Tigecycline: A New Glycylcycline for Treatment of Serious Infections
- Department of Medicine, Northwestern University, Feinberg School of Medicine, and Division of Infectious Diseases, Northwestern Memorial Hospital, Chicago, Illinois
- Reprints or correspondence: Dr. Gary A. Noskin, Div. of Infectious Diseases, Northwestern Memorial Hospital, 251 East Huron St., Galter 3-210, Chicago, IL 60611 (gnoskin{at}northwestern.edu).
Abstract
Tigecycline is a new semisynthetic glycylcycline for the treatment of serious infections. Of the glycylcyclines, tigecycline is the most studied and appears to hold promise as a new antimicrobial agent that can be administered as monotherapy to patients with many types of serious bacterial infections. For patients with serious infections, the initial choice for empirical therapy with broad-spectrum antibiotics is crucial, and, if the choice is inappropriate, it may have adverse consequences for the patient. Tigecycline has been designed to overcome many existing mechanisms of resistance among bacteria and confers broad antibiotic coverage against vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and many species of multidrug-resistant gram-negative bacteria. Tigecycline has been efficacious and well tolerated in human clinical phase 2 studies, which warranted further evaluation of tigecycline in larger studies for treatment of many indications, including complicated skin and skin-structure infections, complicated intra-abdominal infections, and infections of the lower respiratory tract.
In general, when hospitalized patients have a serious infection, diagnostic cultures and other tests are performed, and empirical therapy with broad-spectrum antibiotics is initiated. The initial choice for empirical therapy is crucial, and, if the choice is inappropriate, it may have adverse consequences for the patient [1, 2]. Changing patterns of antimicrobial resistance among bacteria that commonly cause serious infections present difficult challenges for clinicians, often necessitating the use of newer and broader-spectrum agents, especially when prescribing initial or empirical therapy to severely ill patients [3].
Important criteria for empirical antimicrobial therapy include an agent with proven clinical activity, limited potential for the development of resistance, and low potential for adverse events and drug interactions. Certain antibiotics (e.g., the carbapenems, cephalosporins, penicillins, and fluoroquinolones) may be appropriate for empirical therapy for serious infections, but increasing antimicrobial resistance among enterococci, staphylococci, and gram-negative bacteria has complicated this approach [3, 4].
The increase in the prevalence of multidrug-resistant bacteria has led to greater use of combination therapy, in which 2 or even 3 antimicrobial agents are commonly used for empirical therapy. The advantage of empirical combination antibiotic therapy is the greater likelihood of prescribing at least 1 active agent during the initial period of infection, before culture results are available. The disadvantages of empirical combination antibiotic therapy are the increased costs associated with acquisition and administration of the drug and increased risks of adverse drug reactions and drug interactions. Ideally, a single antimicrobial agent that confers broad-spectrum coverage with potent activity against drug-resistant pathogens would be an important addition to our therapeutic armamentarium. However, clinicians must be prudent when prescribing any antimicrobial for treatment of serious infections, because misuse and overuse may encourage the emergence of resistance.
The glycylcyclines are being developed to specifically overcome mechanisms of microbial resistance. The glycylcyclines exhibit potent activity against a broad spectrum of gram-positive and gram-negative bacteria, including strains for which the mechanisms of resistance to other antibiotics include drug efflux pumps and protection of ribosomes [5].
Tigecycline (9-t-butylglycylamido-minocycline; GAR-936, formerly TBG-MINO; Wyeth Laboratories) is a new, semisynthetic glycylcycline that just received approval from the US Food and Drug Administration. Tigecycline has demonstrated potent in vitro antibacterial activity against a wide range of clinically important gram-positive and gram-negative aerobic bacteria and anaerobes, including Staphylococcus aureus, Enterococcus species, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, most Enterobacteriaceae, and Bacteroides fragilis [6]. This agent has limited or no activity against Pseudomonas aeruginosa and has reduced activity against Proteus mirabilis [7]. Notably, tigecycline is not affected by most of the known mechanisms of resistance to tetracycline encountered in bacteria [8], and it has activity against bacterial isolates that are resistant to other antibiotic classes, such as β-lactams and fluoroquinolones. Promising microbiological, pharmacodynamic, and pharmacokinetic data have led to further evaluation of tigecycline for use as monotherapy for serious infections in human clinical studies [9, 10]. Tigecycline is approved by the US Food and Drug Administration for the treatment of skin, soft-tissue, and intra-abdominal infections [11, 12].
