1From the Department of Pharmacy Services, Baylor University Medical Center, Dallas, Texas.
Corresponding author: Nickie D. Greer, PharmD, BCPS, Department of Pharmacy Services, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, Texas 75246 (e-mail: NickiG@BaylorHealth.edu).
Tigecycline is the first drug in the glycylcycline class of antibiotics. Although it is structurally related to minocycline, alterations to the molecule resulted in its expanded spectrum of activity and decreased susceptibility to the development of resistance when compared with other tetracycline antibiotics. Tigecycline has a broad spectrum of activity, including activity against drug-resistant gram-positive organisms. Randomized trials have shown tigecycline to be efficacious for the treatment of complicated intraabdominal infections and complicated skin and skin structure infections. The dose of tigecycline is 50 mg intravenously every 12 hours after a 100-mg loading dose. Nausea, vomiting, and diarrhea were the most common adverse events reported with tigecycline therapy and may result in discontinuation of therapy.
Resistant organisms remain a concern in hospitalized patients and are becoming an increased concern in community-acquired infections. Gram-positive organisms continue to increase in resistance, and very few agents are available to treat these infections. Available options include vancomycin, linezolid, daptomycin, and quinupristin/ dalfopristin. These antimicrobials have improved treatment of resistant gram-positive organisms but may have adverse events that require discontinuation. For this reason, new antimicrobials are needed to treat resistant organisms without sacrificing safety.
Tetracyclines are broad-spectrum antibiotics that have been available since the mid-1900s, but use in recent years has been limited by widespread resistance to these agents. Resistance generally occurs by alterations in tetracycline efflux or ribosomal protection. The glycylcyclines were developed to help overcome these resistance mechanisms. Tigecycline, approved by the Food and Drug Administration (FDA) on June 15, 2005, is the first drug in this class of antimicrobials. Alterations to the tetracycline structure allow tigecycline to maintain activity against tetracycline-resistant organisms, including resistant gram-positive organisms such as penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), and vancomycin-resistant Enterococcus (VRE) species. Tigecycline is approved for the treatment of complicated skin and skin structure infections (cSSSI) and complicated intraabdominal infections caused by susceptible organisms (1).
Tigecycline is a glycylcycline antimicrobial structurally related to minocycline. Like minocycline, tigecycline binds to the bacterial 30S ribosome, blocking the entry of transfer RNA. This ultimately prevents protein synthesis by halting the incorporation of amino acids into peptide chains and thus limits bacterial growth (1–3). However, the addition of an N,N,-dimethylglycylamido group at the 9 position of the minocycline molecule increases the affinity of tigecycline for the ribosomal target up to 5 times when compared with minocycline or tetracycline (4). This allows for an expanded spectrum of activity and decreased susceptibility to the development of resistance (1, 2, 5).
Pharmmacokinetics and Pharmacodynamics
Because it is administered intravenously, tigecycline is 100% bioavailable (1). Tigecycline is highly protein bound and has a large volume of distribution (7–9 L/kg) when compared with the other available tetracyclines. Concentrations of tigecycline in the gallbladder, lung, and colon are higher than serum concentrations (1), while concentrations of tigecycline in the bone and synovial fluid are lower than serum concentrations (7). In vitro studies have shown that tigecycline is not extensively metabolized (1). A slight amount of metabolism may occur via glucuronidation. Tigecycline has an elimination half-life of approximately 36 hours (1, 3). It is mainly eliminated as unchanged drug and metabolites in the bile and feces (59%). Another 22% of the drug is excreted as unchanged drug in the urine.
Based on pharmacokinetic studies, no dosage adjustment is required based on age, sex, or race (1–3, 8).
A study evaluated the pharmacokinetics of tigecycline in patients with mild, moderate, and severe hepatic impairment (Child-Pugh class A, B, and C, respectively) (1). Compared with healthy control subjects, patients with mild hepatic impairment did not have alterations in the pharmacokinetic profile. Patients with moderate hepatic impairment had an increase in the half-life of tigecycline by 23% and a decrease in systemic clearance by 25%. Tigecycline clearance was reduced by 55% and the half-life was lengthened by 43% in patients with severe hepatic impairment. Based on this information, dosage adjustments are not recommended in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment should receive a 100-mg loading dose of tigecycline followed by a maintenance dose of 25 mg every 12 hours.
