The goal of this lesson is to provide information on new drugs approved and/or introduced into therapy during the first-half of 2005. Drugs discussed include Aptivus, Baraclude, Byetta, Enablex, Levemir, Lunesta, Mycamine, Naglazyme, Rozerem, Symlin, Tygacil, and Ventavis. Emphasis is on new molecular entities. Advice to convey to patients to maximize compliance and treatment outcomes is included.

At the conclusion of this lesson, the reader should be able to:

1. Coordinate the new drugs by generic name, trade name, and chemical name when relevant;
2. Identify the indication(s), pharmacologic action(s), and significant pharmacokinetic principles of the drugs;
3. Recognize important therapeutic uses of the drugs and their applications in specified pathologies;
4. Demonstrate an understanding of adverse effects and toxicity, and significant drug-drug and drug-food interactions;
5. Identify the dose range and dosage form(s) available for the new drugs; and,
6. Select specific information to convey to patients or their caregivers when counseling on the drugs and/or conditions for which they are indicated.

BACKGROUND

The new drugs and biologicals approved during the first six months of 2005 that were submitted to FDA via the New Drug Application (NDA) process (Table 1) include eight that were new molecular entity (NME) compounds (Table 2). Four additional NME drugs are included in Table 2 and discussed within this lesson: three were approved near the end of 2004 and one was approved in July 2005. These four are included in this lesson for completeness. Biologicals are approved by the Center for Biologics Evaluation and Research (CBER), a separate branch of FDA. In contrast, drugs are approved within the jurisdiction of FDA’s Center for Drug Evaluation and Research (CDER). Continuing pharmacy education programs that discuss other new drugs that were approved during the past couple years can be found at www.thecesolution.com.

_____________
*Includes approvals for January through July, 2005
±Chemical Types:
1 – New molecular entity
2 – New ester, new salt, or other noncovalent derivative
3 – New formulation
4 – New combination
5 – New manufacturer
6 – New indication
7 – Drug already marketed, but without an approved NDA

Therapeutic Potential:
P – Priority Review: Significant improvement compared to marketed products,
in the treatment, diagnosis, or prevention of a disease
S – Standard Review: The drug appears to have therapeutic qualities similar to
those of one or more already marketed drugs
O – Designated Orphan Drug: The sponsor of the drug has officially requested
and received orphan designation pursuant to Section 526 of the Orphan Drug Act
(Public Law 97-414 as amended)
^‡Biological

In Tables 1 and 2, drugs are classed as P or S. P (ie, priority) drugs are those that represent significant improvements compared to available therapy in the treatment, diagnosis, or prevention of a disease. Or, they are indicated for patients with HIV infections, cancer, or another condition for which there is no existing approved therapy in the United States. FDA gives priority drugs a “fast-track” review.

Drugs in the S (ie, standard) category appear to have therapeutic qualities similar to those of one or more previously approved drugs. They may be better than currently available drugs for some patients in the target population, but at the time of application their sponsor did not provide sufficient data to support priority status.

Note also that in both tables, the new drugs are assigned a numerical designation that describes their chemical type. The meaning of these numbers is presented in the footnote to Table 1. This classification system (ie, #1 through #7) is of interest to pharmacists and other health care providers in that it categorizes the new drugs objectively.

Drug approval does not necessarily correlate with drug product availability. Approval is a function of the FDA. Item availability is a function of its sponsor/manufacturer/distributor. Thus, products listed in Table 2 may or may not have been released into therapy at the time this monograph was prepared.

A monograph of this nature must be restrictive in both extent and depth of information it presents. It provides a brief introduction to a limited number of new drugs. It is not intended to go beyond offering an overview of the topic. The reader is therefore urged to consult each product’s Package Information leaflet (ie, its label; package insert) and other references for detailed descriptions including outcomes of comparative clinical trials with other (ie, comparator) drugs.