Mechanism Of Action Of Tigecycline And Overcoming Antimicrobial Mechanisms Of Resistance
Glycylcyclines are modified antimicrobial agents that possess the central 4-ring carbocyclic skeleton that is essential for antibacterial activity. Substitution of an N-alkyl-glycylamido group at the 9 position on the D ring confers to these new agents a broader spectrum of activity and permits evasion of resistance to tetracycline (figure 1). Tigecycline has a 9-t-butyl-glycylamido side chain on the central skeleton of minocycline (figure 2). The formula for tigecycline is C29H39N5O8; the drug has a molecular mass of 585.65 Da [9].
Figure 1
Basic structure of glycylcyclines [8]
Figure 2
Structure of tigecycline [8]
This structural class of antimicrobials is bacteriostatic, and the drugs act by binding to the bacterial 30S ribosomal subunit and by blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. Amino acid residues are prevented from becoming incorporated into elongating peptide chains, which leads to inhibition of protein synthesis [10, 13].
Tigecycline is known to overcome the 2 major determinants of tetracycline resistance: active efflux of drug from inside the bacterial cell and protection of ribosomes [14, 15]. Tigecycline appears to overcome these mechanisms as a result of steric hindrance produced by the large substituent at position 9 [13], as evidenced by dimethylsulfate modification of tigecycline binding sites, mutational analysis of 16S rRNA, and structural modeling of tigecycline at a binding site in the 30S ribosomal subunit [8].
The activity of tigecycline has been evaluated in Escherichia coli KAM3 (acrB) strains harboring plasmids encoding the various different tetracycline-specific efflux transporter genes: tet(B), tet(C), and tet(K). Multidrug transporter genes (acrAB, acrEF, and bcr) were also examined. Tigecycline exhibited potent in vitro activity against all 3 of the tet-expressing, tetracycline-resistant strains, as evidenced by the fact that MICs for the mutant strains are equal to that for the original host strain. This study suggests that tigecycline is not recognized by the tet efflux transporter at a low concentration, which likely accounts for the ability of tigecycline to maintain significant antibacterial activity. In addition, the tigecycline MICs for organisms containing the multidrug efflux proteins AcrAB and AcrEF were increased 4-fold. Tigecycline may be a substrate of AcrAB and its close homologue, AcrEF, which are resistance-modulation-division-type multicomponent efflux transporters [16].
In addition, many bacterial mutants have been generated in the laboratory and have exhibited only marginal differences in susceptibility to tigecycline. Because of this, it is believed that resistance will not arise by trivial mutations in existing resistance genes [13].
Antimicrobial Activity Of Tigecycline
The antimicrobial activity of tigecycline is reported in table 1 (aerobic gram-positive bacteria), table 2 (aerobic gram-negative bacteria), table 3 (anaerobes), and table 4 (atypical organisms).
Table 1
In vitro activity of tigecycline against aerobic gram-positive organisms.
Table 2
In vitro activity of tigecycline against aerobic gram-negative organisms.
Table 3
In vitro activity of tigecycline against anaerobic organisms.
Table 4
In vitro activity of tigecycline against atypical organisms.
Evaluation of large collections of multiple species of bacteria. In a study of bacteremia, 5092 isolates obtained by culture of blood were collected by 29 laboratories from the United Kingdom and Ireland in 2001 and 2002. Resistance to oxacillin was reported for 42% of S. aureus strains and 76% of coagulase-negative staphylococci. Tigecycline MICs were low for gram-positive bacteria, including a large proportion of Enterococcus faecium isolates, and for Enterobacteriaceae, except for Proteus and Enterobacter species [42].
