSE). INVANZ MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TOADMINISTRATION. 1. Reconstitute the contents of a 1 g vial of INVANZ with 10 mL ofone of the following: Water for Injection, 0.9% Sodium ChlorideInjection or Bacteriostatic Water for Injection. 2. Shake well to dissolve and immediately withdraw a volume equalto 15 mg/kg of body weight (not to exceed 1 g/day) and dilute in 0.9%Sodium Chloride Injection to a final concentration of 20 mg/mL orless. 3. Complete the infusion within 6 hours of reconstitution. Preparation for intramuscular administration: INVANZ MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION. 1. Reconstitute the contents of a 1 g vial of INVANZ with 3.2 mLof 1.0% lidocaine HCl injection*** (without epinephrine). Shake vialthoroughly to form solution. 2. Immediately withdraw a volume equal to 15 mg/kg of body weight(not to exceed 1 g/day) and administer by deep intramuscular injectioninto a large muscle mass (such as the gluteal muscles or lateral partof the thigh). 3. The reconstituted IM solution should be used within 1 hourafter preparation. NOTE: THE RECONSTITUTED SOLUTION SHOULD NOT BEADMINISTERED INTRAVENOUSLY. Parenteral drug products should be inspected visually forparticulate matter and discoloration prior to use, whenever solutionand container permit. Solutions of INVANZ range from colorless to paleyellow. Variations of color within this range do not affect thepotency of the product. ** Cockcroft and Gault equation: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976 *** Refer to the prescribing information for lidocaine HCl. STORAGE AND STABILITY Before reconstitution Do not store lyophilized powder above 25(degree)C (77(degree)F). Reconstituted and infusion solutions The reconstituted solution, immediately diluted in 0.9% SodiumChloride Injection (see DOSAGE AND ADMINISTRATION, PREPARATION OFSOLUTION), may be stored at room temperature (25(degree)C) and usedwithin 6 hours or stored for 24 hours under refrigeration (5(degree)C)and used within 4 hours after removal from refrigeration. Solutions ofINVANZ should not be frozen. HOW SUPPLIED INVANZ is supplied as a sterile lyophilized powder in single dosevials containing ertapenem for intravenous infusion or forintramuscular injection as follows: No. 3843--1 g ertapenem equivalent NDC 0006-3843-71 in trays of 10 vials No. 3843--1 g ertapenem equivalent NDC 0006-3843-45 in trays of 25 vials. CLINICAL STUDIES Adults Complicated Intra-Abdominal Infections Ertapenem was evaluated in adults for the treatment of complicatedintra-abdominal infections in a clinical trial. This study comparedertapenem (1 g intravenously once a day) with piperacillin/tazobactam(3.375 g intravenously every 6 hours) for 5 to 14 days and enrolled665 patients with localized complicated appendicitis, and any othercomplicated intra-abdominal infection including colonic, smallintestinal, and biliary infections and generalized peritonitis. Thecombined clinical and microbiologic success rates in themicrobiologically evaluable population at 4 to 6 weeks posttherapy(test of cure) were 83.6% (163/195) for ertapenem and 80.4% (152/189)for piperacillin/tazobactam. Complicated Skin and Skin Structure Infections Ertapenem was evaluated in adults for the treatment of complicatedskin and skin structure infections in a clinical trial. This studycompared ertapenem (1 g intravenously once a day) withpiperacillin/tazobactam (3.375 g intravenously every 6 hours) for 7 to14 days and enrolled 540 patients including patients with deep softtissue abscess, posttraumatic wound infection and cellulitis withpurulent drainage. The clinical success rates at 10 to 21 daysposttherapy (test of cure) were 83.9% (141/168) for ertapenem and85.3% (145/170) for piperacillin/tazobactam. Diabetic Foot Infections Ertapenem was evaluated in adults for the treatment of diabeticfoot infections without concomitant osteomyelitis in a multicenter,randomized, double-blind clinical trial. This study compared ertapenem(1 g intravenously once a day) with piperacillin/tazobactam (3.375 gintravenously every 6 hours). Test-of-cure was defined as clinicalresponse between treatment groups in the clinically evaluablepopulation at the 10-day posttherapy follow-up visit. The studyincluded 295 patients randomized to ertapenem and 291 patients topiperacillin/tazobactam. Both regimens allowed the option to switch tooral amoxicillin/clavulanate for a total of 5 to 28 days of treatment(parenteral and oral). All patients were eligible to receiveappropriate adjunctive treatment methods, such as debridement, as istypically required in the treatment of diabetic foot infections, andmost patients received these treatments. Patients with suspectedosteomyelitis