Tigecycline

Updated January, 2010   

 

David R.P. Guay, PharmD, FCP, FCCP, FASCP

CLASS

Chemical Structure

               Glycylcycline (9-t-butylglycylamido derivative of minocycline) (Figure 1).

Structure-Activity Relationships

               The glycylcyclines are semisynthetic tetracycline analogues in which a substituted glycyl moiety has been inserted at the C-9 position. The design of the glycylcyclines was based on the premise that a peptide substituent would enhance ribosomal permeation and binding. Structure activity studies demonstrated that the minocycline core, in which a dimethylamino group is present at C-7, was one of the preferred starting points for subsequent modification. For the side chain at C-9, a basic nitrogen must be present for activity.

               Early work showed that the nitrogen can be either disubstituted with small alkyl groups (eg. dimethylglycyl-minocycline or DMG-MINO) or part of a ring. It is believed that 9-glycyl substitution prevents recognition of the agent by the Tet A efflux protein, a major effector of tetracycline resistance (3). Further modification of the glycyl substituent led to the discovery of GAR-936 (tigecycline), a t-butyl substituted glycine derivative. Smaller groups than t-butylamino, such as methylamino, were less potent while n-propyl, n-butyl, and n-hexyl substituted amines had similar potency. The t-butylamino group can also be replaced with a small, cyclic amine to give derivatives with good activity, although somewhat less potent than GAR-936 (16).

Projan, S.J.  Francis Tally and the Discovery and Development of Tigecycline: A Personal Reminiscence.  Clin Infect Dis 2010;50:S24-25.

 

ANTIMICROBIAL ACTIVITY

Spectrum

               See Table 1 (4,5,6,7,9,10,11,12,17,18,21,22,24,25,26,27,28,29,30,31,33,34,36,37,

38,39,40,47,55,58,59,62,63,64,65,66,67,71,76,77,78)

               The activity of tigecycline is not affected by the presence of resistance to penicillin (for S. pneumoniae and viridans group streptococci), (9,11,24,33,34,55,58,59,66,77) vancomycin (for enterococci and staphylococci), (11,12,17,25,33,55,58,59,66,67) methicillin (for staphylococci), (6,9,10,12,24,25,28,33,34,37,55,59, 62,66,67) or erythromycin (for S. pyogenes and S. agalactiae) (5). As tigecycline is structurally unrelated to the beta-lactams, it would be expected that tigecycline would be unaffected by beta-lactamase enzymes. Indeed, its activity against H. influenzae, E. coli, and K. pneumoniae is not affected by the presence of beta-lactamase (9, 12, 24, 27, 33, 66, 78) Tigecycline also retains activity against tetracycline- and minocycline-resistant strains (8, 11, 25, 27, 29, 34,37, 38,39, 40, 58,59,66,67).

Pharmacodynamic Effects

Bacteriostatic vs. Bactericidal: Tigecycline is bacteriostatic against E. faecalis, E. coli, S. aureus, vancomycin-resistant S. aureus, and K. pneumoniae and both bacteriostatic and bactericidal against S. pneumoniae (in-vitro time-kill studies) (10, 13, 34, 51, 74). Tigecycline + gentamicin has enhanced in vitro activity against vancomycin-resistant E. faecalis and S. aureus compared to tigecycline monotherapy (46). In contrast to vancomycin, daptomycin, and teicoplanin, tigecycline has equivalent bacteriostatic and bactericidal activity against adherent and free-floating S. epidermidis in an in vitro adherent-cell biofilm model of foreign device infection (42). Tigecycline is also bacteriostatic against S. aureus sequestered within human polymorphonuclear neutrophils (PMNs) (54).