ANTI-INFECTIVE AGENTS: ENTECAVIR, MICAFUNGIN, TIGECYCLINE, TIPRANAVIR

HEPATITIS B

Among the viral hepatitides, the immunopathogenesis of hepatitis B has been studied most extensively.¹ Hepatitis B virus (HBV) is the prototype member of the Hepadnaviridae (hepatotropic DNA virus) family.^2,3 The existence of inactive HBV carriers who continue to exhibit normal liver histology and function suggests that the virus is not directly cytopathic.^4,5 Immunocompetent patients are more likely to remain infected chronically rather than to clear the virus, which supports the role of cellular immune responses in the pathogenesis of HBV-related hepatic injury.¹ It is estimated that 1 million people in the United States and 39.4 million people worldwide are infected with HBV.⁶ HBV causes up to a million deaths worldwide each year,⁷ making it the ninth most common cause of death worldwide.⁸

Percutaneous inoculation has long been identified as a major source of HBV transmission. The outmoded designation “serum hepatitis” is an inaccurate description of the epidemiologic characteristics of HBV infection.⁵ Most hepatitis transmitted by blood transfusion is not caused by HBV. Many cases of hepatitis B result from less obvious modes of nonpercutaneous transmission.² Almost every body fluid from infected individuals contains HBV antigens, and at least some of these fluids, especially semen and saliva, are infectious. The two nonpercutaneous routes that have the greatest impact are intimate contact, especially sexual, and perinatal transmissions.³ Oral ingestion of the virus is an inefficient route of exposure.

Conservative estimates are that from 350 million² to approximately 400 million⁹ people worldwide are carriers of HBV, and constitute its main reservoir in humans. The virus is found infrequently (0.1%-0.5%) in normal populations in the United States and Western Europe. Persons with Down’s syndrome, leprosy, leukemia, Hodgkin’s disease, and polyarteritis nodosa; patients with chronic renal disease on hemodialysis; and injection drug users are more likely to be carriers.¹ Other groups with higher than normal rates of HBV infection include spouses of acutely infected persons, sexually promiscuous individuals (particularly men who have sex with men), health care workers exposed to blood, individuals who require repeated transfusions especially with pooled blood product concentrates (eg, hemophiliacs), residents and staff of custodial institutions for the developmentally handicapped, prisoners, and to lesser extent, family members of chronically infected patients.¹

Chronic Hepatitis
Chronic hepatitis is a late complication of acute HBV, occurring in 2%-7% of patients with acute disease.³ It is more common in men and immunocompromised persons who have a chronic infection without having experienced previous acute illness. The clinical course of HVB infection is complex and influenced by a number of factors (Table 3).¹⁰ Progression of acute to chronic hepatitis is suggested by lack of complete resolution of clinical symptoms of anorexia, weight loss, fatigue, and the persistence of hepatomegaly; the presence of multilobular hepatic necrosis on liver biopsy during protracted, severe acute viral hepatitis; failure of serum aminotransferase, bilirubin, and globulin levels to return to normal within 6-12 months after the acute illness; and the persistence of HBV antigens 3 or more months after acute hepatitis.¹ The disease is defined as chronic if there is evidence of ongoing injury for 6 months or longer.¹¹

The likelihood of chronicity after acute hepatitis B infection is a function of age. Infection at birth is associated with clinically silent acute infection but a 90% chance of chronic infection. Infection in young adulthood in immunocompetent persons is associated with clinically apparent acute hepatitis but a risk of chronicity of only approximately 1%. Most cases of chronic hepatitis B in adults occur in patients who never experienced a recognized episode of clinically apparent acute viral hepatitis. The extent of liver injury in patients with chronic hepatitis B is variable, ranging from none in inactive carriers, to mild injury, to severe pathology with end-stage, fatal hepatic failure.^5,12 Symptom onset is insidious in most patients except for a few individuals in whom chronic disease follows failure of resolution of clinically apparent acute hepatitis B. Fatigue and persistent or intermittent jaundice are common features in advanced cases. Intermittent deepening of jaundice and recurrent malaise and anorexia, as well as worsening fatigue, are reminiscent of acute hepatitis; such exacerbations may occur spontaneously and lead to progressive liver injury with hepatic decompensation.¹³

Cirrhosis develops in about 20% of victims of chronic hepatitis B,⁵ with complications including ascites, edema, bleeding gastroesophageal varices, hepatic encephalopathy, carcinoma, coagulopathy, or spleenomegaly in end-stage chronic hepatitis. Extrahepatic complications of chronic hepatitis B include arthralgias and arthritis, and rare purpuric cutaneous lesions (leukocytoclastic vasculitis), immune-complex glomerulonephritis, and generalized vasculitis (polyarteritis nodosa).¹² Most deaths from HBV are due to chronic carriage, that is, presence of the virus for more than 6 months, leading to complications of cirrhosis identified above, including hepatocellular carcinoma.^7,14 Overall, chronic hepatitis progresses to end-stage liver disease in 15%-40% of patients.¹⁰

Treatment
Treatment of acute hepatitis is largely supportive⁸; most patients with acute hepatitis B do not require treatment. Those with fulminant hepatic failure should be considered for liver transplantation.¹⁰ Individuals with HBV infection should undergo a detailed evaluation to assess baseline liver function and the necessity for further treatment and follow up.

