Results of a multicenter, randomized, open-label efficacy and safety study of two doses of tigecycline for complicated skin and skin-structure infections in hospitalized patients

CLINICAL THERAPEUTICS® / VOL. 26, NO. 5, 2004

Results of a Multicenter, Randomized, Open-Label Efficacy and Safety Study of Two Doses of Tigecycline for Complicated Skin and Skin-Structure Infections in Hospitalized Patients Russell G. Postier, MD,1 Stephen L. Green, MD,2 Stanley R. Klein, MD,3 E.J. Ellis-Grosse, PhD,4 and Evan Loh, MD,4 for the Tigecycline 200 Study Group* 1University

Virginia,

of Oklahoma Medical Center, Oklahoma City, Oklahoma, 2Hampton Roads Medical Specialists, Hampton, Medical Center, Torrance, California, and 4Wyeth Research, Collegeville, Pennsylvania

3Harbor-UCLA

ABSTRACT

Background: Tigecycline is a broad-spectrum glycylcycline antibiotic being investigated for the treatment of serious infections in hospitalized patients. Tigecycline has been shown to be efficacious against serious infections in animals, and preliminary studies in healthy adults have shown that tigecycline has an acceptable tolerability profile. Objective: This study compared the clinical and microbiological efficacy, pharmacokinetic properties, and tolerability of 2 doses of tigecycline in hospitalized patients with a complicated skin and skin-structure infection (cSSSI). Methods: This Phase II, randomized, open-label study was conducted between September 1999 and March 2001 at 14 investigative centers across the United States. Patients were randomized to receive tigecycline 25 or 50 mg IV q12h for 7 to 14 days. The primary efficacy end point was the clinically observed cure rate among clinically evaluable (CE) patients at the test-of-cure visit. Secondary end points were the clinical cure rate at the end of treatment and bacteriologic response in microbiologically evaluable (ME) patients. Also, in vitro tests of susceptibility to tigecycline were performed for selected pathogens known to cause skin infections, including methicillinresistant and methicillin-susceptible Streptococcus pyogenes, Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, and Enterococcus faecium. Tolerability assessments also were conducted. Results: A total of 160 patients received ≥1 dose of tigecycline; 109 patients were CE, and 91 were ME. The majority of patients (74%) were men, and the mean (SD) age was 49.0 (14.8) years. At the test-of-cure visit, the clinical cure rate in the 25-mg group was 67% (95% CI, 53.3%–79.3%) and in the 50-mg group was 74% (95% CI, 60.3%–85.0%). In the 25-mg group, 56% of the patients had eradication (95% CI, 40.0%–70.4%) of the pathogens compared with 69% (95% CI, 54.2%–82.3%) in the 50-mg group. Values for the minimum concentration of tigecycline that is inhibitory for 90% of all isolates ranged from 0.06 to 0.50 µg/mL for the selected pathogens. Both tigecycline doses were generally well tolerated. Nausea and vomiting were the most common adverse events. Conclusions: In this study, tigecycline appeared efficacious and showed a favorable pharmacokinetic profile and an acceptable safety profile in the treatment of hospitalized patients with cSSSI. In patients who received 50-mg doses of tigecycline q12h, the clinical cure rates and microbial eradication rates were 74% and 70%, respectively, and were 67% and 56% in patients who received 25-mg doses. (Clin Ther. 2004;26:704–714) Copyright © 2004 Excerpta Medica, Inc. Key words: tigecycline, glycylcycline, skin and skin-structure infection, antimicrobial resistance. The data in this study were presented in part at the 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, September 14–17, 2003. Abstract 3624. *Members of the Tigecycline 200 Study Group are listed in the Acknowledgments. Accepted for publication March 29, 2004. Printed in the USA. Reproduction in whole or part is not permitted.

704

0149-2918/04/$19.00

Copyright © 2004 Excerpta Medica, Inc.

R.G. Postier et al.