               An extensive interaction study of tigecycline with 13 antimicrobials and a wide variety of gram-positive and -negative isolates found no instances of antagonism and only one of synergy (with amikacin versus A. baumannii) (57). Another in vitro study has evaluated the effect of vancomycin-resistant E. faecalis on the activity of tigecycline against methicillin-resistant S. aureus in a mixed-organism pharmacodynamic model. A tigecycline dosing regimen of 100 mg every 24 hours was simulated. Tigecycline was bacteriostatic against both the staphylococcus and the enterococcus in the absence of each other. However, tigecycline became bactericidal against the staphylococcus and remained bacteriostatic against the enterococcus in the mixed-organism model. Of interest, when tigecycline was combined with arbekacin (the latter in a simulated regimen of 100 mg every 12 hours), the combination was bactericidal against the staphylococcus but antagonistic against the enterococcus in the mixed-organism model. Results of this study support further research into the effect of polymicrobial infections on antimicrobial activity (43)

Postantibiotic Effects: Tigecycline exhibits post antibiotic effect (PAE) durations in vitro of 4.1 hours (tetracycline-susceptible S. aureus), > 3 hours (tetracycline-resistant S. aureus), 2.9 hours (tetracycline-susceptible E. coli) and 1.8-2.6 hours (tetracycline-resistant E. coli) (61). In vivo PAE durations of 4.9 hours (E. coli) and 8.9 hours (S. pneumoniae) have been reported (74).

Pharmacodynamic Correlates with Outcome: In animals, the area under the curve (AUC)/MIC ratio appears to be the pharmacokinetic parameter best correlated with efficacy (74, 45). No data are available in humans. However, the relatively long terminal disposition half-life in humans (see below) in conjunction with the prolonged in vivo PAE durations support the likelihood that AUC/MIC will also be the best prediction of efficacy in humans.

Kuti JL, et al. A pharmacodynamic simulation to assess tigecycline efficacy for hospital-acquired pneumonia compared with other common intravenous antibiotics. J Chemother. 2008 Feb;20(1):69-76.

Susceptibility Testing: Interpretative criteria are available for both broth- or agar-dilution minimum inhibitory concentration (MIC) and disk diffusion testing. For all S. aureus isolates, susceptible MIC and zone diameter parameters are ≤ 0.5 mg/L and ≥ 19 mm, respectively. For streptococci other than S. pneumoniae and E. faecalis (vancomycin-susceptible isolates only), corresponding values are ≤ 0.25 mg/L and ≥ 19 mm. For Enterobacteriaceae, susceptible/intermediate/resistant MIC and zone diameter parameters are ≤ 2/4/≥ 8 mg/L and ≥ 19/15-18/≤ 14 mm respectively. Lastly, for anaerobes, the corresponding agar-dilution MIC values are ≤ 4/8/≥ 16 mg/L (1). For broth MIC testing, media must be fresh (<12 h old) or have the biocatalytic oxygen-reducer oxyrase added in older to optimally standardize the results (14, 35, 56).               

               Epidemiological MIC cut-off values (i.e. susceptibility breakpoints based upon analysis of entire wild-type bacterial populations) have been established for tigecycline. The normalized resistance interpretation method was applied to Etest results from 4771 clinical isolates from three Swedish university hospitals. Table 2 illustrates these breakpoint values together with corresponding U.S. Food and Drug Administration-approved breakpoint values (41).

 

MECHANISMS OF ACTION

               Tigecycline is felt to exert its antibacterial effects via the same mechanism as the tetracyclines, i.e. inhibition of bacterial protein synthesis by binding to the 30S subunit of the ribosome, thus blocking the entry of aminoacyl transfer RNA (3).

 

MECHANISMS OF RESISTANCE

Organisms Commonly Resistant

               Based on MIC data for intermediate susceptibility and resistance, organisms commonly of intermediate susceptibility include Legionella sp., U. urealyticum, Proteus sp., Providencia sp., M. morganii, A. baumanii, B. fragilis group, and B. fragilis. Organisms commonly resistant include P. aeruginosa, B. cepacia, M. marinum, M. kansasii, M. lentiflavum, and M. avium complex.

Mechanisms of Resistance

               Resistance to the tetracyclines is usually mediated by either ribosomal protection mechanisms or efflux. Novel efflux mutants have already been discovered which enhance the efflux of glycylcyclines and these will probably be the focus around which resistance development will occur once they enter clinical use. These include naturally-occurring tet (A) mutants present in veterinary strains of Salmonella and tet A (B) mutants developed in the laboratory (73).