The goal of treatment of chronic hepatitis B is to prevent progression to cirrhosis and hepatocellular carcinoma by preventing viral replication and suppressing inflammation. Because of its unpredictable clinical course and poor response to treatment, as well as consideration regarding its cost effectiveness, therapeutic decisions become difficult. To date, antiviral treatment has not been shown to provide clear benefit in patients with decompensated cirrhosis. For them, liver transplantation may be the only option.¹⁰

ENTECAVIR (Baraclude)

Baraclude has been approved for treatment of chronic hepatitis B infection. Approval was based on three unpublished, randomized, double-blind clinical trials.¹⁵ Taken orally as monotherapy, Baraclude appears to be superior to other antiviral drugs for treatment of chronic HBV infection.^13,16

Mechanism of Action/Microbiology
Entecavir is a guanosine nucleoside analogue with activity against HBV polymerase.¹⁵ A prodrug, entecavir is phosphorylated to its active triphosphate form, entecavir triphosphate, that competes with the natural substrate deoxyguanosine triphosphate to inhibit all three activities of HBV polymerase (reverse transcriptase): (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir exhibits in vitro activity specifically against hepadnaviruses. It has little or no activity against other viral pathogens.¹³

Adverse Effects
One thousand seven-hundred and twenty patients with chronic HBV infection received entecavir 0.5 mg/day, 1 mg/day, or lamivudine for up to 107 weeks in premarketing studies. The most often reported adverse events of any severity in subjects receiving entecavir were headache, fatigue, dizziness, and nausea. The most common events in patients receiving the comparator (lamivudine) were headache, fatigue, and dizziness. One percent of patients in the entecavir group, compared with 4% of lamivudine-treated patients, discontinued therapy because of adverse events or abnormal laboratory test results.

Severe acute exacerbations of hepatitis B have occurred in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely in patients who discontinue therapy, with follow-up for at least several months. Therapy may be reinstated if appropriate.

Safety and efficacy of Baraclude in liver transplant recipients are unknown. If Baraclude treatment is necessary for a liver transplant recipient who has received or is receiving immunosuppressant therapy such as cyclosporine or tacrolimus that may affect renal function, renal function must be carefully monitored throughout treatment with Baraclude. Dosage adjustment downward is warranted for individuals with creatinine clearance <50 mL/min, including patients on hemodialysis or peritoneal dialysis. Figure 1 shows the boxed warning for Baraclude.

Figure 1. Boxed warning for Baraclude¹⁵

Drug Interactions
Co-administration of Baraclude with drugs that reduce renal function or compete for active tubular secretion may increase blood levels of either entecavir or the co-administered drug. Concomitant administration of Baraclude with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not result in significant drug interactions in premarketing clinical trials. The outcome of administration of Baraclude with other drugs that are eliminated by renal mechanisms or are known to affect renal function has not been evaluated and patients should be monitored for adverse events when Baraclude is taken with such drugs.

Indications and Uses
Baraclude is indicated for the treatment of chronic HBV infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST), or histologically active disease. This indication is based on histologic, virologic, biochemical, and serologic responses after one year of treatment in nucleoside-treatment-naïve and lamivudine-resistant adult patients with chronic HBV infection and compensated liver disease, and on limited data in adult patients with HIV/HBV co-infection who have received prior lamivudine therapy.

Dosage and Availability
The recommended dose of Baraclude for chronic HBV infection in nucleoside-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily. The recommended dose in adults and adolescents aged 16 years and older who have a history of hepatitis B viremia while receiving lamivudine or who have lamivudine resistant mutations is 1 mg once daily. Baraclude should be taken on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal). The optimal duration of treatment is unknown; in Phase 3 clinical trials, patients discontinued Baraclude or lamivudine treatment after 52 weeks.

Baraclude Oral Solution contains 0.05 mg of entecavir per milliliter. Ten milliliters of the solution, therefore, provides a 0.5 mg dose.

Patient Information
The following patient information is relevant to the use of Baraclude. The Product Information leaflet should be consulted for guidance.