In another study of 1087 bacterial strains isolated in 12 medical centers located throughout Spain, the antimicrobial activity of tigecycline against 14 bacterial species was compared with that of other antimicrobial agents. Tigecycline showed antibacterial activity against a wide spectrum of aerobic and anaerobic bacteria, including methicillin-resistant S. aureus, coagulase-negative staphylococci, penicillin-resistant S. pneumoniae, E. faecium, Acinetobacter baumannii, and Stenotrophomonas maltophilia. One hundred two S. pneumoniae isolates were collected in that study, of which 62.7% were intermediately resistant to penicillin, 37.3% were highly resistant to penicillin, and 54.9% were resistant to erythromycin. Tigecycline was noted to be highly active against these pneumococcal isolates, regardless of their resistance or susceptibility to β-lactams or macrolides. Tigecycline MICs ranged from ⩽0.06 to 0.125 µg/mL. Tigecycline was very active against staphylococci, with MICs of ⩽0.5 µg/mL for all strains tested. Tigecycline was also reported to be equally effective against E. faecium and Enterococcus faecalis. The activity of tigecycline against vancomycin-resistant enterococci could not be studied, because no vancomycin-resistant isolates were identified in this series [17].
The tigecycline MIC90 for all of the tested Enterobacteriaceae isolates ranged from 0.5 to 2 µg/mL. After polymyxin B, tigecycline was the most active agent against A. baumannii, with >90% of A. baumannii strains being inhibited by 8 µg/mL tigecycline. Other antimicrobial agents with activity, as determined by MIC50 and MIC90 (listed in descending order of activity), were sulbactam, levofloxacin, ampicillin-sulbactam, imipenem, cefepime, piperacillin-tazobactam, and gentamicin. In this collection of A. baumannii isolates, resistance to imipenem was detected in 28.1% of isolates tested. At a concentration of 4 µg/mL, tigecycline inhibited 86.7% of all anaerobes tested, and its activity did not vary among the different species tested, which included B. fragilis, other members of the B. fragilis group, and toxigenic Clostridium difficile. For the C. difficile isolates, tigecycline had the most in vitro activity of all of the antibiotics evaluated, including metronidazole. Tigecycline inhibited 92.7% of strains, at a concentration of 0.125 µg/mL [17].
In another study, the in vitro activity of tigecycline was compared with that of minocycline, doxycycline, tetracycline, moxifloxacin, penicillin G, and erythromycin. Isolates were collected from infected wounds resulting from bites by humans and animals and consisted of 268 aerobic and 148 anaerobic strains of bacteria (including Pasteurella, Eikenella, Moraxella, Bergeyella, Neisseria, EF-4, Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Staphylococcus, Streptococcus, Enterococcus, Corynebacterium, Propionibacterium, Peptostreptococcus, and Actinomyces species). The tigecycline MIC90 was ⩽0.25 µg/mL against all aerobic gram-positive and gram-negative strains, including tetracycline-resistant strains of Enterococcus and Streptococcus and coagulase-negative staphylococci, except for Enterococcus corrodens (for which the MIC90 was ⩽4 µg/mL). Tigecycline was also very active against all anaerobic species, with an MIC90 of ⩽0.25 µg/mL. Erythromycin-resistant and moxifloxacin-resistant fusobacteria were also highly susceptible to tigecycline, with an MIC90 of 0.06 µg/mL [18].
The activity of tigecycline was also evaluated against 1924 clinical isolates collected in Europe. Excellent activity was reported against all gram-positive cocci. With regard to gram-negative bacteria, tigecycline was very potent against most Enterobacteriaceae, with most MIC90 values ⩽2 µg/mL. In addition, good activity was reported against Acinetobacter species and S. maltophilia [19].