A single-dose study compared pharmacokinetic parameters of tigecycline in 6 healthy subjects, 6 patients with a creatinine clearance <30>1, 2). Half of the patients with ESRD received tigecycline prior to hemodialysis and half received it after hemodialysis. Patients with renal impairment (creatinine clearance <30>
Multiple studies have been conducted to evaluate the pharmacodynamic parameters of tigecycline (2–4). One study evaluated the pharmacodynamic activity of tigecycline against Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae using the neutropenic murine thigh model. All isolates were susceptible to tigecycline, with activity dependent on the time above the minimum inhibitory concentration (MIC). The study found that optimal activity was achieved when tigecycline levels were maintained above the MIC for >50% of the dosing interval. A postantibiotic effect of 9 hours and 5 hours was noted against Streptococcus pneumoniae and Escherichia coli, respectively, following a 3-mg/kg dose. This postantibiotic effect was shown to be superior to that of minocycline for all tested species.
Tigecycline has been shown to be a bacteriostatic agent against Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, and Staphylococcus aureus (4). Bacteriostatic activity and bacteriocidal activity have been reported against Streptococcus pneumoniae.Spectrum of Activity
As shown in Table 2, tigecycline has a broad spectrum of activity against many gram-positive, gram-negative, and anaerobic organisms (1, 3, 4, 9). Coverage includes many multidrug-resistant strains of gram-positive organisms, such as MRSA and MRSE, penicillin-resistant Streptococcus pneumoniae, and VRE species. Tigecycline has also shown activity against organisms that have developed resistance to tetracycline via various mechanisms.
Minocycline remains more active than tigecycline against methicillin-susceptible Staphylococcus aureus and Staphylococcus epidermidis, while tigecycline is more active against the methicillin-resistant strains of these organisms. Tigecycline has demonstrated improved activity against Streptococcus species, including penicillin-susceptible, penicillin-intermediate, and penicillin-resistant strains of Streptococcus pneumoniae. Tigecycline also has improved activity against Enterococcus species when compared with the other tetracycline agents. Tigecycline, minocycline, and doxycycline have better activity against Listeria monocytogenes when compared with tetracycline.
Equal activity is seen against many gram-negative organisms among the tetracyclines (1, 3, 4). Tigecycline does display improved activity in vitro when compared with the other tetracyclines against the following organisms: Citrobacter freundii, Escherichia coli, Enterobacter cloacae, Klebsiella species, Salmonella species, Serratia marcescens, and Shigella species. Tigecycline and minocycline cover Acinetobacter species (10). Tigecycline is less active than minocycline against Stenotrophomonas maltophilia and Burkholderia cepacia. None of the tetracyclines have coverage against Pseudomonas aeruginosa. Tigecycline also does not have activity against certain Proteus strains, including Proteus mirabilis.
Tigecycline may be more effective than other tetracyclines against anaerobic organisms such as Bacteroides fragilis, Peptostreptococcus species, and Propionibacterium acnes. Tigecycline is also active against some atypical organisms.
LaPlante and Rybak conducted a study to evaluate the activity of arbekacin, tigecycline, daptomycin, and vancomycin against glycopeptide-intermediate staphylococci (GISS) and heterogeneous glycopeptide-intermediate staphylococci (hGISS) (11). An hGISS is a staphylococci isolate that is susceptible to vancomycin but contains subpopulations that are intermediately susceptible to vancomycin. A total of 47 strains of hGISS and GISS were obtained from various locations worldwide. The majority of isolates were Staphylococcus aureus (n = 35). MICs were determined according to guidelines from the National Committee for Clinical Laboratory Standards. A total of 25 isolates (53.2%) were categorized as GISS (MIC, 8 μg/mL to vancomycin), and 22 isolates (46.8%) were categorized as hGISS (MIC, 4 μg/mL to vancomycin). The minimum inhibitory concentration required to inhibit the growth of 90% of organisms (MIC90) for arbekacin, daptomycin, tigecycline, and vancomycin was 2, 1, 25 mg or 50 mg of tigecycline intravenously every 12 hours for 7 to 14 days. Patients in the 25-mg group received a loading dose of 50 mg, and patients in the 50-mg group received a loading dose of 100 mg. Patients could be discharged home after 3 days and continue receiving infusions as an outpatient. The primary endpoint was clinically observed cure rate at the “test-of-cure” visit (approximately 3 weeks after initiation of therapy) among evaluable patients. Cure was defined as the resolution of all signs and symptoms of the infection to the extent that no further antibiotic therapy was needed. The secondary endpoints were clinical cure rates at the end of treatment and microbial eradication rates.