• Baraclude is a drug used for chronic infection with hepatitis B virus in adults who also have liver damage. The medicine will not cure the infection or stop it from spreading to other people through having sex, sharing needles, or being exposed to infected blood.
• Call your doctor right away if you get any of the following signs of lactic acidosis: weakness; muscle pain; nausea, vomiting or stomach pain; dizziness or lightheadedness; cold sensation especially in your arms and legs; or fast or irregular heartbeat.
• Call your doctor right away if you get any of the following signs of liver problems: your skin or the white part of your eyes turn yellow; dark urine or light-colored stools; loss of appetite for several days; nausea; or lower stomach pain.
• Before you start taking this medicine tell your doctor if you have kidney problems, are pregnant or planning to become pregnant, or are breastfeeding.
• Tell your doctor about any other prescription or nonprescription medicines, vitamin/mineral supplements, and herbal remedies you are taking.
• Take this medicine once a day on an empty stomach, at least 2 hours after a meal and at least 2 hours before your next meal. Try to take it at the same time each day.
• Take this medicine exactly as prescribed; do not miss any doses. After you stop taking this medicine, be sure to stay under your doctor’s professional care.
• If you forget to take a dose, take it as soon as you remember (but on an empty stomach). If it is almost time for your next dose, skip the missed dose. Do not take two doses at the same time.
• Do not take this medicine if you are less than 16 years old.
• Store these tablets or solution at room temperature. Discard (ie, flush tablets in the toilet or pour liquid into the sink) any medicine that is no longer needed or is outdated.

FUNGAL INFECTIONS

Fungi appear microscopically as either rounded, budding forms (yeastlike organisms) or hyphae (molds). Yeastlike colonies appear as smooth colonies, while mold is a fuzzy fungus that grows as yeast. Yeast includes species of Candida and Cryptococcus. Fungi that grow as mold include Aspergillus and Rhizopus species, and dermatophytes (ringworm).

Pathogenic fungi in humans are saprophytes that cause infection when airborne spores invade the tissue of the lungs or paranasal sinus, or when hyphae or spores are inadvertently inoculated into the skin or cornea. Infection from another person or animals has been reported for ringworm but is extremely rare with other mycoses. Hospitalized patients with fungal infections therefore do not usually require special isolation. Ingestion of fungi rarely causes infection. Candida albicans, a normal inhabitant of the mouth and intestine, rarely reaches deeper tissues, but infection can occur when mucosal or cutaneous barriers are damaged by disease, surgery, trauma, or catheterization.¹⁷

Exposure to fungi may impart partial protection against reinfection. People living in areas where mycoses are endemic are less subject to infection than newcomers into the area. Immunoglobulin deficiencies do not appear to predispose to any fungus, whereas neutropenia is common among patients who develop deep-seated candidiasis. Cell-mediated immunity is of paramount importance in most other deep mycoses.¹⁷

Candida albicans is the most common cause of mucosal candidiasis, being responsible for about half of all cases of candidal infections in hospitalized patients. Candidiasis is a general term that describes a number of clinical syndromes caused by Candida.¹⁸ Candida species, taken together, constitute the fifth leading cause of nosocomial (ie, hospital or institutionally acquired) blood infections in the United States.¹⁹

Candidiasis is often preceded by increased colonization due to broad-spectrum antibiotic therapy. Oropharyngeal thrush is especially prone to occur in neonates and individuals with diabetes mellitus or HIV infection. It is common in persons with poorly fitting dentures.¹⁸ Vulvovaginal candidiasis is especially common in the third trimester of pregnancy. Candida can enter the urinary tract through an indwelling bladder catheter. Cutaneous candidiasis usually involves macerated skin, such as that in the diapered area of infants. Candida can pass from the colonized surface into deep tissue when the integrity of the mucosa or skin is violated, as for example, by perforation of the gastrointestinal tract through trauma, surgery, peptic ulceration, or by mucosal damage due to cytotoxic drug therapy used for treating cancer. Although Candida is not normally a resident of the skin, secretions from the mouth, rectum, or vagina, as well as drainage from surgical wounds or tracheostomy sites, can contaminate the hub or skin site of a catheter in an umbilical or central vein. Intravenous drug abuse or third-degree burns are other conditions that can lead to deep candidiasis.¹⁹

Esophageal Candidiasis
One of the most common deep-seated Candida infections, esophageal candidiasis, is often asymptomatic, although it can cause substernal pain or a sense of obstruction on swallowing.^18,20 The infection is often associated with significant morbidity but is seldom fatal.²⁰ Most lesions occur in the distal third of the esophagus, appearing on endoscopy as areas of redness and edema, focal white patches, or ulcers.