Activity against gram-positive bacteria. In a study of a worldwide collection of 10,127 staphylococci, streptococci, and enterococci, the in vitro activity of tigecycline was compared with that of 9 other agents. Bacterial isolates were collected by 93 medical centers in 29 countries from 4 continents. Tested strains included 5077 strains of S. aureus, 1585 strains of S. pneumoniae, 1432 strains of coagulase-negative staphylococci, 1416 strains of Enterococcus species, 405 strains of β-hemolytic streptococci, and 212 strains of viridans streptococci. Tigecycline inhibited all streptococci at a concentration of ⩽2 µg/mL. Tigecycline was equally active against oxacillin-susceptible and oxacillin-resistant subsets of S. aureus and coagulase-negative staphylococci, with an MIC90 of 0.5 µg/mL. Tigecycline was also the most active antibiotic against vancomycin-susceptible and vancomycin-resistant strains of enterococci. The potent activity of tigecycline was demonstrated against all S. pneumoniae, viridans group streptococci, and β-hemolytic streptococci, with MIC90 values of ⩽0.12 µg/mL. The authors concluded that tigecycline displays a very broad spectrum of activity and potency against staphylococci, streptococci, and enterococci [20].
The in vitro activities of tigecycline against vancomycin-resistant enterococci and staphylococci with diminished susceptibility to glycopeptides were evaluated in 157 clinical isolates collected during 1998–2001 in Madrid. The isolates consisted of 97 vancomycin-resistant enterococci (25 E. faecalis, 41 E. faecium, 21 Enterococcus casseliflavus, 10 Enterococcus gallinarum), of which 28 expressed the VanA phenotype, 38 expressed the VanB phenotype, and 31 expressed the VanC phenotype. Fifty-four coagulase-negative staphylococci and 6 S. aureus isolates with reduced susceptibility to glycopeptides were also tested [21].
All isolates were inhibited by tigecycline at concentrations between ⩽0.03 and 1 µg/mL, and the tigecycline MIC90 was 0.5 µg/mL. All isolates, including those that were resistant to tetracycline, were inhibited at a concentration of ⩽1 µg/mL. The MIC90 of tigecycline against coagulase-negative staphylococci was 0.5 µg/mL, and that for the combined Enterococcus species was 0.12 µg/mL. Fifty-five of the enterococcal isolates were tetracycline resistant (MIC, >8 µg/mL), and all of the isolates were inhibited by tigecycline at a concentration of 0.5 µg/mL. Tigecycline exhibited good activity against glycopeptide-resistant enterococci, including VanA, VanB, and VanC phenotypes. All S. aureus isolates, including those that were resistant to tetracycline, were inhibited by 1 µg/mL tigecycline [21].
Among the isolates tested, tigecycline did not exhibit bactericidal activity, with an MBC90 of >32 µg/mL. Three enterococcal isolates were killed with tigecycline at concentrations of 4, 8, and 16 µg/mL, and one coagulase-negative staphylococcal isolate was killed at a concentration of 16 µg/mL. The authors reported that tigecycline is largely a bacteriostatic antimicrobial agent that inhibits protein synthesis. In that study, tigecycline exhibited good activity against vancomycin-resistant enterococci and against methicillin-resistant staphylococci that exhibited reduced susceptibility to glycopeptides. In addition, tigecycline maintained in vitro activity against the collected clinical isolates independent of resistance or susceptibility to tetracycline [22].
In another study of 602 North American isolates of methicillin-susceptible and methicillin-resistant S. aureus, tigecycline MICs for all isolates ranged from 0.06 to 1.0 µg/mL. Tigecycline appeared to be highly active, with MIC50 and MIC90 values of 0.12 and 0.25 µg/mL for methicillin-susceptible S. aureus and 0.25 and 0.5 µg/mL for methicillin-resistant S. aureus, respectively [22]. In another study of 527 gram-positive clinical isolates collected in a Boston hospital, tigecycline inhibited all strains at concentrations of ⩽2 µg/mL, except for 2 strains of group JK diphtheroids, for which the MIC was 4 µg/mL [23].
In France, a total of 133 S. aureus and 105 S. pneumoniae epidemiologically unrelated multidrug-resistant strains were studied. Tigecycline was highly active in vitro, with MICs ranging from 0.25 to 1 µg/mL for S. aureus isolates and from 0.06 to 0.5 µg/mL for S. pneumoniae isolates [24].
