Claudio Faria, PharmD

More than 160 million antibioticprescriptions are writteneach year in the UnitedStates. Approximately 235 millionantibiotic doses are used annually,with 20% to 50% taken unnecessarily.

Moreover, roughly 70% of bacteriacausing hospital-acquired infectionsare resistant to one or more commonlyused agents.

The increase in bacterialresistance over the years has promptedan array of antibiotic products. Tygacil,manufactured by Wyeth PharmaceuticalsInc, has been approved for use asmonotherapy of complicated skin andskin structure infections (cSSSIs) andcomplicated intra-abdominal infections(cIAIs) in adults.

Tygacil, derived from the tetracyclinefamily, is part of a new classknown as 

. It has activityagainst gram-positive, gram-negative,and anaerobic microorganisms, as wellas methicillin-resistant 

Tygacil exerts its actions viainhibition of protein translation inbacteria by binding to the 30S ribosomalsubunit and blocking the entry ofamino-acyl tRNA molecules into the Asite of the ribosome.

Two randomized, double-blind, multinationalstudies evaluated tigecyclinein adults for the treatment of cSSSIs.

Tigecycline at an initial dose of 100 mgintravenous (IV), followed by subsequentdoses of 50 mg every 12 hours,was compared with vancomycin 1 gand aztreonam 2 g every 12 hours for 5to 14 days.

The study included patientswith a known or suspected diagnosis ofcSSSI, who were expected to require IVantibiotic therapy for at least 5 days,and who had one or more prespecifiedindicators of infection. Patients wereexcluded from the study if theyreceived more than 2 doses of nonstudyantibacterial therapy after the originalcure was obtained and before the studydrug was administered.

The results were summarized into 2categories: the clinically evaluable (CE)and the clinically modified intent-totreat(c-mITT) populations. A favorableclinical response was observed in theNorth American trial for both the CEand the c-mITT categories, for the tigecyclineand the vancomycin-aztreonamtreatment groups, respectively.

Favorableresponses also were observed in aglobal trial for the CE and for the cmITTcategories, respectively.

In addition, tigecycline was evaluatedin patients with a cIAI. Two randomized,double-blind, active-controlled,multinational studies compared tigecyclineat an initial dose of 100 mg IV, followedby 50 mg every 12 hours, andimipenem/cilastatin at a dose of 500 mgIV every 6 hours for a total of 5 to 14days.

Inclusion criteria comprised aknown or suspected diagnosis of cIAIand previous consideration for or a previouslaparotomy, laparoscopy, or percutaneousdrainage of an intra-abdominalabscess.

Patients were excludedfrom participation if more than onedose of nonstudy antibacterial therapywas administered, after the original cultureand before the study drug.

The results were divided into 2groups: those for patients who exhibiteda clinical and microbiological response(ME) and those for the microbiologicallymodified intent-to-treat(m-mITT) group. A favorable responsewas observed in the first trial in boththe ME and the m-mITT groups, withtigecycline and imipenem/cilastatin,respectively.

In a second trial, a similarfavorable clinical response wasobserved in both the ME and the mmITTgroups, respectively.

The most common adverse eventsreported with the use of tigecyclinewere nausea and vomiting. Tygacil is inpregnancy category D and is notadvised for pregnant or breast-feedingwomen. Generally, Tygacil does notrequire any renal adjustments. Patientswith severe hepatic impairment (Child-Pugh Class C), however, should receivean initial dose of 100 mg followed by25 mg every 12 hours.

Tygacil is supplied as 50-mg lyophilizedpowder for reconstitution insingle-dose 5-mL glass vials. The recommendedinitial dose is 100 mg, followedby subsequent doses of 50 mg IVadministered over 30 to 60 minutesevery 12 hours for 5 to 14 days. Tygacilappears to be a safe and favorableantimicrobial option.

Drs. Faria and Soo are both senior research

pharmacists with the Investigational Drug

clinical clerkship in the Investigational Drug

Articles

Tygacil (tigecycline)

Deep vein thrombosis (DVT) occurs when the flow of blood is restricted and a clot forms. A clot most commonly forms in the legs following surgery, where it can then mobilize into the lungs and become fatal. Complications from DVT contribute to more deaths each year than AIDS and breast cancer combined.

DVT has an average occurrence of 24% to 27% following hip fracture surgery, 31% to 47% following knee replacement surgery, and 16% to 30% following hip replacement surgery.