INTRODUCTION

Virtually all of the most common infectious bacteria have developed mechanisms of resistance to ≥1 class of antibiotics.1 Tigecycline is a broad-spectrum glycylcycline antibiotic2 that is being investigated for the treatment of serious infections, such as complicated skin and skin-structure infection (cSSSI), in hospitalized patients. Tigecycline was designed to circumvent 2 of the more commonly evolved drug-resistance mechanisms of bacteria—efflux and ribosomal protection.3 It inhibits protein synthesis and cell growth in bacteria, presumably by binding to the bacterial 30S ribosomal subunit and blocking amino acyl transfer RNA molecules from entering the A site of the ribosome.4 Tigecycline has excellent in vitro activity against a broad range of pathogens, including methicillinresistant Staphylococcus aureus (MRSA), methicillinsusceptible S aureus (MSSA), Escherichia coli, Enterococcus faecalis, and Enterococcus faecium.5 Although tigecycline has demonstrated in vitro bactericidal activity, it is considered to be bacteriostatic.6 Animal studies7,8 have shown that intravenously delivered tigecycline is distributed into several tissues, including skin, lung, bone, kidney, liver, and heart, and that the drug is efficacious in the treatment of serious infections. Ascending-dose studies in healthy adults9,10 have shown tigecycline to be generally well tolerated in fed subjects at doses ≤100 mg q12h. Because animal studies have shown lower doses of tigecycline to be effective against experimental infections, 25- and 50-mg– dose regimens were chosen for the present trial. This article presents the clinical and microbiological efficacy, pharmacokinetic properties, and tolerability of 2 doses of tigecycline in a Phase II clinical trial. PATIENTS AND METHODS Study Design

This Phase II, randomized, open-label, dosecomparison study was conducted between September 1999 and March 2001 at 14 investigative centers across the United States. Each center received approval of the study protocol from its independent institutional review board. Patients

Eligible study participants were hospitalized men and women aged 18 to 85 years with a cSSSI that involved deep soft tissue or required significant surgical

intervention. cSSSIs included infected ulcers, burns, or bites; major abscesses; and superficial infections or abscesses with a high risk for infection by anaerobic or gram-negative pathogens. Patients were excluded if they had necrotizing fasciitis, gangrene, osteomyelitis contiguous to the cSSSI site, or a concomitant infection that required treatment with another antimicrobial agent. Patients were also excluded if they were hypersensitive to tigecycline or tetracycline agents or had renal insufficiency. Pregnant, possibly pregnant, or breastfeeding women were excluded from the study. These patients were excluded because the teratogenic effects of the drug are not well known.Women of childbearing age were required to use an effective method of birth control throughout the study. All eligible patients provided written informed consent to participate. Methods

Dose levels and the timing of drug infusions were based on results from previous studies.9,10 Patients were randomized in a 1:1 ratio, according to a randomization schedule generated by the Biostatistics Section of Wyeth Research (Collegeville, Pennsylvania) and accessed through a central computerized randomization/enrollment system, to receive tigecycline, 25 or 50 mg IV q12h for 7 to 14 days. The drug was administered by a nurse. Patients assigned to the 25-mg group received an initial (loading) dose of 50 mg tigecycline; patients in the 50-mg group received a loading dose of 100 mg. Tigecycline was infused over 1-hour periods. After 3 days of inpatient treatment, patients could be discharged to receive tigecycline infusions at home from registered nurses or could continue therapy in the hospital setting. All patients who met the inclusion criteria and received ≥1 dose of study medication were included in the intent-to-treat (ITT) population. Patients were considered to be clinically evaluable (CE) if they received no concomitant antibiotic after their first dose of tigecycline, were maintained on tigecycline for 7 to 14 days (or treatment failed after 4 doses of tigecycline), and had test-of-cure visits ~3 weeks (±1 week) after therapy began. Patients were not CE if they received nonstudy antibiotics during the trial. CE patients were microbiologically evaluable (ME) if their baseline skin culture produced an identified causative pathogen with known susceptibility to antibiotics. 705

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Blood cultures were obtained by a nurse before treatment began, and skin cultures were also obtained by a nurse from the primary site of each patient’s cSSSI. All specimens were sent to local laboratories for primary isolation of the pathogens, which were tested for susceptibility to tigecycline using minimum inhibitory concentration (MIC) data or KirbyBauer disk-diffusion zones. The provisional MIC break points, based on in vitro susceptibility testing and numerous animal models, were as follows: ≤2 µg/mL = susceptible, >2–<8 µg/mL = intermediate, and ≥8 µg/mL = resistant. Recovered isolates were subcultured and tested for sensitivity using procedures published by the NCCLS.11–13 Results were reviewed and monitored for resistance to tigecycline with use of the disk-diffusion method. Efficacy End Points