At the end of therapy, 78% of patients in the 25-mg group and 85% of patients in the 50-mg group were considered cured. At the test-of-cure visit, 67% of patients in the 25-mg group and 74% of patients in the 50-mg group were deemed clinically cured. Six patients per group experienced cure at the end of treatment and then were deemed a “failure” at the test-of-cure visit. At the end of therapy, bacterial eradication occurred in 62% of patients in the 25-mg group and 74% of patients in the 50-mg group. At the test-of-cure visit, bacterial eradication occurred in 56% of patients in the 25-mg group vs 69% of patients in the 50-mg group. Adverse events were similar in the 25-mg and 50-mg groups, with nausea being the most common adverse event noted. Nausea occurred in 28% of patients, but only two patients discontinued therapy due to this adverse event. Laboratory abnormalities probably related to tigecycline included elevated serum levels of transaminases, alkaline phosphatase, and blood urea nitrogen as well as anemia. All of these were rare occurrences. The authors 0.5, and 8 μg/mL, respectively, against GISS isolates. Time-kill results showed that daptomycin demonstrated bactericidal activity throughout the 24-hour period. Arbekacin and tigecycline displayed bacteriostatic activity at 24 hours.
Dose-ranging study Postier and colleagues conducted a multicenter, randomized, open-label, dose-ranging study to evaluate the efficacy and safety of two doses of tigecycline for the treatment of skin and skin structure infections in 160 patients (12). Patients received either concluded that tigecycline is safe and efficacious for the treatment of cSSSI. This dose-ranging study showed that 50 mg twice daily of intravenous tigecycline had higher rates of cure, so this dose was chosen for further clinical study.
Complicated intraabdominal infections The Infectious Diseases Society of America published updated guidelines for the treatment of complicated intra-abdominal infections in 2003 (13). The guidelines recommend treating mild to moderate community-acquired intraabdominal infections with ampicillin/sulbactam, cefazolin plus metronidazole, or ertapenem. If patients can take oral therapy, use of a fluoroquinolone, such as levofloxacin, plus metronidazole or amoxicillin/clavulanate alone is acceptable treatment. High-risk patients, defined as patients with other medical conditions or immunosuppression, are recommended to receive treatment with carbapenems (e.g., imipenem/cilastatin, ertapenem, or meropenem), piperacillin/tazobactam, a fluoroquinolone plus metronidazole, or a third- or fourth-generation cephalosporin (e.g., ceftriaxone, cefepime) plus metronidazole. Hospital-acquired intraabdominal infections are more likely to be caused by resistant organisms due to length of hospital stay and prior antimicrobial therapy. In this case, combination therapy is usually indicated and should include one of the above regimens plus vancomycin if resistant gram-positive organisms are suspected. Empiric enterococcal coverage is not routinely recommended in patients with community-acquired infections and is recommended in hospital-acquired infections only when Enterococcus isolates are recovered.
Babinchak and colleagues reported on a pooled analysis of two phase 3 double-blind trials conducted to evaluate the safety and efficacy of tigecycline vs imipenem/cilastatin for the treatment of complicated intraabdominal infections in 1642 patients (14). Patients were entered into the study if they were at least 18 years of age and required surgery to treat a complicated intraabdominal infection (Table 3).
Exclusion criteria for the study are listed in Table 4. Patients with neutropenia, active malignancy, AIDS, and abdominal malignancy within the past 6 months were excluded from the study, which makes it difficult to extrapolate the results to these populations. Additionally, patients with hepatic and renal dysfunction were excluded from the study, as were patients receiving concomitant ganciclovir.