 Postsurgery complications eventually can lead to pulmonary embolism, which has a 10% mortality rate.

Arixtra, marketed by GlaxoSmithKline, is indicated for the prophylaxis of DVT in hip fracture surgery, knee replacement surgery, and hip replacement surgery.

Arixtra is a pentasaccharide antithrombotic agent and the only synthetic selective factor Xa inhibitor. Selective binding to antithrombin III neutralizes Xa, which then interrupts the blood coagulation cascade. This disruption inhibits thrombin formation and thrombus development. Arixtra is not a heparin and does not directly inhibit thrombin. At the recommended dose, it does not affect fibrinolytic activity or bleeding time.

In a double-blind, randomized study, researchers assigned 2309 patients who were undergoing elective hip replacement surgery to once-daily, subcutaneous injections of 2.5 mg fondaparinux, starting postoperatively, or 40 mg enoxaparin, starting preoperatively. The primary efficacy outcome was venous thromboembolism (VTE) up to day 11, defined as DVT detected by mandatory bilateral venography. By day 11, VTEs were recorded in 4% of patients assigned to fondaparinux and in 9% assigned to enoxaparin (difference: -5.2%, 

<.0001). The relative risk reduction was 55.9% (95% confidence interval [CI]: 33.1-72.8).

In another double-blind study, 1049 patients undergoing elective major knee surgery were randomly assigned to receive postoperative subcutaneous doses of either 2.5 mg of fondaparinux once daily or 30 mg of enoxaparin twice daily. The primary efficacy outcome was VTE up to postoperative day 11, defined as DVT detected by mandatory bilateral venography. The fondaparinux group showed a significantly lower incidence of VTE by day 11 (12.5%) than the enoxaparin group (27.8%; 95% CI: 36.2-70.2). Investigators concluded that, in patients undergoing elective major knee surgery, postoperative treatment with once-daily fondaparinux significantly prevented DVT more effectively than enoxaparin twice daily.

There has been no reported incidence of immune-mediated heparin-induced thrombocytopenia associated with Arixtra. If platelet count falls below 100,000/mm, however, Arixtra should be discontinued.

After discontinuation, its anticoagulant effects may persist for 2 to 4 days in patients with normal renal function and longer in patients with renal impairment. Patients should be monitored frequently for signs and symptoms of neurologic impairment. Arixtra is contraindicated in patients with severe renal impairment; in patients with body weight <50 kg undergoing hip fracture, hip replacement, or knee replacement surgery; and in patients with active major bleeding or bacterial endocarditis.

Arixtra should be administered 6 to 8 hours following surgery, because doses given within 6 hours post-surgery have been associated with an increased risk of bleeding.

Treatment should continue for at least 5 days or until a therapeutic oral anticoagulant effect is established (international normalized ratio 2.0-3.0). 

HealthCare System. Ms. Kohl is a sixth-year

rotation in the Investigational Drug Service

RxPRODUCT NEWS: PROFILE: Arixtra (fondaparinux)

Although several techniques areavailable to control postoperativepain, these options can becostly and inconvenient and oftenresult in low patient satisfaction.

In2004, the FDA approved DepoDur, anextended-release liposomal formulationof morphine sulfate. Marketed byEndo Pharmacuticals Inc and developedby SkyePharma, DepoDur isadministered epidurally at the lumbarlevel and is indicated for the treatmentof pain following major surgery,including hip replacement, lowerabdominal, and elective cesarean sectionsurgery.

DepoDur is an opiate agonist,specifically at the receptor.

At highdoses, it may interact with other opiatereceptors.

Resembling opioids likeenkephalins and endorphins, Depo-Dur produces analgesia in the centralnervous system.