The primary efficacy end point was the clinically observed cure (defined later) rate among CE patients at the test-of-cure visit. A secondary end point was the clinical cure rate at the end of treatment. Other secondary efficacy end points were the following 3 measures of bacteriologic response in ME patients at the test-of-cure visit: microbial eradication (defined later) rates in patients, microbial eradication rates of selected baseline organisms, and MIC values for the susceptibility of selected baseline organisms to tigecycline. Clinical End Points

Clinical assessment considered the presence or absence of erythema, swelling, edema, tenderness, pain, and warmth, and the extent of infection (width, length, and depth). The response to treatment was deemed to be a cure if all signs and symptoms of the original cSSSI were resolved or improved to such an extent that no further antibacterial therapy was necessary. The response was deemed to be a failure if the patient required additional antibacterial therapy or surgery after the initial dose of tigecycline and before or at the test-of-cure visit. A third category, indeterminate, was used if a patient was lost to follow-up or died for a non–infection-related reason. Bacteriologic End Points

In ME patients, microbial responses were classified as eradicated, persistent, superinfection, or indeterminate (the last as defined earlier). Eradication was defined as 706

the absence (presumed or documented) of the baseline pathogen in a repeat culture from the original cSSSI site, or as a clinical cure that precluded collection of a follow-up specimen. A response was considered as persistent if a baseline pathogen was identified in a follow-up culture from any infection site; if a new antimicrobial therapy was started to treat the original cSSSI; if tigecycline was continued beyond 14 days; or, in the absence of microbiologic data, if the original cSSSI recurred. Superinfection was defined as the emergence of a new pathogen at the original cSSSI site or at a distant site. At the pathogen level, eradication rates were determined for the selected baseline isolates: MRSA, MSSA, Streptococcus pyogenes, E coli, E faecalis, and E faecium. Responses in ME patients were classified as eradicated, indeterminate, or persistent, with persistence defined as the presence of a baseline pathogen in a repeat culture from the original cSSSI or by classification of the patient’s response to treatment as a clinical failure. Eradication rates of individual isolates were also analyzed with regard to MIC values, if available. Susceptibility Analyses

A secondary objective of the study was to assess the in vitro susceptibility to tigecycline of cSSSI-related bacteria. Susceptibility of the selected pathogens was measured with regard to MIC50 and MIC90 values, the MICs required to inhibit 50% and 90% of the pathogens, respectively. Pharmacokinetic Analyses

Blood samples were obtained to determine serum pharmacokinetic profiles. On the day before or the day of discharge, blood was drawn by a nurse before the morning dose (hour 0), within 1 minute of the end of the morning infusion (hour 1), and at 3 hours (±0.5 hour) and 6 hours (±0.5 hour) after the start of the morning infusion. Blood was collected in a 5-mL tube and centrifuged within 5 minutes of collection in a centrifuge at 4°C to 6°C. The serum was collected and transferred in equal amounts into 2 labeled polypropylene tubes and stored at –20°C until shipped. Pharmacokinetic data for tigecycline were estimated with use of noncompartmental methods14 for peak concentrations at steady state (Css,max), area under the plasma concentration–time curve at steady

R.G. Postier et al.

state (AUCss), and systemic clearance (CL). Values for Css,max were obtained directly from the observed data. AUCss was determined with use of the trapezoidal rule14 from hours 0 to 12, the latter being an assigned value derived from the trough steady-state concentration at hour 0. CL was calculated as: CL = (dose/AUCss)/body weight (kg). Tolerability Analyses

Tolerability assessments were conducted for all ITT patients and consisted of hematologic analyses, blood chemistry assessments, determination of coagulation parameters, routine urinalyses, and physical examinations for vital signs as well as clinical signs and symptoms of infections and patient interview/questioning. Adverse events (AEs) were recorded throughout the study period, with the following information: the specific event or condition, whether the event was present during the prestudy period, the dates and times of occurrence, severity, relationship to test article, specific countermeasures, and outcome. An adverse event was defined as any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiologic observations, regardless of causal relationship.