Esophagography (barium swallow) is diagnostically insensitive but may reveal spasm or mucosal irregularities. Esophageal candidiasis can cause bleeding and impaired gastrointestinal function. Hematogenous dissemination from the esophagus probably occurs in some neutropenic patients but is rare in HIV-infected individuals.¹⁹

Invasive Fungal Infections in Hematopoietic Stem Cell Transplantation
Invasive fungal infections now constitute one of the most important causes of morbidity and mortality in hematopoietic stem cell transplantation recipients.^21-23 Autograft recipients may develop invasive fungal infections due to neutropenia, but allogeneic hematopoietic stem cell transplantation recipients are at greater risk due to graft-versus-host disease and its treatment, and the delay in immune reconstitution.²⁴ Depending on risk factors (Table 4), the incidence of invasive fungal infections in hematopoietic stem cell transplantation recipients ranges between 14% and 25%.^22,25 C albicans and Aspergillus species account for the majority of cases.²⁴

Table 4. Risk Factors for Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients²⁴

• Host factors
  -Age >40 years
  -AMV seropositivity
  -Hematological malignancy in other than first remission
  -Myelodysplastic syndrome
• Environmental exposure
  -Previous history of invasive aspergillosis
• Type of stem cell transplant
  -Umbilical cord blood
  -HLA-donor-recipient mismatch
  -T cell depletion
• Therapeutic interventions
  -Fludarabine-based conditioning regimen
  -Infliximab anti-GVHD* therapy
• Transplant complications
  -Prolonged neutropenia and blood neutrophils <100/µl
  -Graft failure
  -Higher grade acute GVHD*
  -Extensive chronic GVHD*
__________________
*Graft-versus-host disease

MICAFUNGIN (Mycamine)

Historically, the mainstay for management of invasive fungal infections has been amphotericin B. A broad-spectrum antifungal with potent fungicidal activity, amphotericin B touts a notorious toxicity profile.²⁶ A search, therefore, has been underway for effective but less toxic antifungals. Itraconazole and fluconazole were introduced in the 1980s. Unfortunately, the use of these azole antifungals, despite their widespread acceptance, has been limited by their rather narrow spectra of activity and increasing concern regarding the emergence of azole-resistant Candida species.²⁷

In response to the need for additional antifungals, science has focused on developing new agents that exhibit fungicidal activity against a broad spectrum of fungi and possess fewer adverse effects and drug interactions in contrast to currently available drugs. Micafungin, marketed as Mycamine, is an outgrowth of research to meet this need. Micafungin is a novel, water-soluble lipopeptide obtained by semisynthetic modification of a naturally occurring hexapeptide.²⁸ Addition of a fatty N-acyl side chain enhances its antifungal property. Micafungin was isolated via enzymatic cleavage of the fungus Coleophoma empedri.²⁹ It belongs to a new class of antifungals known as echinocandins (“candins”), which currently includes caspofungin.³⁰

Mechanism of Action/Microbiology
Micafungin inhibits an enzyme, 1,3-beta-D-glucan synthase, that is required for synthesis of 1,3-beta-D-glucan, an essential component of fungal cell walls.^28,30,31 Because mammalian cells lack a cell wall component, the antifungal is less toxic to human cells.

The fungal cell wall provides shape and stability during growth and serves as a protective barrier against injury and osmotic instability that can lead to cell lysis.³² It also possesses adhesive molecules that permit the fungus to attach to and invade the host.³³ When 1,3-beta-D-glucan synthase is inhibited, the fungal cell forms a wall deficient in 1,3-beta-glucan.³⁰ Glucan is a fibrillar polysaccharide consisting of three helically entwined linear polymers of glucose, and its presence is critical to fungal cell walls. It comprises 30%-60% of Candida cell walls.²⁹ As a result of its inhibition, the integrity of the cell wall is compromised and cells can become irregularly shaped and swollen. Mature cells also often fail to separate from the parent cells and instead, form aberrant buds.³³ Micafungin exhibits in vitro activity against C albicans. C glabrata, C krusei, C parapsilosis, and C tropicalis. The potential for development of drug resistance is unknown.³¹

Adverse Effects
Safety was assessed in 1980 patients and 422 volunteers in premarketing clinical trials. Patients received single or multiple doses of micafungin ranging from 12.5 mg and up to and more than 150 mg/day. Overall, 84% of subjects experienced an adverse event; those considered to be drug related were noted in 29.9% of subjects.