               Tet(X) protein induces tigecycline resistance by catalyzing the conversion of the parent compound into the 11a-hydroxy metabolite, a much weaker inhibitor of protein translocation. Tet(X) has not yet been isolated from clinical strains (48). Staphylococcus aureus isolates from phase 3 clinical trials of tigecycline in complicated skin and skin structure infections were assessed for the presence of common genetic determinants of methicillin and tetracycline resistance. Of 503 unique strains, 120 (23.9%) were methicillin-resistant. All 120 strains expressed the mecA gene, which exhibited widely-varying prevalence rates based on geography (from 6.5% in Eastern Europe to 50.9% in North America). The tet(M) and/or tet (K) genes were found in 19.2 percent of the 120 methicillin-resistant strains (tet[K] in 73.9%, tet[M] in 13.0% and both in 13.0%). Again, prevalence rates varied by geographic region (11.9% in North America to 46.2% in Eastern Europe). One or both of these tetracycline resistance markers were found in 11.0 percent of 383 methicillin-sensitive S. aureus strains (tet[K] in 73.8%, tet[M] in 21.4%, and both in 4.8%). Prevalence rates ranged from 2.5 to 16.1 percent, depending on the geographic region (37).

               A recently-identified MATE family efflux pump (mepA) is associated with the development of S. aureus isolates with reduced susceptibility to tigecycline (44). The reduced intrinsic susceptibility of P. mirabilis to tigecycline is due to the AcrAB multidrug efflux pump (75). It is not known why this pump acts on tigecycline in P. mirabilis and not in other genera. Resistance of P. aeruginosa to tigecycline is also mediated by an efflux pump mechanism (20). The recognition of tigecycline by the resistance-nodulation-division (RND) efflux transporter family may facilitate the development of resistance when the use of tigecycline becomes more widespread (32).

Video: Mechanism of Resistance -- Efflux

PHARMACOKINETICS

Absorption

               Not available for oral use as bioavailability is too poor. Only available for IV use.

Distribution

               In vitro protein binding studies revealed increasing protein binding with increasing drug concentration, attributable in part to the formation of metal-ion complexes as documented previously with the tetracyclines (45). In human plasma, the percentages protein bound at 0.1 and 1.0 mg/L were 71 and 87 percent (ultrafiltration method) and 73 and 79 percent (ultracentrifugation method), respectively (45).

               After single IV doses of 12.5, 25, 50, 75, 100, 200, and 300 mg over 1 hour (12.5-300 mg cohorts) or 4 hours (200 and 300 mg cohorts) to healthy volunteers, mean volume of distribution at steady state (Vss) exceeded 10 L/kg (49). In a study of similar design conducted in healthy Japanese volunteers, Vss increased with increasing dose (mean 4.4, 7.1, 9.1, and 10.8 L/kg after 25, 50, 100, and 200 mg IV doses over 1 hour) (68). Tigecycline penetrates well into inflammatory skin blister fluid (mean ± SD 74 ± 7% based on AUC data) (69). It also penetrates into epithelial lining fluid, with concentrations being approximately equivalent to concurrent serum concentrations (19). In contrast, tigecycline concentrates in pulmonary alveolar cells, with concentrations being up to 110-fold those of concurrent serum concentrations (19). The percentage of the dosing interval where the concentration exceeded the MIC90 of 5 representative respiratory pathogens (S. pneumoniae, C. pneumoniae, M. pneumoniae, M. catarrhalis, H. influenzae) was 100 percent )(19). Tigecycline penetrates rapidly into human PMNs, achieving dose-dependent intracellular concentrations of (mean ± SD) 15.83 ± 11.09 and 264 ± 55 mg/L at media concentrations of 1 and 10 mg/L, respectively. Intracellular concentrations exceed those extracellular by 20- to 30-fold. Efflux from PMNs occurs as a first-order process with a half-life of 1.39 hours (54).

Routes of Elimination

Metabolism: Based on the modest fractional elimination of parent compound in the urine and the feces, metabolism followed by biliary excretion of parent compound and metabolites probably constitutes the major route of elimination while renal excretion of the same moieties is the secondary route of elimination (1). Specific metabolic pathways of tigecycline include nonenzymatic epimerization, hydroxylation, glucuronidation, N-acetylation, and cleavage into t-butylaminoacetic acid and 9-aminominocycline (each ≤ 16% of the dose) (1, 45).