RESULTS

A total of 164 patients were enrolled (see Figure 1 for disposition of study patients). Because 4 enrollees failed to meet the inclusion criteria, the number of patients constituting the ITT population was 160. By random assignment, 79 ITT patients were included in the 25-mg group and 81 ITT patients were included in the 50-mg group. Both groups had statistically similar demographic characteristics, clinical diagnoses, and causes of infection (Table I). The majority of ITT patients were men (74%), and the mean (SD) age was 49.0 (14.8) years. The chief clinical diagnosis among ITT patients was ulcer with an acute infection (35%), followed by major abscess (31%). Blood samples were available for pharmacokinetic analysis in 134 patients. Excluding 3 patients with indeterminate responses, the number of CE patients was 109 (55 and 54 patients in the 25- and 50-mg groups, respectively). Ninety-one patients had identifiable pathogens at baseline and at the test-of-cure visit and thus were ME (45 and 46 patients in the 25- and 50-mg groups, respectively). Within the ME group, 75 patients (82%) were infected with ≥1 of the selected pathogens. The total number of selected isolates tested for susceptibility by MIC was 80.

Statistical Analysis

We used 95% CIs in the statistical analyses to estimate the true proportion of favorable clinical response to tigecycline in CE patients. The primary efficacy analysis focused on clinical cure rates. A sample size of 160 was chosen, with the expectation that 80 patients (40 per treatment group) would be assessable. A sample size of 40 patients per group would provide good estimates of clinical response and ensure that the distance to the bounds of a 2-sided 95% CI does not exceed 14.2% when the proportion of favorable clinical responses lies between 70.0% and 90.0%. Similarly, 95% CIs were used to estimate the true proportion of favorable microbiologic responses in ME patients. Efficacy analyses of microbiologic responses focused on eradication versus all other categories. Finally, the Fisher exact test was used to compare the percentages of AEs that occurred in the 25-mg and 50-mg dose groups. SAS software version 6.12 (SAS Institute Inc., Cary, North Carolina) was used to calculate the data.

Efficacy Results

Patients receiving 50 mg of tigecycline had clinical cure and microbial eradication rates (74% [95% CI, 60.3%–85.0%] and 69% [95% CI, 54.2%–82.3%], respectively) similar to those of the 25-mg group (67% [95% CI, 53.3%–79.3%] and 56% [95% CI, 40.0%–70.4%, respectively]). Although the differences between the 2 groups were not statistically significant, the observed differences were generally consistent from 1 analysis to the next (Figure 2 and Table II). Clinical Cure Rates

At the end of therapy, 78% (95% CI, 65.0%– 88.2%) of CE patients in the 25-mg group were cured and 85% (95% CI, 72.9%–93.4%) of CE patients in the 50-mg group were cured (Figure 2). At the test-of-cure visit, 67% (95% CI, 53.3%–79.3%) of patients in the 25-mg group and 74% (95% CI, 60.3%–85.0%) in the 50-mg group were cured. In 707

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164 Patients enrolled and randomized

160 Patients met inclusion criteria (ITT)

Tigecycline 25 mg

Tigecycline 50 mg

79 ITT patients

81 ITT patients

55 CE patients

54 CE patients

45 ME patients

46 ME patients

38 Patients with selected isolates*

37 Patients with selected isolates*

Figure 1. Disposition of study patients. ITT = intent to treat; CE = clinically evaluable; ME = microbiologically evaluable. *Selected isolates = methicillin-resistant and methicillin-susceptible Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Enterococcus faecalis, and Enterococcus faecium.

every case in which a patient’s response changed from cure at the end of treatment to failure at the test-ofcure assessment (6 patients per group), the patient had received additional antibiotic therapy or an additional surgical procedure in the interval. Bacteriologic Responses

Rates of eradication of causative pathogens in the ME group are shown in Table II. At the end of therapy, bacterial eradication occurred in 62% (95% CI, 46.5%–76.2%) of patients receiving 25 mg of tigecycline and in 74% (95% CI, 58.9%–85.7%) of patients receiving 50 mg of tigecycline. At the test-of-cure assessment, bacteriologic eradication occurred in 56% (95% CI, 40.0%–70.4%) of patients in the 25-mg group versus 69% (95% CI, 54.2%–82.3%) of patients in the 50-mg group. 708