A randomized, double-blind, placebo-controlled, parallel-group, doserangingstudy compared single epiduraldoses of DepoDur (15, 20, and 25mg) versus placebo in patients undergoinghip arthroplasty. The 194patients who underwent surgerywere able to self-administer intravenousfentanyl for breakthroughpain. Results demonstrated that allDepoDur doses significantlydelayed the time to the first dose offentanyl and reduced fentanyladministration versus placebo (

<.0001). Postoperative pain control(48 hours postdose) had also improvedin all DepoDur groups versus placebo(

Another similarly designed studyinvolved approximately 500 patientsundergoing lower abdominal surgery.The trial compared 6 different treatmentsfor postoperative pain for up to48 hours, such as single epidural dosesof DepoDur 10, 15, 20, and 25 mg, single-dose DepoDur 5 mg, and standardepidural morphine sulfate 5 mg. Adose-response relationship betweenthe DepoDur doses and postsurgicalPCA fentanyl use for breakthroughpain was also established 48 hoursafter the procedure. Results revealedthat patients using 10, 20, and 25 mgDepoDur used significantly less fentanylversus DepoDur 5 mg (

= .0001, respectively).Moreover, the DepoDur 10-, 15-, 20-,and 25-mg groups obtained significantlylower pain intensity scores andgreater pain relief.

DepoDur is an effective option forthose who may have impaired hepaticor renal function. This is attributed toless morphine metabolite accumulationbecause of single-dose administration.

DepoDur is contraindicated inpatients with known morphine hypersensitivity,respiratory depression,acute or severe bronchial asthma,upper airway obstruction, paralyticileus, head injury, or increasedintracranial pressure. Common adverseevents include hypotension, urinaryretention, nausea, vomiting, constipation,pruritus, pyrexia, anemia,headache, and dizziness. Respiratorydepression is a severe side effect andcan occur at high doses.

DepoDurshould not be substituted for othermorphine products, since its liposomalformulation allows for extendedrelease for up to 48 hours.

DepoDur is available in 10-mg/mL,15/1.5-mg/mL, and 20/2-mg/mL preservative-free, single-use, amber vialsand must be refrigerated. DepoDur is aSchedule II controlled substance, soaddiction and diversion could presentproblems, but these concerns shouldnot deter proper postoperative painmanagement.

DepoDur appears to bean effective option for the treatmentof pain in postsurgical patients.

Investigational Drug Service at Brigham and

RxPRODUCT NEWS: PROFILE: DepoDur (morphine sulfate extended-release liposome injection)

Diabetes mellitus is a chronicdisease that affects 18.2 millionpeople in the UnitedStates.

Type 2 diabetes is the most commonlydiagnosed type; it is frequentlycaused by peripheral insulin resistanceor impaired insulin secretion.

Combinationtherapy is often necessary whena single drug fails to control plasma glucose.The FDA has approved Byetta(exenatide), manufactured by AmylinPharmaceuticals Inc, as an adjunctivetherapy for the treatment of type 2 diabetesin patients who cannot achieveblood sugar control on metforminand/or sulfonylurea.

Byetta is an incretin mimetic agentthat is composed of a 39-amino acidpeptide. Incretins improve glucose-dependentinsulin secretion andinhibit glucagon release. Byetta leadsto an increase in insulin secretion, adecrease in glucagon release, adecrease in food intake, delayed gastricemptying, and an elevated beta-cellproduction.

A triple-blind, placebo-controlledstudy evaluated the effectiveness oftwice-daily subcutaneous injections ofByetta (5 mcg and 10 mcg) withmatching placebo. The trial included377 patients with type 2 diabetes whohad been treated with sulfonylureamonotherapy for 3 months prior toinitiating the study therapy. Allpatients continued sulfonylurea therapythroughout the study. After 30weeks, hemoglobin A

) changesfrom baseline were -0.86 + 0.11,-0.46 + 0.12, and 0.12 + 0.09% in the10-mcg, 5-mcg, and placebo arms,respectively (

<.001). For participantswith baseline HbA

 >7%, the 10-mcgand 5-mcg Byetta arms reached anHbA

 &#8804;7%, significantly greater thanthe placebo arm (

<.0001). Furthermore,progressive dose-dependentweight loss was observed in the 10-mcg and 5-mcg Byetta arms, comparedwith baseline.

Another 28-day, triple-blind, parallel-group, placebo-controlled studyexamined the efficacy and safety of 3different subcutaneous Byetta regimens.A total of 109 patients with type2 diabetes who had been stable on asulfonylurea and/or metformin regimenfor 6 months took part in thisstudy. Patients were enrolled to receiveByetta twice daily at breakfast and dinner,Byetta twice daily at breakfast andbedtime, Byetta 3 times daily (at breakfast,dinner, and bedtime), or placebo.At day 28, patients in the Byetta armshad a statistically significant reductionin serum fructosamine (

<.006), compared with thosein the placebo arm. Furthermore, end-of-study HbA

 of <7% was achieved by15% of all Byetta patients, comparedwith 4% of placebo-treated patients.Moreover, the beta-cell index for Byettapatients at day 14 and day 28ranged from 50% to 100% greater thanbaseline, while the beta-cell index forthe placebo group showed no change.