Injection site reactions, including phlebitis and thrombophlebitis, have been reported at doses of 50-150 mg/day. These events occurred more often in patients receiving Mycamine via peripheral intravenous administration.

Isolated cases of serious hypersensitivity (anaphylaxis and anaphylactoid) reactions, including shock, have been reported with Mycamine. Other histamine-mediated symptoms included rash, pruritus, facial swelling, and vasodilatation.

Drug Interactions
Eleven clinical drug-drug interaction studies were undertaken in healthy volunteers to evaluate the potential for interaction between Mycamine and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. No interaction that altered the pharmacokinetics of Mycamine was observed. A single dose or multiple doses of Mycamine did not alter the pharmacokinetics of mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, or fluconazole.

Sirolimus AUC increased 21% with no effect on C_max in the presence of steady-state Mycamine compared with sirolimus alone. Nifedipine AUC and C_max were increased 18% and 42%, respectively, in the presence of steady-state Mycamine compared with nifedipine alone. Patients receiving sirolimus or nifedipine concurrently with Mycamine should be monitored for sirolimus or nifedipine toxicity, with the dosage of sirolimus or nifedipine reduced as appropriate.

Micafungin is not an inhibitor of P-glycoprotein. It, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. Since the drug is not metabolized by cytochrome P450 enzymes, fewer interactions are predicted than those reported for azole antifungals.^28,29

Indications and Uses
Mycamine is indicated for treatment of patients with esophageal candidiasis, and prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. Its efficacy against infections caused by fungi other than Candida has not been established. In fact, the major limitations to Mycamine appear to be its lack of effectiveness against C neoformans, Fusarium solani, and Pseudallescheria boydii, as well as poor bioavailability that necessitates intravenous administration.²⁹

Dosage and Availability
Mycamine is administered at 50 mg/day for prophylaxis of Candida infections in hematopoietic stem cell transplantation recipients, and 150 mg/day for treatment of esophageal candidiasis. Doses are given by intravenous infusion over 1 hour. More rapid infusions may result in more frequent histamine mediated reactions. Mycamine should not be mixed or co-infused with other medications since it precipitates when combined with a number of other drugs.

Mycamine is supplied in single-use vials containing 50 micafungin.

Patient Information
The following patient information is relevant to the use of Mycamine. The Product Information leaflet should be consulted for guidance.

• This medicine is used to treat certain fungus infections. It is available only in injection form.
• Tell your doctor if you have liver or kidney problems, are pregnant or contemplating pregnancy, or are breastfeeding.
• Tell your doctor about all prescription or nonprescription medicines, vitamin/mineral supplements, or herbal remedies you are taking.
• This medicine may cause gastrointestinal side effects such as nausea, vomiting, diarrhea, and abdominal pain. It may also cause certain blood disorders including anemia; and fever, rigors (chills), and pain at the site of injection.

THE QUEST FOR IMPROVED “RESISTANCE-RESISTANT” ANTIBIOTICS

The clinical successes obtained with antimicrobial drugs fanned a widespread misconception in the late 1960s and early 1970s that many infectious diseases had been conquered. Four decades later however, infectious diseases remain the third-leading cause of death in the United States,³⁴ and second-leading cause of death worldwide.³⁵ Moreover, the emergence of resistant bacteria (Table 5) has resulted in a number of life-threatening diseases for which there are few or no treatment options.^36-39 Antibiotic resistance costs the US economy between $4 billion and $5 billion annually.⁴⁰

Table 5. Multiresistant Bacteria for Which There are Currently Few Available Treatment Options³⁸

• Gram-negatives
  -Acinetobacter baumannii
  -Pseudomonas aeruginosa
  -Stenotrophomonas maltophilia
  -Some Klebsiella pneumoniae sp.
• Gram-positives
  -Methicillin-resistant Staphylococcus aureus
  -S. aureus with reduced susceptibility to vancomycin and/or Linezolid
  -Methicillin-resistant coagulase-negative staphylococci
  -Vancomycin-resistant enterococci
  -Multidrug-resistant Mycobacterium tuberculosis, rapidly growing mycobacteria,
   Mycobacterium avium complex

There continues to be growing concern about the increasing prevalence of bacterial resistance to antimicrobial drugs. This is especially true among gram-positive organisms including drug-resistant pneumococci and enterococci, and methicillin-resistant staphylococci.^41,42 There is a limited number of antimicrobials that remain effective in combating these resistant bacteria.