could be enrolled if all the infected bone was removedwithin 2 days of initiation of study therapy, and preferably withinthe prestudy period. Investigators had the option to add open-labelvancomycin if enterococci or methicillin-resistant Staphylococcusaureus (MRSA) were among the pathogens isolated or if patients had ahistory of MRSA infection and additional therapy was indicated in theopinion of the investigator. Two hundred and four (204) patientsrandomized to ertapenem and 202 patients randomized topiperacillin/tazobactam were clinically evaluable. The clinicalsuccess rates at 10 days posttherapy were 75.0% (153/204) forertapenem and 70.8% (143/202) for piperacillin/tazobactam. Community Acquired Pneumonia Ertapenem was evaluated in adults for the treatment of communityacquired pneumonia in two clinical trials. Both studies comparedertapenem (1 g parenterally once a day) with ceftriaxone (1 gparenterally once a day) and enrolled a total of 866 patients. Bothregimens allowed the option to switch to oral amoxicillin/clavulanatefor a total of 10 to 14 days of treatment (parenteral and oral). Inthe first study the primary efficacy parameter was the clinicalsuccess rate in the clinically evaluable population and success rateswere 92.3% (168/182) for ertapenem and 91.0% (183/201) for ceftriaxoneat 7 to 14 days posttherapy (test of cure). In the second study theprimary efficacy parameter was the clinical success rate in themicrobiologically evaluable population and success rates were 91%(91/100) for ertapenem and 91.8% (45/49) for ceftriaxone at 7 to 14days posttherapy (test of cure). Complicated Urinary Tract Infections Including Pyelonephritis Ertapenem was evaluated in adults for the treatment of complicatedurinary tract infections including pyelonephritis in two clinicaltrials. Both studies compared ertapenem (1 g parenterally once a day)with ceftriaxone (1 g parenterally once a day) and enrolled a total of850 patients. Both regimens allowed the option to switch to oralciprofloxacin (500 mg twice daily) for a total of 10 to 14 days oftreatment (parenteral and oral). The microbiological success rates(combined studies) at 5 to 9 days posttherapy (test of cure) were89.5% (229/256) for ertapenem and 91.1% (204/224) for ceftriaxone. Acute Pelvic Infections Including Endomyometritis, Septic AbortionAnd Post-Surgical Gynecological Infections Ertapenem was evaluated in adults for the treatment of acutepelvic infections in a clinical trial. This study compared ertapenem(1 g intravenously once a day) with piperacillin/tazobactam (3.375 gintravenously every 6 hours) for 3 to 10 days and enrolled 412patients including 350 patients with obstetric/postpartum infectionsand 45 patients with septic abortion. The clinical success rates inthe clinically evaluable population at 2 to 4 weeks posttherapy (testof cure) were 93.9% (153/163) for ertapenem and 91.5% (140/153) forpiperacillin/tazobactam. Prophylaxis of Surgical Site Infections Following ElectiveColorectal Surgery Ertapenem was evaluated in adults for prophylaxis of surgical siteinfection following elective colorectal surgery in a multicenter,randomized, double-blind clinical trial. This study compared a singleintravenous dose of ertapenem (1 g) versus cefotetan (2 g)administered over 30 minutes, 1 hour before elective colorectalsurgery. Test-of-prophylaxis was defined as no evidence of surgicalsite infection, post-operative anastomotic leak, or unexplainedantibiotic use in the clinically evaluable population up to andincluding at the 4-week posttreatment follow-up visit. The studyincluded 500 patients randomized to ertapenem and 502 patientsrandomized to cefotetan. The modified intent-to-treat (MITT)population consisted of 451 ertapenem patients and 450 cefotetanpatients and included all patients who were randomized, treated, andunderwent elective colorectal surgery with adequate bowel preparation.The clinically evaluable population was a subset of the MITTpopulation and consisted of patients who received a complete dose ofstudy therapy no more than two hours prior to surgical incision and nomore than six hours before surgical closure. Clinically evaluablepatients had sufficient information to determine outcome at the 4-weekfollow-up assessment and had no confounding factors that interferedwith the assessment of that outcome. Examples of confounding factorsincluded prior or concomitant antibiotic violations, the need for asecond surgical procedure during the study period, and identificationof a distant site infection with concomitant antibiotic administrationand no evidence of subsequent wound infection. Three-hundred forty-six(346) patients randomized to ertapenem and 339 patients randomized tocefotetan were