In ME patients with selected pathogens (n = 75), eradication rates varied by type of pathogen but were apparently higher in patients receiving the higher dose of tigecycline (Table III). Similar results were obtained when eradication rates were assessed by baseline pathogen MIC values (available for 80 isolates). The MIC ranges in which tigecycline was active against the isolates were as follows: MRSA, 0.12 to 0.50 µg/mL; MSSA, 0.12 to 2.00 µg/mL; S pyogenes, ≤0.015 to 0.06 µg/mL; E coli, 0.25 µg/mL; E faecalis, 0.06 to 0.12 µg/mL; and E faecium, 0.06 µg/mL (Table IV). None of these or other baseline pathogens identified in the ME population developed resistance to tigecycline during the study. Susceptibility Findings

In vitro MIC50 and MIC90 values were determined for the 80 isolates of interest. At the 25-mg dose of

R.G. Postier et al.

Table I. Baseline demographic and clinical characteristics of study patients (intent-to-treat ITT population).*†

Characteristic Age, y Mean (SD) Range Sex, no. (%) Men Women Ethnicity, no. (%) White Hispanic Black Other Body weight, mean (SD), kg Chief clinical diagnosis, no. (%) Ulcer with an acute infection Major abscess Superficial abscess/infection Infected human or animal bite Other‡ Cause of infection, no. (%) Spontaneous infection Underlying medical condition Trauma Previous surgery Human or animal bite Other §

Tigecycline Dose

All ITT Patients (N = 160)

25 mg (n = 79)

50 mg (n = 81)

49.0 (14.8) 18–82

49.3 (15.1) 18–82

48.7 (14.6) 20–78

118 (74) 42 (26)

53 (67) 26 (33)

65 (80) 16 (20)

83 40 31 6 86.1

(52) (25) (19) (4) (26.4)

41 16 18 4 85.8

(52) (20) (23) (5) (26.6)

42 24 13 2 86.3

(52) (30) (16) (2) (26.6)

56 50 31 4 19

(35) (31) (19) (3) (12)

26 (33) 23 (29) 16 (20) 2 (3) 12 (15)

30 (37) 27 (33) 15 (19) 2 (2) 7 (9)

53 38 33 13 3 20

(33) (24) (21) (8) (2) (13)

25 22 15 7 1 9

28 16 18 6 2 11

(32) (28) (19) (9) (1) (11)

(35) (20) (22) (7) (2) (14)

*No

significant between-group differences were found. may not total 100% due to rounding. ‡Includes cellulitis, infected surgical incision, infected burn, spider bite, bursitis, and infection associated with injection-drug use. §Includes infection associated with injection-drug use, cellulitis secondary to venous stasis, spider bites, puncture wounds, and infection of unknown etiology. †Percentages

tigecycline, MIC50 values for MRSA, MSSA, S pyogenes, E coli, E faecalis, and E faecium ranged from 0.06 to 0.25 µg/mL, and MIC90 values ranged from 0.06 to 0.50 µg/mL. At the 50-mg dose, the corresponding MIC50 values ranged from 0.03 to 0.31 µg/mL, and MIC90 values ranged from 0.06 to 0.50 µg/mL (Table V).

(AUCss,0–12h), and weight-adjusted CL were 0.265 (0.206) µg/mL, 1.43 (0.668) µg/mL·h, and 0.246 (0.114) L/kg·h, respectively. For patients treated with 50 mg of tigecycline, mean values for Css,max, AUCss,0–12h, and weight-adjusted CL were 0.403 (0.182) µg/mL, 2.24 (0.894) µg/mL·h, and 0.313 (0.124) L/kg·h.

Pharmacokinetic Results

Safety Profile

The dose-normalized serum tigecycline concentrations at the hours 0, 1, and 3 were not significantly different between the 2 dose groups. For patients treated with 25 mg of tigecycline, mean (SD) values for tigecycline Css,max, area under the plasma concentration– time curve at steady state from 0 to 12 hours

Both the 25-mg and 50-mg dosing regimens of tigecycline were generally well tolerated and had a safety profile consistent with that seen in Phase I studies.9,10,15 As shown in Table VI, the 2 groups had similar rates of treatment-emergent AEs (TEAEs), that is, AEs that occurred or worsened 709

CLINICAL THERAPEUTICS®

Tigecycline 25 mg (n = 55) Tigecycline 50 mg (n = 54)

100 85 78

% of Patients Cured

80

74 67

60

40

20

0

65.0–8.2

72.9–93.4

End of Treatment

53.3–79.3

60.3–85.0

95%CI

Test of Cure

Figure 2. Clinical cure rates at the end of treatment and at the test-of-cure visit in clinically evaluable patients (n = 109).