Excretion: In the single dose studies mentioned previously, the fractional elimination of tigecycline as parent compound in the urine was < 15 percent and 14-17 percent of the administered dose (49, 68). Fractional elimination as parent compound in the feces was <14 percent (68). However, fractional elimination of tigecycline as parent compound and metabolites in the urine and feces are 33 and 59 percent, respectively (1).

Pharmacokinetic Parameters

               Peak plasma concentration (Cmax) and area under the plasma concentration-versus-time curve (AUC) are dose-proportional, rising from mean 0.11 mg/L and 0.9 mg/L per hour, respectively, after 12.5 mg (IV over 1 hour) to 2.8 mg/L and 17.9 mg/L per hour, after 300 mg (IV over 1 hour) in one healthy volunteer study (49) and from mean 0.20 mg/L and 0.8 mg/L per hour after 25 mg (IV over 1 hour) to 1.52 mg/L and 8.6 mg/L per hour after 150 mg (IV over 1 hour) in another healthy volunteer study (68). Terminal disposition half-life (t 1/2) was dose-independent in one healthy volunteer study (mean 36 hours) (49) but was dose-dependent (i.e., increased with increasing dose; mean 8.2, 15.7, 24.3, and 35.5 hours after 25, 50, 100, and 150 mg, respectively) in another healthy volunteer study (68). Total body clearance (CL) is dose-independent, with means ranging from 0.2 to 0.5 L/h/kg in healthy volunteers (49, 68).

Effect of Demographics and Disease States

               Age and gender effects on the pharmacokinetics of tigecycline have been evaluated after single 100 mg IV dose administration to healthy males and females in 3 age groups: 18-50, 65-75, >75 years old (N=5-9 in each group). Mean Cmax ranged from 0.85 to 1 mg/L across the groups. The lowest AUCs were noted in males under 50 years old (mean 4.2 mg/L per hour) and the highest in males over 75 years old (mean 5.8 mg/L per hour). Mean AUCs across the three female age groupings clustered around 5 mg/L per hour. Mean Vss was approximately 350 and 500 L in females and males, respectively. Age and gender were not felt to substantially alter tigecycline pharmacokinetics (50).

               These relationships were further investigated in a pooled analysis of tigecycline pharmacokinetics in 175 healthy subjects in five phase I trials (45). A strong relationship between Cmax and weight was observed which could not be fully explained by normalizing by body weight. Comparing populations within similar weight ranges, there was a trend for female subjects to have a higher dose-normalized Cmax compared with male subjects in the same weight range. A significant relationship in dose-normalized Cmax by age was also found (p < 0.001), despite similar weight distributions across the three age categories. Dose-normalized Cmax was approximately 20 percent higher in subjects over 75 years old compared to the young subjects. Similar findings were noted for AUC data. Within similar weight ranges, the median AUC∞s for the 100 mg dose were 5.94 and 4.78 mg•h/L for male and female subjects, respectively. However, significant differences in dose-normalized AUC by age were not seen across all age categories. Again, sample sizes were small and the clinical relevance of these differences is not established (45).

               Race also does not appear to substantially alter drug pharmacokinetics (1).

               The effects of severe renal impairment (SRI, defined as creatinine clearance < 30 mL/min) and hemodialysis (HD) on tigecycline pharmacokinetics have been evaluated after single 100 mg IV dose administration to six healthy volunteers (HV), six patients with SRI, and 8 patients undergoing HD (N=4 received the dose 2 h pre-dialysis and N=4 received the dose post-dialysis). In the SRI compared to the HV group, mean Cmax was similar (0.604 mg/L in both groups) while AUC was 40 percent higher (4.758 vs. 3.330 mg/L per hour) and urinary recovery of parent drug was lower (5 vs. 16% of the dose). In the HD compared to the HV group, the mean Cmax was 60 percent higher (0.961 vs. 0.604 mg/L) and AUC was 20 percent higher (4.041 vs. 3.330 mg/L per hour). The dialysis procedure had no significant effect on tigecycline pharmacokinetics and the amount of drug recovered in the dialysate was negligible (72).

               In a study evaluating the effect of hepatic impairment on tigecycline pharmacokinetics, single-dose drug disposition was not significantly altered in the presence of mild hepatic impairment (Child-Pugh class A). However, in the presence of moderate hepatic impairment (Child-Pugh class B), CL was reduced by a mean of 25 percent and t 1/2 was prolonged by a mean of 23 percent. In the presence of severe hepatic impairment (Child-Pugh class C), CL was reduced by 55 percent and t 1/2 was prolonged by 43 percent (1).