The most common adverse eventreported with Byetta was dose-dependentmild-to-moderate nausea. Otheradverse events included vomiting,diarrhea, jitters, dizziness, headache,and dyspepsia.

When Byetta is usedwith a sulfonylurea, mild-to-moderatehypoglycemia is observed; thus dosereduction is advisable. This effect hasnot been witnessed with metformin.

In addition, Byetta is not recommendedfor patients with severe renalimpairment, end-stage renal disease(creatinine clearance <30 mL/min), orsevere gastrointestinal disease.

The delayed gastric emptying thatmay occur with Byetta may affect someconcentration-sensitive drugs—for example,antibiotics and/or oral contraceptives.Patients should be advised totake these medications at least 1 hourbefore a Byetta injection. Byetta is inPregnancy Risk Category C.

The appealing side-effect and efficacyprofile of Byetta, along with theconvenience of prefilled pens, grantshealth care practitioners another therapeuticoption for the control of type2 diabetes, subsequent to unsuccessfultreatment with metformin or a sulfonylurea.

Rx PRODUCT NEWS PROFILE: Byetta (exenatide)

infectionsare 2 of the leading causes ofpersistent diarrhea in humans.

These organisms are transmittedthrough water, food, or personal contact.They are responsible for >200million illnesses annually in the UnitedStates and are an increased causeof mortality throughout the world.

These infections may produce symptomsof diarrhea, abdominal pain,cramping, and/or bloating.

Alinia(nitazoxanide), marketed by RomarkLaboratories, has received FDAapproval for the treatment of giardiasis,as well as the treatment of

-induced diarrhea in childrenfrom 1 to 11 years of age.

Alinia is a first-in-class, broad-spectrumantiparasitic drug.

It interfereswith the pyruvate ferredoxin oxidoreductaseenzyme-dependent electrontransfer reaction, which plays a majorrole in anaerobic metabolism.

It is anitrothiazolyl-salicylamide derivativeand a prodrug, converting to theactive metabolite, tizoxanide.

These2 components also exhibit activityagainst intestinal parasites and bacterialpathogens.

A prospective, randomized, double-blind,placebo-controlled study evaluatedthe efficacy of Alinia in the treatmentof diarrhea caused by 

Fifty adults and adolescents (>11 yearsof age) were given 500 mg of Alinia orplacebo twice daily for 3 days, while50 children (&#8804;11 years old) received100 mg, 200 mg, or matching placebotwice daily for 3 days. Efficacy wasmeasured by resolution of diarrheaafter 7 days. Of the 99 patients whocompleted the study, resolutionoccurred in 39 of 49 patients (80%) inthe active group versus 20 of 49 (41%)in the placebo group (

Stoolsamples also were examined for post-treatment

oocytes. In thisportion of the study, 67% of thepatients receiving active treatmentand 22% of the patients receivingplacebo had no oocyst detection(

A second randomized, placebo-controlledstudy was designed to assessthe safety and efficacy of Alinia in thetreatment of diarrhea caused by 

Eighty-nineadults and adolescents (12-65 years ofage) were given Alinia 500 mg orplacebo twice daily for 3 days. Theclinical response rate in the Aliniagroup was 81%, compared with 40%in the placebo group (

Resolutionof diarrhea took a median of 3days in the active group, while 60% ofthe patients in the placebo group stillhad diarrhea during the follow-upperiod. Parasitologic cure wasachieved for 71% of those treatedwith Alinia. No patients in the placeboarm showed parasitologic cure(

Overall, Alinia is well-tolerated. Alladverse effects reported have beenmild or transient in nature. The mostcommon adverse events reported areabdominal pain, dyspepsia, worseningdiarrhea, discoloration of urine,drowsiness, dizziness, and nausea.

The safety of Alinia in HIV-positivepatients and in patients with hepatic,bilary, or renal impairment has notbeen established; therefore, use inthese patient populations is contraindicated.

Alinia is supplied as a 100-mg/5-mLsuspension containing 1.48 g of sucroseper 5 mL. Due to this significantamount of sucrose, Alinia also is contraindicatedin diabetic patients. Aliniais a Pregnancy Category B agent.