To illustrate, consider the tetracycline class of antibiotics. Some of the tetracycline antibiotics have been available for more than 50 years, but over the decades of widespread use, development of resistance has greatly reduced their clinical usefulness.^43,44

Structural alteration of the basic tetracycline molecule has led to development of more stable compounds, members of a new class referred to as the glycylcyclines.^45,46 Tigecycline, a representative glycylcycline, shows promising clinical activity against many pathogenic gram-positive and gram-negative organisms, including resistant gram-positive strains.^43,47-49

Antibiotics typically elicit their therapeutic response by binding to a specific receptor site within the invading organism. The primary receptor site for tigecycline and the tetracyclines is located in the bacterial ribosome. Tigecycline enters the bacterium via energy-dependent pathways or passive diffusion, and then binds reversibly to the 30S subunit of the ribosome. This binding prevents the crucial incorporation of transfer RNA into the ribosome with subsequent interference with incorporation of amino acid residues into elongating peptide chains (ie, protein synthesis).⁴⁶ Tigecycline is bacteriostatic in activity, most likely because of its reversible binding. This binding affinity is considerably stronger than for tetracycline or minocycline, resulting in less chance that resistant strains to the new drug will develop rapidly.⁴⁵

The possibility of development of resistance is always of significant concern with any new antimicrobial. The primary mechanism in tetracycline resistance involves export of the antibiotic from the cell through an efflux pump, or ribosomal protection that interferes with drug binding to the organisms’ receptor site. Over two dozen tetracycline-resistant genes have been characterized, some genes coding for the efflux mechanism, with others enhancing ribosomal protection. In gram-negative microorganisms, efflux genes are equally responsible for resistance to tetracycline, minocycline, and doxycycline. In contrast, genes in gram-positive organisms target tetracycline predominantly and have less influence on its derivatives.⁵⁰ Tigecycline is unique in its stability against the common mechanisms involved in tetracycline resistance, and has shown activity against bacterial strains containing the genes that code for either or both major forms of tetracycline resistance.⁴⁵

The mechanism that seems to protect against bacterial resistance to tigecycline is not clear. It is hypothesized that the antimicrobial is not recognized by resistant genes, or that its bulky side chain at position #9 prohibits the active efflux pump from exporting the compound.⁴⁴ Additionally, tigecycline has a much greater binding affinity for the ribosomal receptor site compared with tetracycline and its derivatives.⁵¹

TIGECYCLINE (Tygacil)

Tigecycline is a novel first compound in a new class of antibiotics, the glycylcyclines (a third-generation tetracycline class) to be approved for use in the United States. It was designed to circumvent the two major resistance mechanisms that have limited the use of many antibiotics: efflux pumps and ribosomal protection.^52,53

Mechanism of Action/Microbiology
Tigecycline inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome.⁵⁴ This blocks addition of amino acid residues into peptide chains to prevent their elongation. Tigecycline is not affected by the two major mechanisms that impart bacterial resistance: ribosomal protection and efflux pumps. Tigecycline therefore has in vitro and in vivo activity against most strains of a broad spectrum of bacterial pathogens (Table 6).

Adverse Effects
Phase 3 clinical trials included 1415 patients treated with Tygacil. Treatment was discontinued due to adverse events in 5.0% of patients compared to 4.7% for all comparator antimicrobials. The most common treatment-emergent adverse events were nausea and vomiting, which generally appeared during the first 2 days of therapy.

Tygacil may cause fetal harm when administered to pregnant women. A woman who becomes pregnant while taking Tygacil should be apprised of the potential hazard to the fetus. The use of Tygacil during tooth development (last half of pregnancy, infancy, and childhood to age 8 years) may cause permanent discoloration of the teeth.

Pseudomembranous colitis has been reported with nearly all antibacterial agents including Tygacil and range in severity from mild to life-threatening. This diagnosis must be considered in patients who develop diarrhea subsequent to the administration of any antibacterial drug.