 

DOSAGE

               Initial dose is 100 mg followed by 50 mg every 12 h (administer over 0.5-1 h) (1). In the presence of severe hepatic impairment (Child-Pugh class C), the maintenance dose should be reduced to 25 mg every 12 h (1).

 

ADVERSE EFFECTS

Mechanism

               Similar to minocycline, the major adverse effects of tigecycline are nausea and vomiting (1, 2, 15, 23, 52, 53, 60). These events are dose-dependent and may necessitate drug discontinuation or be dose-limiting (68). The mechanism is presumably the same as that for minocycline, i.e. vestibulotoxicity.

Risk Factors

               No data are available.

Treatment and Avoidance

               Administering tigecycline on a full stomach improves tolerability, allowing use of a higher dose of drug (49). Administration in a fed state does not alter tigecycline pharmacokinetics (49). Prolonging the infusion time does not improve tolerability (49).

Overdoses

               Single doses up to 300 mg use associated with dose-related increases in the incidences of nausea and vomiting. Hemodialysis is ineffective at augmenting drug clearance (1).

 

DRUG INTERACTIONS

               Tigecycline does not affect steady-state digoxin pharmacokinetics and electrocardiographic pharmacodynamics to a clinically-relevant degree (1). In vitro studies using human hepatic microsomes indicated that tigecycline has no significant effect on the activities of the following isozymes of cytochrome P450: 1A2, 2C8, 2C9, 1C19, 2D6, and 3A4 (1). Tigecycline alters the single-dose pharmacokinetics of warfarin but not its pharmacodynamics (INR response). Tigecycline reduced the oral CL of R-warfarin/S-warfarin by means of 40/23 percent, increased Cmax by 38/43 percent, and increased AUC by 68/29 percent (1). It would be prudent to monitor PT/INR if the two drugs are coadministered.

 

CLINICAL INDICATIONS

               Tigecycline is approved for the treatment of complicated skin/skin structure infections and complicated intra-abdominal infections in adults caused by specified aerobic and anerobic microorganisms (1).

Complicated Intra-Abdominal Infections

               In a phase 2, multicenter, open-label trial, tigecycline was evaluated in the management of complicated intra-abdominal infections (cIAI) in hospitalized patients. Patients received a 100 mg loading dose followed by a maintenance dose of 50 mg every 12 hours for 5 to 14 days. Enrollees numbered 111 (77 male, 18-80 years old). Efficacy-evaluable subjects numbered 66 and, in these subjects, clinical cure rates at the test-of-cure visit and end-of-therapy visit were 67 and 76 percent, respectively. Corresponding intent-to-treat cure rates were 55 and 72 percent. Nausea and vomiting were the most frequent adverse events (details not provided) (52).

               Results of a multinational, double-blind, randomized, active-controlled trial in patients with cIAI have recently been published. Tigecycline (100 mg loading dose followed by 50 mg every 12 hours for 5-14 days) was compared to imipenem-cilastatin (I-C) (500 mg every 6 hours for 5-14 days). Analyses were conducted on the basis of the following subgroupings: intent-to-treat (ITT, all randomized subjects, N =834), modified ITT (mITT, received at least 1 dose of drug, N = 825), clinical mITT (c-mITT, N = 807), clinically-evaluable (c-e, N = 692), microbiological mITT (m-m ITT, N = 621), and microbiologically-evaluable (m-e, N = 502). Clinical cure rates at the test of cure visit (14-35 days after therapy) were as follows: c-e tigecycline 82.7 percent, I-C 84.0 percent; c-mITT tigecycline 74.3 percent, I-C 79.4 percent; m-e (all infections) tigecycline 80.6 percent, I-C 82.4 percent; m-e (monomicrobial) tigecycline 89.9 percent, I-C 88.5 percent; m-e (polymicrobial) tigecycline 75.3 percent, I-C 78.1 percent; m-mITT (all infections) tigecycline 73.5 percent, I-C 78.2 percent; m-mITT (monomicrobial) tigecycline 79.3 percent, I-C 85.2 percent; and m-mITT (polymicrobial) tigecycline 69.7 percent, I-C 73.4 percent. Clinical cure rates were similar in the two groups when data were analyzed on the basis of individual types of cIAI and bacteremia present at baseline. Bacteriologic eradication occurred in 80.6 and 82.4 percent of m-e tigecycline and I-C recipients, respectively. Generally, eradication at the isolate level was similar in the two groups as well. Premature study discontinuation due to adverse events occurred in 6.5 percent of tigecycline and 3.6 percent of I-C recipients (p = NS). The most common adverse events in both groups were digestive system events (tigecycline 56.9%, I-C 49.8%; p = 0.043), nausea (tigecycline 31%, I-C 24.8%; p = 0.052), vomiting (tigecycline 25.7%, I-C 19.4%; p = 0.037) and diarrhea (tigecycline 21.3%, I-C 18.9%; p = NS) (53).