In a study of 201 isolates of S. pneumoniae, tigecycline MICs ranged from ⩽0.016 to 0.125 µg/mL. In addition, tigecycline was bactericidal against 11 of 12 tested strains [43]. In another study, 6991 unique isolates of S. pneumoniae with varying degrees of susceptibility to penicillin were collected from 25 medical centers throughout Canada. Tigecycline was reported to be highly active when tested against these isolates [25].
In a recently published study, the activity of tigecycline was tested against 107 Streptococcus pyogenes and 98 Streptococcus agalactiae isolates from Madrid. All isolates were resistant to erythromycin, whereas resistance to tetracycline was variable. Among S. pyogenes strains, the most prevalent resistance gene was mef(A) (91.6% of strains). The erm(B) gene was the most prevalent (65.3%) among S. agalactiae strains. Fourteen S. pyogenes isolates (13.1%) and 88 S. agalactiae isolates (89.8%) were resistant to tetracycline and were tested for the presence of tetracycline resistance genes tet(M), tet(O), tet(K), and tet(L) by PCR. The majority (76.5%) of tetracycline-resistant streptococcal isolates in that study contained tet(M), which provides resistance to both tetracycline and minocycline. The 12 tetracycline-resistant S. pyogenes isolates were found to contain only tet(M). Among the 88 tetracycline-resistant S. agalactiae isolates, 66 (75%) contained the tet(M) gene and 19 (21.6%) contained the tet(O) gene. No genes conferring tetracycline resistance were found in 5 tetracycline-resistant isolates (2 S. pyogenes and 3 S. agalactiae). Neither the tet(L) nor the tet(K) gene was found to be present in the studied bacteria. Tigecycline proved to be very active against all of the isolates tested (MIC90, 0.06 µg/mL), including those resistant to tetracycline [26]. Tetracycline-resistant S. agalactiae and S. pyogenes isolates were inhibited by ⩽0.25 and ⩽0.06 µg/mL tigecycline, respectively. The potent in vitro activity of tigecycline against all of the isolates studied, regardless of resistance to erythromycin or tetracycline, suggests that tigecycline may be an effective alternative to penicillin for the treatment of infections caused by these organisms [26].
The activity of tigecycline has been compared with that of vancomycin in a rat model of endocarditis. Treatment with tigecycline or vancomycin began 24–36 h after injection of bacteria. In this model, tigecycline reduced titers of bacteria in vegetations by >2 log10 cfu, compared with those in untreated controls, for both vancomycin-susceptible and vancomycin-resistant (VanA and VanB) E. faecalis strains and by >4 log10 cfu for the methicillin-resistant S. aureus isolate. Overall, tigecycline was more effective at a lower dose than was vancomycin. The authors concluded that the study demonstrated the therapeutic potential of tigecycline and that further investigations were warranted [44].
Tigecycline was investigated in a mouse peritonitis model against 3 E. faecalis and 4 E. faecium isolates with differing susceptibilities to vancomycin and tetracyclines, all of which were inhibited by ⩽0.125 µg/mL tigecycline. Administered as a single subcutaneous dose, tigecycline displayed a protective effect against all strains tested, including those containing the tet(M) tetracycline resistance determinant, as well as VanA and VanB strains [45].
The activity of tigecycline was evaluated against 37 clinical isolates of vancomycin-resistant enterococci (including organisms carrying the vanA, vanB, vanC-1, and vanC-2/3 genes), 26 isolates of methicillin-resistant S. aureus and 30 isolates of S. pneumoniae with high-level penicillin resistance. Tigecycline was highly active in vitro: all isolates of vancomycin-resistant enterococci, methicillin-resistant S. aureus, and penicillin-resistant S. pneumoniae were inhibited by ⩽1, ⩽2, and ⩽0.25 µg/mL tigecycline, respectively. In addition, time-kill experiments with vancomycin-resistant enterococci failed to show synergy or antagonism between tigecycline and quinupristin-dalfopristin [27].