Table II. Microbial response rates* (%) at the test-of-cure visit in microbiologically evaluable patients (n = 91). Tigecycline Dose 25 mg (n = 45)

50 mg (n = 46)

End of treatment Eradication (95% CI)† Persistence‡ Superinfection§ Indeterminate\

62 (46.5–76.2) 33 2 2

74 (58.9–85.7) 17 2 7

Test of cure Eradication (95% CI)† Persistence‡ Superinfection§ Indeterminate\

56 (40.0–70.4) 31 7 7

69 (54.2–82.3) 20 2 9

Study Visit/Response

*Percentages

may not add to 100% due to rounding. = the absence of the baseline pathogen in a repeat culture from the original complicated skin and skin-structure infection (cSSSI) site, or as a clinical cure that precluded collection of a follow-up specimen. ‡Persistence = a baseline pathogen was identified in a follow-up culture from any infection site; a new antimicrobial therapy was started to treat the original cSSSI; tigecycline was continued beyond 14 days; or, in the absence of microbiologic data, the original cSSSI recurred. §Superinfection = the emergence of a new pathogen at the original cSSSI site or at a distant site. \Indeterminate = patient was lost to follow-up or died for a non–infectionrelated reason. †Eradication

710

during treatment, whether or not related to the use of tigecycline. Nausea was the most commonly reported TEAE, occurring in 22% of ITT patients in the 25-mg group and in 35% of patients in the 50-mg group. One patient (1%) in the 25-mg group discontinued treatment because of fever, an event which the investigator considered to be unrelated to tigecycline use. In the 50-mg group, 5 patients (6%) discontinued therapy because of the following TEAEs: 2 had nausea and vomiting, 1 had diarrhea, 1 had paresthesia, and 1 had an allergic reaction (itching around the torso). No life-threatening AEs occurred. Most abnormal laboratory test results were consistent with patients’ underlying medical conditions or the use of concomitant medications. However, abnormalities in 9 patients appeared to be possibly or probably related to tigecycline. These included elevated (mild to moderate) serum transaminase in 5 patients (1 patient in the 25-mg group and 4 patients in the 50-mg group), elevated serum alkaline phosphatase in 2 patients (1 per group), elevated blood urea nitrogen in 1 patient (in the 50-mg group), and anemia in 1 patient (who had a history of injection-drug use and alcoholism, in the 25-mg group). None of the patients in the study discontinued because of abnormal laboratory test results.

R.G. Postier et al.

Table III. Microbial response rates to selected pathogens at the test-of-cure visit in microbiologically evaluable patients.*† (Values are expressed as no./total [%] of patients.) Tigecycline Dose Baseline Pathogen/ Response

25 mg

50 mg

MRSA Eradication‡ Persistence§ Indeterminate\

2/4 (50) 2/4 (50) 0 (0)

1/4 (25) 2/4 (50) 1/4 (25)

MSSA Eradication‡ Persistence§ Indeterminate\

13/19 (68) 4/19 (21) 2/19 (11)

14/20 (70) 6/20 (30) 0 (0)

Streptococcus pyogenes Eradication‡ Persistence§ Indeterminate\

1/3 (33) 2/3 (67) 0 (0)

5/7 (71) 2/7 (29) 0 (0)

Escherichia coli Eradication‡ Persistence§ Indeterminate\

3/5 (60) 2/5 (40) 0 (0)

3/3 (100) 0 (0) 0 (0)

Enterococcus faecalis Eradication‡ Persistence§ Indeterminate\

4/6 (67) 2/6 (33) 0 (0)

3/3 (100) 0 (0) 0 (0)

Enterococcus faecium Eradication‡ Persistence§ Indeterminate\

1/1 (100) 0 (0) 0 (0)

0 (0) 0 (0) 0 (0)

MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillinsusceptible S aureus. *Some patients had >1 pathogen; MIC values were not available for all isolates. †No significant between-group differences were found. ‡Eradication = the absence of the baseline pathogen in a repeat culture from the original complicated skin and skin-structure infection (cSSSI) site, or as a clinical cure that precluded collection of a follow-up specimen. §Persistence = a baseline pathogen was identified in a follow-up culture from any infection site; a new antimicrobial therapy was started to treat the original cSSSI; tigecycline was continued beyond 14 days; or, in the absence of microbiologic data, the original cSSSI recurred. \Indeterminate = patient was lost to follow-up or died for a non–infectionrelated reason.