               Recently, results of a pooled analysis of two phase 3, multicenter, double-blind, randomized clinical trials of tigecycline in cIAI were published. One of these 2 studies was the study just reviewed (53). These studies, of similar design, compared tigecycline (100 mg loading dose followed by 50 mg every 12 hours for 5-14 days) and I-C (500 mg every 6 hours for 5-14 days). Analyses were conducted on the basis of the following subgroupings (see definitions in reference 53): ITT (N = 1658), mITT (N = 1642), c-m ITT (N = 1601), c-e (N = 1382), m-m ITT (N = 1262), and m-e (N = 1025). Clinical cure rates at the test-of-cure visit after the end of therapy were as follows: c-e tigecycline 86.7 percent, I-C 87.1 percent; c-mITT tigecycline 79.8 percent, I-C 82.0 percent; m-e tigecycline 86.1 percent, I-C 86.2 percent; and m-m ITT tigecycline 80.2 percent, I-C 81.5 percent. Clinical cure rates were virtually the same for the two treatments when subdivided into monomicrobial and polymicrobial infections. They were also virtually the same when subdivided by baseline infection diagnosis. Microbiological response (by m-e subject) at the test-of-cure visit were as follows: eradication tigecycline 86.1 percent, I-C 86.2 percent; persistence tigecycline 11.7 percent, I-C 13.3 percent; and superinfection tigecycline 2.1 percent, I-C 0.6 percent. Microbiological responses were unaffected by monomicrobial vs. polymicrobial infection status. Eradication rates at the isolate level were also similar for the two drugs. No inter-treatment comparison in efficacy parameters achieved statistical significance. Adverse events occurred in 73.8 and 71.6 percent of tigecycline and I-C recipients, respectively (p = 0.35). The only adverse events for which there were statistically-significant inter-treatment differences in rates (listed as tigecycline/I-C) were headache (3.4/5.8%, p = 0.025), phlebitis (2.0/4.0%, p = 0.019), overall digestive system (44.4/39.4%, p = 0.040), nausea (24.4/19.0%, p = 0.010), vomiting (19.2/14.3%, p = 0.008), leukocytosis (4.4/2.4%, p = 0.030), and hypoproteinemia (5.9/3.6%, p = 0.037). The rates of premature withdrawal due to adverse events were 2.6 and 1.5 percent in the tigecycline and I-C groups, respectively (p = 0.116) (2).

Complicated Skin and Skin Structure Infections

               A phase 2, multicenter, randomized, open-label trial evaluated the appropriate tigecycline dosing regimen for use in phase 3 trials of complicated skin and skin structure infections (cSSSI). Patients with cSSSI were randomized to receive either a 50 mg loading dose followed by 25 mg every 12 hours for 7-14 days or a 100 mg loading dose followed by 50 mg every 12 hours for 7-14 days. A total of 160 patients received at least one dose of study drug while 109 and 91 patients were clinically- and microbiologically-evaluable, respectively. Clinical cure rates at the test-of-cure visit in the 50 mg and 25 mg groups were 74 and 67 percent, respectively, while the microbiological eradication rates (by subject) were 69 and 56 percent, respectively (p = NS for both). There were no significant inter-treatment differences in treatment-emergent adverse event rates. As expected, the most frequent adverse events were nausea (in 22/35% of 25 mg/50 mg recipients, respectively), vomiting (in 13/19%), and diarrhea (in 11/9%). On the basis of this trial, a tigecycline regimen of 100 mg loading dose followed by 50 mg every 12 hours was selected for further cSSSI trials (60).