Patients received tigecycline (100-mg loading dose followed by 5 mg every 12 hours, both given intravenously) or imipenem/cilastatin 500 mg intravenously every 6 hours. Imipenem/cilastatin doses were adjusted for body weight and creatinine clearance results. The primary endpoint was clinical response at the test-of-cure visit (12–42 days after therapy) for the microbiologically modified-intention-to-treat (m-mITT) and microbiologically evaluable populations (n = 1262 and n = 1025, respectively). Safety was assessed on the modified-intention-to-treat (m-ITT) population (n = 1642). Baseline characteristics were similar between the groups. Cure rates for the m-mITT population were 80.2% for the patients treated with tigecycline vs 81.5% for the patients in the imipenem/ cilastatin group (P <>
Adverse events on the whole were similar between the groups. However, patients treated with tigecycline experienced significantly more nausea and vomiting than patients treated with imipenem/cilastatin(P = 0.01 and P = 0.008, respectively). Patients in the tigecycline group also experienced higher rates of infection and leukocytosis than patients in the imipenem/ cilastatin group (P < p =" 0.03," p =" 0.038).">
This study did show the noninferiority of tigecycline. However, infection and postoperative wound infection rates were significantly higher in the tigecycline group. The rate or type of infection was not addressed by the authors, so it is unclear if these represented recurrent infections or new resistant infections. The authors stated that although the wound infection rates were higher in the tigecycline group, the rates were similar to those published in the literature. No comment was made on the higher rate of leukocytosis in these patients, but that may be an adverse effect to watch for as use of tigecycline increases.
Complicated skin and skin structure infectionsThe Infectious Diseases Society of America published practice guidelines for the treatment of skin and soft tissue infections in 2005 (15). The guidelines recommend nafcillin or cefazolin for patients with cSSSI caused by suspected methicillin-sensitive Staphylococcus aureus. Clindamycin or vancomycin may be used for those patients who are allergic to penicillin. Vancomycin or linezolid may be used for the treatment of cSSSI caused by suspected MRSA. A penicillin plus a beta-lactamase inhibitor (e.g., ampicillin/sulbactam or piperacillin/tazobactam), carbapenems, or a fluoroquinolone plus clindamycin may be used for cSSSI caused by multiple organisms.
Ellis-Grosse and colleagues reported on pooled data from two randomized, double-blind trials evaluating the safety and efficacy of tigecycline vs vancomycin/aztreonam for the treatment of cSSSI in 1116 patients (16). Inclusion and exclusion criteria are shown in Table 5
Patients received a tigecycline 100-mg intravenous loading dose followed by 50 mg intravenously every 12 hours. Vancomycin was given at a dose of 1 g intravenously every 12 hours and could be adjusted based on renal function. Aztreonam was given at a dose of 2 g intravenously every 12 hours and could be discontinued after 48 hours at the investigators' discretion. Treatment was continued for up to 14 days. The primary endpoint was clinical response within the clinically evaluable and the clinical m-ITT populations at the test-of-cure visit (days 12–92 after the last dose of study drug). The clinical m-ITT group included 1057 patients, and the clinically evaluable group included 833 patients. The cure rates in the clinical m-ITT groups were 79.7% in the tigecycline group and 81.9% in the vancomycin/aztreonam group (P <>
Significantly more patients in the tigecycline group had gastrointestinal adverse events (diarrhea, anorexia, dyspepsia, nausea, and vomiting) than patients in the vancomycin/aztreonam group (46% vs 21%, P <>Resistance
Because of widespread use of the various tetracycline agents in the past, resistant organisms are commonly seen. Tetracycline resistance typically results from one of the following: chemical modification, efflux of the antibiotic out of the cell, or decreased binding of the antibiotic to the target receptor due to ribosomal protection (2, 3, 5, 17, 18). Numerous tetracycline-resistant genes have been identified. These genes code for efflux or ribosomal protection. Gram-negative organism resistance to tetracycline, minocycline, and doxycycline is mainly due to efflux genes. Gram-positive organism resistance to tetracycline is due to efflux genes, but efflux is not as important for resistance to the tetracycline derivatives.