Four deaths occurred during the course of the study (2 patients per group). Three of these patients died because of cardiac arrest; the fourth died because of metastatic colon cancer. None of the deaths were considered by investigators to be related to treatment with tigecycline.

DISCUSSION

In this preliminary study, tigecycline appeared to be both clinically and microbiologically efficacious at both the 25- and 50-mg doses in the treatment of hospitalized patients with cSSSI. For patients receiving 50 mg of tigecycline, the clinical cure rate at the test-of-cure visit was 74%. Eradication rates were somewhat lower than clinical cure rates, which is consistent with reports from other studies16,17 and with clinical experience in which baseline organisms appear to persist despite a clinical cure. Nonetheless, tigecycline appeared to be active against a wide spectrum of pathogens commonly linked to cSSSI. Susceptible pathogens included the gram-positive aerobes S aureus, S pyogenes, and Enterococcus spp. and the gram-negative E coli.

Table IV. Eradication rates of selected pathogens at the test-of-cure visit, by minimum inhibitory concentration (MIC).*† (Values are expressed as no./total [%] of isolates.) Tigecycline Dose Baseline Pathogen/ MIC, µg/mL

25 mg

50 mg

MRSA 0.12 0.25 0.50

1/4 (25) 1/1 (100) 0 (0)

0/2 (0) 0 (0) 1/2 (50)

MSSA 0.12 0.25 0.50 2.00

10/13 2/3 1/2 0

(77) (67) (50) (0)

11/16 2/3 0 1/1

(69) (67) (0) (100)

Streptococcus pyogenes ≤0.015 0.03 0.06

0 (0) 0 (0) 1/3 (33)

2/2 (100) 4/4 (100) 3/4 (75)

Escherichia coli 0.25

4/6 (67)

3/3 (100)

Enterococcus faecalis 0.06 0.12

0 (0) 4/6 (67)

2/2 (100) 1/1 (100)

Enterococcus faecium 0.06

1/1 (100)

0 (0)

MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillinsusceptible S aureus. *Some patients had >1 pathogen; MIC values were not available for all isolates. †No significant between-group differences were found.

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Table V. Susceptibility of selected baseline pathogens, by minimum inhibitory concentration.*† Tigecycline Dose 25 mg (n = 39 isolates) Baseline Pathogen MRSA MSSA Streptococcus pyogenes Escherichia coli Enterococcus faecalis Enterococcus faecium –

50 mg (n = 41 isolates)

No. of Isolates

MIC50, µg/mL

MIC90, µg/mL

No. of Isolates

MIC50, µg/mL

MIC90, µg/mL

5 18 3 6 6 1 –

0.12 0.12 0.06 0.25 0.12 0.06

0.25 0.50 0.06 0.25 0.12 0.06

4 21 10 3 3 0

0.31 0.12 0.03 0.25 0.06 –

0.50 0.25 0.06 0.25 0.12 –

MIC50 = minimum inhibitory concentration for 50% of all isolates; MIC90 = minimum inhibitory concentration for 90% of all isolates; MRSA = methicillinresistant Staphylococcus aureus; MSSA = methicillin-susceptible S aureus. *Some patients had >1 pathogen; MIC values were not available for all isolates. †No significant between-group differences were found.