               A randomized, double-blind, active-controlled trial in patients with cSSSI was conducted in 21 countries in Europe, Asia, Africa, and Australia. Tigecycline (100 mg loading dose followed by 50 mg every 12 hours for up to 14 days) was compared to vancomycin (2 g/day) plus aztreonam (4 g/day), both agents for up to 14 days. Analyses were conducted on the basis of the following subgroups (see definitions in reference 53): c-e (N = 436), c-m ITT (N = 520), m-e (N = 312), and m-m ITT (N = 400). Clinical cure rates at the test of cure visit (12-42 days after the last dose) were as follows: c-e tigecycline 89.7 percent, combination 94.4 percent; c-m ITT tigecycline 84.3 percent, combination 86.9 percent; m-e (all infections) tigecycline 90.2 percent, combination 96.6 percent (p = 0.0372); m-e (monomicrobial infections) tigecycline 92.2 percent, combination 96.3 percent; m-e (polymicrobial infections) tigecycline 87.8 percent, combination 97 percent; m-m ITT (all infections) tigecycline 88.2 percent, combination 90.3 percent; m-m ITT (monomicrobial infections) tigecycline 91.2 percent, combination 89.2 percent; and m-m ITT (polymicrobial infections) tigecycline 84.4 percent, combination 91.8 percent. The two treatments were also not significantly different during exploratory subgroup analyses by type of cSSSI and by stratification on the basis of concomitant diabetes mellitus, peripheral vascular disease, and bacteremia at baseline. In the m-e population, bacteriologic eradication rates by subject at the test of cure visit were 84.8 and 93.2 percent in the tigecycline and combination groups, respectively (p = 0.0243). Bacteriologic eradication rates at the isolate level were similar in the two groups for S. aureus (MRSA and MSSA), S. pyogenes, S. agalactiae, E. faecalis (all isolates were vancomycin-susceptible), E. coli, and B. fragilis. Premature study discontinuation due to adverse events occurred in 2.2 and 4.8 percent of tigecycline and combination therapy recipients, respectively. For the most part, the two groups were comparable in terms of the frequencies and types of adverse events. However, some significant (p < 0.05) intergroup differences did occur (listed as tigecycline/combination): digestive system events in 32.5/14.1 percent, nausea in 25.2/5.2 percent, vomiting in 12.0/2.2 percent, increased aspartate transaminase in 1.5/5.2 percent, increased alanine transaminase in 1.8/6.7 percent, and skin and appendages events in 7.3/13.8 percent (15).

               Recently, results of a pooled analysis of two phase 3, multicenter, double-blind, randomized clinical trials of tigecycline in cSSSI were published. One of these 2 studies was the study just reviewed (15). These studies, of similar design, compared tigecycline (100 mg loading dose followed by 50 mg every 12 hours for up to 14 days) and the combination of vancomycin (1 g every 12 hours for up to 14 days) and aztreonam (2 g every 12 hours for up to 14 days). Analyses were conducted on the basis of the following subgroupings (see definitions in reference 73): ITT (N = 1129), mITT (N = 1116), c-mITT (N = 1057), c-e (N = 833), m-e (N = 540), and m-mITT (N = 769). Clinical cure rates at the text-of-cure visit 12 to 42 days after the end of therapy were as follows: c-e tigecycline 86.5 percent, combination 88.6 percent; c-mITT tigecycline 79.7 percent, combination 81.9 percent; m-e tigecycline 86.4 percent, combination 88.5 percent; and m-mITT tigecycline 84.4 percent, combination 84.4 percent. Clinical cure rates were virtually the same for the two treatments when subdivided into monomicrobial and polymicrobial infections. They were also virtually the same when subdivided by baseline infection diagnosis. Microbial eradication occurred in 82.1 and 86.2 percent of m-e tigecycline and combination recipients, respectively. Corresponding eradication rates were 76.2 and 79.1 percent in the m-mITT population. Microbial eradication rates at the isolate level were also similar for the two treatments. No inter-treatment difference in efficacy parameters achieved statistical significance. Adverse events occurred in 67.7 percent of tigecycline recipients and 61.1 percent of combination recipients (mITT pop., p = 0.024). There were significant inter-treatment differences in the rates of selected adverse events (listed as tigecycline/combination): fever (2.3/4.9%, p = 0.023), overall cardiovascular system (8.8/14.7%, p = 0.003), overall digestive system (45.6/20.5%, p < 0.001), anorexia (3.4/0.4%, p < 0.001), diarrhea (8.5/5.1%, p = 0.032), dyspepsia (3.7/0.9%, p = 0.002), nausea (34.5/8.2%, p < 0.001), vomiting (19.6/3.6%, p < 0.001), prolonged activated partial thromboplastin time result (3.5/1.5%, p = 0.034), increased aspartate aminotransferase (1.8/5.1%, p = 0.003), increased alanine aminotransferase (1.4/6.2%, p < 0.001), overall skin and appendages (10.6/19.3%, p < 0.001), pruritus (4.2/7.3%, p = 0.039), rash (1.9/5.8%, p < 0.001), and overall urogenital system (3.4/3.8%, p = 0.005) (23).