clinically evaluable. The prophylactic success rates at4 weeks posttreatment in the clinically evaluable population were70.5% (244/346) for ertapenem and 57.2% (194/339) for cefotetan(difference 13.3%, (95% C.I.: 6.1, 20.4), pless than 0.001).Prophylaxis failure due to surgical site infections occurred in 18.2%(63/346) ertapenem patients and 31.0% (105/339) cefotetan patients.Post-operative anastomotic leak occurred in 2.9% (10/346) ertapenempatients and 4.1% (14/339) cefotetan patients. Unexplained antibioticuse occurred in 8.4% (29/346) ertapenem patients and 7.7% (26/339)cefotetan patients. Though patient numbers were small in somesubgroups, in general, clinical response rates by age, gender, andrace were consistent with the results found in the clinicallyevaluable population. In the MITT analysis, the prophylactic successrates at 4 weeks posttreatment were 58.3% (263/451) for ertapenem and48.9% (220/450) for cefotetan (difference 9.4%, (95% C.I.: 2.9, 15.9),p=0.002). A statistically significant difference favoring ertapenemover cefotetan with respect to the primary endpoint has been observedat a significance level of 5% in this study. A second adequate andwell-controlled study to confirm these findings has not beenconducted; therefore, the clinical superiority of ertapenem overcefotetan has not been demonstrated. Pediatric Patients Ertapenem was evaluated in pediatric patients 3 months to 17 yearsof age in two randomized, multicenter clinical trials. The first studyenrolled 404 patients and compared ertapenem (15 mg/kg IV every 12hours in patients 3 months to 12 years of age, and 1 g IV once a dayin patients 13 to 17 years of age) to ceftriaxone (50 mg/kg/day IV intwo divided doses in patients 3 months to 12 years of age and50 mg/kg/day IV as a single daily dose in patients 13 to 17 years ofage) for the treatment of complicated urinary tract infection (UTI),skin and soft tissue infection (SSTI), or community-acquired pneumonia(CAP). Both regimens allowed the option to switch to oralamoxicillin/clavulanate for a total of up to 14 days of treatment(parenteral and oral). The microbiological success rates in theevaluable per protocol (EPP) analysis in patients treated for UTI were87.0% (40/46) for ertapenem and 90.0% (18/20) for ceftriaxone. Theclinical success rates in the EPP analysis in patients treated forSSTI were 95.5% (64/67) for ertapenem and 100% (26/26) forceftriaxone, and in patients treated for CAP were 96.1% (74/77) forertapenem and 96.4% (27/28) for ceftriaxone. The second study enrolled 112 patients and compared ertapenem(15 mg/kg IV every 12 hours in patients 3 months to 12 years of age,and 1 g IV once a day in patients 13 to 17 years of age) toticarcillin/clavulanate (50 mg/kg for patients less than 60 kg or 3.0 g for patients greater than 60 kg, 4 or 6 times a day) up to 14 days for the treatment of complicated intra-abdominal infections (IAI)and acute pelvic infections (API). In patients treated for IAI (primarily patients with perforated or complicated appendicitis) the clinical success rates were 83.7% (36/43) for ertapenem and 63.6% (7/11) for ticarcillin/clavulanate in the EPP analysis. In patients treated for API (post-operative or spontaneous obstetrical endomyometritis, or septic abortion) the clinical success rates were 100% (23/23) for ertapenem and 100% (4/4) for ticarcillin/clavulanate in the EPP analysis. REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Methods forDilution Antimicrobial Susceptibility Tests for Bacteria that GrowAerobically. Seventh Edition; Approved Standard, CLSI Document M7-A7.Clinical and Laboratory Standards Institute, Wayne, PA, January 2006. 2. Clinical and Laboratory Standards Institute (CLSI). PerformanceStandards for Antimicrobial Susceptibility Testing - SixteenthInformational Supplement. Approved Standard, CLSI Document M100-S16.Clinical and Laboratory Standards Institute, Wayne, PA, January 2006. 3. Clinical and Laboratory Standards Institute (CLSI). PerformanceStandards for Antimicrobial Disk Susceptibility Tests. Ninth Edition;Approved Standard, CLSI Document M2-A9. Clinical and LaboratoryStandards Institute, Wayne, PA, January 2006. 4. Clinical and Laboratory Standards Institute (CLSI). Methods forAntimicrobial Susceptibility Testing of Anaerobic Bacteria - SixthEdition; Approved Standard, CLSI Document M11-A6. Clinical andLaboratory Standards Institute, Wayne, PA, January 2004.MERCK & CO., Inc., 2001Whitehouse Station, NJ 08889, USA By: Laboratories Merck Sharp & Dohme-Chibret 63963 Clermont-Ferrand Cedex 9, France US Patent Nos.: 5,478,820; 5,952,323; 5,652,233 Issued August 2006Registered trademark of MERCK & CO., Inc.COPYRIGHT 2001, 2003, 2004, 2005 MERCK & CO., Inc.All rights reserved