Tigecycline’s pharmacokinetic parameters in patients with cSSSI were consistent with those seen in healthy volunteers. Based on the earlier pharmacokinetic and pharmacodynamic studies, which showed the elimination half-life of tigecycline to be 30 to 40 hours, multiple-dose administration of tigecycline produces steady-state serum concentrations within a few days.9 In the current study, 50 mg of tigecycline produced an AUCss,0–12h of 2.24 µg/mL·h, which translates to a total daily area under the plasma concentration–time curve from 0 to 24 hours of ~4.5 µg/mL·h. Tigecycline has a large volume of distribution at steady state (~700 L), indicating that the drug is extensively distributed into the body’s tissues. Thus, the serum tigecycline concentration significantly underrepresents the exposure of tigecycline in tissues.9 In the present study, tigecycline also appeared to have an acceptable safety profile in patients with cSSSI. Although the drug’s safety profile appears to be comparable to those of other injectable antibiotics, 28% of the ITT patients in the present study reported nausea and 16% reported vomiting after receiving tigecycline. However, 2 of 160 patients (1%) discontinued tigecycline because of nausea and vomiting. In addition, it has been shown that tolerability to tigecycline can be improved when the drug is given with food, which does not affect exposure to the drug.9 The results of the present study warrant 712

Table VI. Treatment-emergent adverse events (TEAEs) that occurred in ≥5% of patients (intent-to-treat population).*† (Values are expressed as no. [%] of patients.) Tigecycline Dose

TEAE

25 mg (n = 79)

50 mg (n = 81)

Nausea

17 (22)

28 (35)‡

Vomiting

10 (13)

15 (19)‡

Diarrhea

9 (11)

7 (9)§

Pulmonary physical finding

9 (11)

3 (4)

Headache

6 (8)

4 (5)

Pain

5 (6)

5 (6)

Fever

4 (5)

5 (6)

Insomnia

4 (5)

5 (6)

Dizziness

4 (5)

2 (3)

Hypertension

4 (5)

2 (3)

Anemia

4 (5)

1 (1)

*No

significant between-group differences were found (Fisher exact test). patients experienced >1 TEAE. None of the TEAEs were life threatening. ‡Two of these patients (2%) withdrew due to this TEAE. §One of these patients (1%) withdrew due to this TEAE. †Some

R.G. Postier et al.

further investigation with the 50-mg tigecycline dose versus an adequate comparator in a Phase III trial. 7. CONCLUSIONS

In this study, tigecycline appeared efficacious and showed a favorable pharmacokinetic profile and an acceptable safety profile in the treatment of hospitalized patients with cSSSI. In patients who received 50-mg doses of tigecycline q12h, the clinical cure rates and microbial eradication rates were 74% and 69%, respectively, and were 67% and 56% in patients who received 25-mg doses. Susceptibility testing in this small, preliminary study suggested that gram-positive and gram-negative pathogens that cause cSSSI were susceptible to tigecycline.

8.

9.

ACKNOWLEDGMENTS

We thank Susan Coyle, PhD, for her assistance in the preparation of the manuscript. We also thank the Tigecycline 200 Study Group for their involvement: W.L. Biffl, P.G. Bove, V. Shawan, S. Green, T. Grenga, S. Klein, C. Lates, W.S. McDonald, W. Mills, M. Patzakis, R.G. Postier, D. Stevens, J.S. Tan, and S.E. Wilson. REFERENCES 1. CDC (Centers for Disease Control and Prevention) Web site. Background on antibiotic resistance. Available at: http://www.cdc.gov/drugresistance/community/. Accessed May 16, 2003. 2. Sum PE, Petersen P. Synthesis and structure-activity relationship of novel glycylcycline derivatives leading to the discovery of GAR-936. Bioorg Med Chem Lett. 1999;9:1459–1462. 3. Chopra I. Glycylcyclines: Third-generation tetracycline antibiotics. Curr Opin Pharmacol. 2001;1:464–469. 4. Projan SJ. Preclinical pharmacology of GAR-936, a novel glycylcycline antibacterial agent. Pharmacotherapy. 2000;20:S219–S223; discussion, S224–S228. 5. Milatovic D, Schmitz FJ, Verhoef J, Fluit AC. Activities of the glycylcycline tigecycline (GAR-936) against 1,924 recent European clinical bacterial isolates. Antimicrob Agents Chemother. 2003;47:400–404. 6. Petersen PJ, Weiss WJ, Labthavikul P, Bradford PA. The post-antibiotic effect and time-kill kinetics of the glycylcyclines, GAR-936 (TBG-MINO and PAM-MINO). In: Programs and Abstracts of the 38th Annual Interscience Conference on Antimicrobial Agents and

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Address correspondence to: Russell G. Postier, MD, University of Oklahoma Medical Center, 920 Stanton Young Boulevard, Room WP2140, Oklahoma City, OK 73104. E-mail: [email protected] 714