Glycylcycline antibiotics are similar in structure to tetracycline antibiotics and may cause similar adverse events. Such events include photosensitivity, pseudotumor cerebri, and pancreatitis; and anti-anabolic action that can lead to elevated BUN, azotemia, acidosis, and hypophosphatemia.

Drug Interactions
Co-administration with warfarin has resulted in decreased clearance of R-warfarin and S-warfarin by 40% and 23%, respectively. Tygacil has increased the C_max of digoxin by 13% without affecting the AUC or clearance of digoxin. Tygacil does not significantly alter the effects of warfarin on the INR. It is recommended that prothrombin time or other suitable anticoagulation test be monitored if Tygacil is administered with warfarin.

Tygacil does not inhibit any of the following cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Therefore, it is not expected to alter the metabolism of drugs metabolized by these enzymes. Moreover, because Tygacil is not metabolized extensively, its clearance is not expected to be affected by drugs that inhibit or induce the activity of these CYP450 isoforms.

Indications and Uses
Tygacil is indicated for the treatment of complicated skin and skin structure infections and complicated intra-abdominal infections caused by susceptible strains of the designated microorganisms listed in Table 6.

Dosage and Availability
The recommended dosage is 100 mg to start, followed by 50 mg every 12 hours. Intravenous infusions of Tygacil should be administered over 30-60 minutes every 12 hours. Treatment for complicated skin and skin structure infections or for complicated intra-abdominal infections should continue over 5-14 days.

Tygacil is supplied in a single-dose 5 mL vial containing 50 mg lyophilized powder for reconstitution.
Patient Information

The following patient information is relevant to the use of Tygacil. The Product Information leaflet should be consulted for guidance.

• Tygacil is an antibiotic used for treating complicated infections of the skin or inside the abdominal cavity in adults 18 years of age and older.
• This medicine may cause birth defects when given to pregnant women, including a darkening of the teeth in babies if given during the last half of pregnancy.
• This medicine can kill healthy bacteria in your intestines to cause severe diarrhea. Be sure to tell your doctor right away if you get diarrhea.
• Before you start taking this medicine tell your doctor if you have severe liver problems, are pregnant or planning to become pregnant, or are breastfeeding.
• Tell your doctor about any other prescription or nonprescription medicines, vitamin/mineral supplements, and herbal remedies you are taking.
• The most common side effects with this medicine are nausea, vomiting, and diarrhea.

HIV/AIDS

Since its identification in the mid-1980s as the causative agent of AIDS,⁵⁵ the human immunodeficiency virus (HIV) has been the focus of in-depth scientific inquiry and many thousands of research-based investigations. HIV is the most studied virus in history.⁵⁶ The incidence of AIDS in the United States increased rapidly from its onset, peaked in the early 1990s, and then declined somewhat beginning in the mid-1990s.⁵⁷ From 1998 however, declines in both incidence and deaths leveled off. Today, the number of persons in the United States living with HIV continues to increase, partly due to longer lifespan resulting from effective drug therapy.⁵⁸

For AIDS to be maximally controlled, HIV-infected persons must be diagnosed early in the progression of their disease and commit to strict adherence with chronic treatment strategies that will continue over their lifetime. They must also adhere to a strict life-style protocol (eg, protected sex) to prevent acquisition or transmission of new infections.⁵⁹ The Centers for Disease Control and Prevention (CDC) estimates that approximately 40,000 persons become infected with HIV each year in the United States.⁶⁰ This includes more than 300 infants each year who contract HIV because their mothers are infected.⁶¹

Epidemiology
HIV is transmitted primarily by behaviors that encourage exchange of blood or body fluids containing the virus and/or HIV infected cells. The virus has been documented in blood and blood products, semen, vaginal secretions, breast milk, tears, urine, cerebrospinal fluid, and saliva. Only HIV in blood, semen, breast milk, and vaginal fluids however, is a serious source of infection.⁶²

The risk of acquiring the infection from a single sexual event is relatively low (Table 7). Transmission via sexual contact depends on the type and frequency of encounters and presence of risk factors such as unprotected sex. The incidence of HIV transmission in persons who do not use condoms or who use them incorrectly is increased significantly, compared with the incidence in persons who do practice protected sex. The greatest per-act risk for HIV transmission is associated with blood transfusion, needle sharing by injection-drug users, receptive anal intercourse, and per cutaneous needlestick injuries. Insertive anal intercourse, penile-vaginal exposures, and oral sex represent substantially less per-act risk.⁶³