Tigecycline has shown activity against organisms containing either efflux or ribosomal protection genes (2, 3). This activity is thought to be due to tigecycline's increased binding affinity for the ribosomes. The tetracycline-resistance gene cannot disrupt the tigecycline-ribosome bond, rendering the gene unable to interact with the ribosome and protect it. It is also speculated that the large side chain added to the tigecycline molecule keeps the efflux pump from pumping it out of the cell.
The development of resistance to tigecycline by organisms normally sensitive to tigecycline has not been noted to date, either in nature or in the laboratory (2, 3). Two veterinary Salmonella strains resistant to earlier investigational glycylcyclines have been isolated, but no resistance to tigecycline was noted.Adverse Effects
Adverse effect information is compiled from data collected on 1415 patients in the phase 3 clinical trials (1, 3, 4). Adverse effects were mild in most patients and similar to placebo (Table 6). In 5% of patients in the tigecycline groups vs 4.7% in the comparator groups, therapy was discontinued due to adverse events. The most common adverse events reported with tigecycline therapy were similar to adverse effects seen with the tetracycline class and included nausea (29.5%), vomiting (19.7%), and diarrhea (12.7%). These events are thought to be caused by an irritant effect of tigecycline on the gastric mucosa.
Hepatic toxicity is a rare occurrence with tetracyclines and occurs mainly in patients who receive high doses (3). Tigecycline was shown to increase hepatic enzymes and bilirubin in clinical trials. Hyperbilirubinemia occurred more often in the tigecycline group than in the comparator group.
Infection-related adverse events were more common with tigecycline therapy (1). The incidence of sepsis and septic shock was significantly higher in tigecycline patients (1.5%) than in comparators (0.5%). Clinical studies reported the higher rate of infection but did not clarify what factors may have contributed to this finding. It may be due to baseline differences in patients' severity of illness prior to initiation of tigecycline.
Tetracyclines can inhibit bone growth in children and cause dental staining due to deposition of drug in the teeth and bone (1, 3). The latter may occur at any time from the last months of gestation to age 8. Tigecycline, like other tetracyclines, is not recommended for pregnant women or children younger than 8 years.
One case of possible tigecycline-related Clostridium difficile infection has been reported to date (1, 4). Additionally, post-marketing reports have associated tigecycline with the development of acute pancreatitis (1).
The recommended dose of tigecycline is 50 mg every 12 hours after a 100-mg loading dose (1). If a patient has severe hepatic impairment (Child-Pugh class C), a dose of 25 mg every 12 hours should be given after a loading dose of 100 mg. Doses are given intravenously over 30 to 60 minutes.
Table 7 lists the cost of tigecycline and other antimicrobials for a 7- and 10-day course of therapy (Baylor University Medical Center acquisition costs). For MRSA and other resistant organisms, vancomycin remains the least expensive and daptomycin the most expensive agent. Tigecycline is less expensive for a course of therapy than both linezolid and daptomycin. Tigecycline is more expensive than imipenem/cilastatin and approximately equivalent in cost to aztreonam plus vancomycin. Tigecycline is also approximately equivalent in cost to imipenem/cilastatin plus vancomycin. For a 10-day course of therapy, tigecycline monotherapy costs about $250 more than piperacillin/tazobactam plus vancomycin; $250 more than 4. Nathwani D. Tigecycline: clinical evidence and formulary positioning. ampicillin/sulbactam plus vancomycin; and $600 more than levofloxacin plus metronidazole.
Tigecycline should be used when coverage is needed for resistant gram-positive organisms as well as gram-negative and anaerobic organisms. It should not be used for patients who are not at risk of resistant infections or in patients who have infections sensitive to vancomycin, unless the patient is not responding to vancomycin therapy. Empiric use of tigecycline may be appropriate in select patients in the intensive care unit, although care must be taken that Pseudomonas aeruginosa coverage is added to those patients at risk of infections caused by that organism. To avoid the development of resistance, tigecycline should not be used for infections caused by gram-positive organisms only, unless other agents have failed to work.
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