Alinia is a safe and effective treatmentoption for the resolution of giardiasisand cyclosporidiosis-inducedpersistent diarrhea. A 3-day treatmentregimen reduces the duration of diarrheaand oocyst excretion in patientswith persistent diarrhea caused by 

Alinia hasshown greater efficacy when treatingpersistent diarrhea over placebo andalso has shown favorable results incases where traditional therapy mayprove resistant.

The beneficial safetyand efficacy profile of Alinia giveshealth care practitioners anotherviable therapeutic treatment optionfor giardiasis and cyclosporidiosis.

Northeastern University, currently working

and Women's Hospital in the Investigational

RxPRODUCT NEWS: PROFILE: Alinia (nitazoxanide)

Ketek is the first agent in a new class of antibiotics known as the ketolides. Manufactured by Aventis, Ketek was recently approved by the FDA for the treatment of acute bacterial exacerbation of chronic bronchitis (

Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis

S pneumoniae, H influenzae, M catarrhalis, Staphylococcus aureus

), and mild-to-moderate community-acquired pneumonia (CAP; 

S pneumoniae, H influenzae, M catarrhalis

Ketek inhibits protein synthesis by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit. By binding to domain II, Ketek is active against gram-positive cocci (eg, 

) in the presence of resistance mediated by methylases (

 genes) that change the domain V binding site of Ketek.

 Following oral administration, Ketek reaches maximal concentration in ~1 hour (0.5-4 hours). 

Adverse events noted in ?2% of patients in phase 3 clinical trials included diarrhea, nausea, dizziness, and vomiting.

Ketek is a strong inhibitor of the cytochrome P450 3A4 system. Coadministration of Ketek tablets and another agent that is primarily metabolized by the cytochrome P450 3A4 enzyme system may result in in-creased plasma concentration of that agent. Therefore, dosage adjustments may be necessary for that drug when coadministered with Ketek. Ketek is designated as a Pregnancy Category C drug.

Three clinical trials were performed to assess the efficacy of Ketek (5-day therapy) in acute exacerbations of chronic bronchitis (AECB) versus cefuroxime 500 mg bid for 10 days, clarithromycin 500 mg bid for 10 days, or amoxicillin/clavulanic acid 500/125 mg tid for 10 days. The Ketek 5-day dosing regimen was found to be as effective as 10-day comparator drug regimens for the treatment of AECB. 

Two randomized, double-blind comparator studies were utilized to assess Ketek in acute sinusitis. These trials compared 5-day Ketek therapy with 10 days of amoxicillin/clavulanate 500/125 mg tid or cefuroxime 250 mg bid. An additional trial compared 5-day and 10-day dosing regimens. Results from controlled studies showed that Ketek 5-day therapy was equally efficacious as 10-day therapy of comparator drugs. Results from the additional trial also showed 5-day and 10-day Ketek therapy to be equally efficacious in terms of clinical cure rates (91.1% vs 91.0%, respectively). 

Four randomized, double-blind studies and 4 open-label studies were performed to assess the efficacy of Ketek in CAP. The comparator drugs included amoxicillin 1000 mg tid for 10 days, clarithromycin 500 mg bid for 10 days, or trovafloxacin 200 mg qd for 7 to 10 days. After 7 to 10 days of Ketek therapy, a clinical cure rate of 83.0% to 95.7% bacterial eradication rate was observed. Ketek 7-day and 10- day dosing regimens were equally effective as those of comparator drugs, which had clinical cure rates ranging from 77.8% to 95.5% bacterial eradication. Ketek also showed 91.7% clinical success against multidrug-resistant 

Ketek is indicated for use in patients with bacterial infections: acute bacterial exacerbation of chronic bronchitis, acute bacterial sinusitis, and CAP. The recommended dose of Ketek tablets is 800 mg taken orally once every 24 hours. The duration of therapy depends on the infection type. Ketek tablets can be given without regard to food.

Dr. Hartman is medication safety officer at UMass Memorial Medical Center, Worcester, Mass. He also is a clinical assistant professor at Northeastern University and an adjunct assistant professor at Massachusetts College of Pharmacy. Dr. Faria is a senior research pharmacist at Brigham and Women's Hospital, Boston, Mass.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@mwc.com.