Review Article:  Lentino JR, Narita M, Yu VL.  New Antimicrobial Agents as Therapy for Resistant Gram-Positive Cocci.

Miscellaneous Infections

               A case report of a 25 year old male in septic shock secondary to multidrug-resistant A. baumannii illustrated the value of tigecycline when added to a failing regimen of colistin and high-dose meropenem. Within 4 days after the introduction of tigecycline, fever was substantially ameliorated and hemodynamic instability had ceased. Soon thereafter, the sepsis syndrome disappeared (70).

Narita M.  In Vitro and animal studies of antibiotic synergy for newer antistaphylococcal agents for Staphylococcus aureus. 2008

 

CONCLUSIONS

               Tigecycline is the 9-t-butylglycylamido derivative of the tetracycline minocycline. It is the first glycylcycline to be marketed. Tigecycline is thought to act via the same mechanism as the structurally-related tetracyclines, i.e. inhibition of bacterial protein synthesis by binding to the 30S subunit of the ribosome. Its antibacterial activity is unaffected by the presence of resistance determinants to tetracycline, minocycline, penicillin, vancomycin, methicillin, and the macrolides as well as extended-spectrum beta-lactamases. Its activity is bacteriostatic in nature and resistance is mediated primarily by efflux pump mechanisms. Despite broad-spectrum activity, organisms commonly of intrinsic intermediate susceptibility include Legionella, Ureaplasma, Proteus, Providencia, Morganella, Acinetobacter, and Bacteroides species. Pseudomonads and atypical mycobacteria are usually intrinsically resistant. Available only for IV use, tigecycline concentrates intracellularly and penetrates well into various respiratory tract compartments and skin blister fluid. Elimination occurs via balanced hepatic metabolism, biliary secretion, and renal excretion. Dosage regimen adjustment is needed only in severe hepatic impairment (Child-Pugh class C; 50% decrease in maintenance dose). Tigecycline has proven equivalent to standard comparators in the treatment of complicated intra-abdominal and skin and skin structure infections. The major dose-limiting adverse events are nausea and vomiting, which may be somewhat ameliorated by dosing on a full stomach. The only drug-drug interaction of potential clinical importance occurs with warfarin, wherein tigecycline may potentiate its hypoprothrombinemic response by reducing the oral clearance of S-warfarin/R-warfarin by means of 40/23 percent.

               Although tigecycline is an important advance in the therapy to infections due to multi-resistant gram-positive aerobes, two findings are of concern. Dose-related nausea and vomiting may seriously compromise the clinician’s ability to use adequate doses of the drug. This may, in turn, promote the development and dissemination of efflux pump resistance determinants, which have already been found in a variety of species (Salmonella, Proteus, Pseudomonas, etc.) and can be passed from one organism to another. It is hoped that these factors will not result in tigecycline having but a brief life span as a useful antimicrobial in humans.

 

TABLES AND FIGURES

Table 1. MIC50 and MIC90 Data for Tigecycline Against Gram-Positive and -Negative Aerobes and Anaerobes

Table 2. Epidemiological MIC Cut-Off Values for Tigecycline and Corresponding FDA-Approved Breakpoint Values

Figure 1. Chemical Structure

 

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