The in vitro activities of tigecycline and daptomycin were studied against staphylococcal, enterococcal, and streptococcal clinical isolates that were routinely collected from various medical centers throughout the United States and Canada between 1990 and 1999. Tigecycline was found to be more active than daptomycin; the tigecycline MIC90 values were 0.12–1 µg/mL, compared with daptomycin MIC90 values of 0.5–16 µg/mL. In a murine model of intraperitoneal infection, both tigecycline and daptomycin demonstrated in vivo activity against S. aureus strains that were intermediately resistant to glycopeptides, methicillin-resistant S. aureus, and methicillin-susceptible S. aureus strains [28].
The activity of tigecycline against Staphylococcus epidermidis was evaluated in an in vitro adherent-cell biofilm model. Tigecycline MBCs ranged from 1 to 8 µg/mL for S. epidermidis growing in a biofilm of adherent cells. In freely growing cells, the MBCs were 0.12 to >32 µg/mL. The killing activity of tigecycline against the adherent bacteria in this model was at least 4-fold better than that of vancomycin and daptomycin [46].
The activity of tigecycline was investigated in vitro and in an animal model of experimental endocarditis due to the susceptible E. faecalis JH2-2 strain, its VanA-type transconjugant BM4316, and E. faecium HB217, a tetracycline-resistant clinical VanA-type strain. Tigecycline MICs were 0.06 µg/mL for the 3 study strains. In vitro pharmacodynamic studies revealed the bacteriostatic activity of tigecycline, which was not augmented by increasing concentrations of antibiotic to >1 µg/mL. A postantibiotic effect was noted, ranging from 1 to 4.5 h for concentrations of 1–20-fold the MIC. Tigecycline homogeneously diffused into the vegetations, and lower clearance of tigecycline occurred from aortic vegetations than from serum. The mean serum elimination half-life ranged from 3.3 to 3.6 h in this rabbit model. No resistant mutants were selected in vivo. The authors concluded that tigecycline performed well in this endocarditis model with a prolonged half-life, a significant postantibiotic effect, and good and homogenous penetration into vegetations [47].
In another study, the in vitro activity of tigecycline was evaluated alone and in combination with other agents against multidrug-resistant strains of E. faecium and S. aureus. The strains selected for study were 2 strains of vancomycin-resistant E. faecium, 3 glycopeptide-intermediate resistant S. aureus strains, and 1 methicillin-resistant S. aureus strain. In time-kill studies and analyses of MICs and MBCs, the activity of tigecycline was compared with that of vancomycin, gentamicin, rifampin, and doxycycline. In addition, time-kill studies were performed to evaluate the activity of tigecycline in combination with vancomycin, gentamicin, rifampin, and doxycycline. In the time-kill studies, tigecycline significantly inhibited the bacterial inoculum from growing for all strains. None of the tigecycline combinations exhibited enhanced killing activity against vancomycin-resistant E. faecium; however, when gentamicin was combined with tigecycline, improved effects were noted. The combination of gentamicin and tigecycline demonstrated enhanced or improved activity against the 3 S. aureus strains [48].
Activity against gram-negative bacteria. The activity of tigecycline was evaluated in a worldwide sample of Enterobactereriaceae and selected nonfermentative gram-negative bacilli. Clinical isolates (2240) were collected from 100 medical centers located in 25 countries on 5 continents. The Enterobactereriaceae were highly susceptible to tigecycline, with an MIC90 of 1 µg/mL, and 99.4% were susceptible to tigecycline at a concentration of ⩽4 µg/mL. Tigecycline was also noted to be very active against extended-spectrum β-lactamase–producing organisms. Less activity was noted against P. mirabilis and indole-positive Proteus species. Among the nonfermentative gram-negative bacilli, tigecycline was very active against Acinetobacter species (96.1% susceptibility at a concentration of ⩽4 µg/mL) and S. maltophilia (100% susceptibility), but its activity against P. aeruginosa was very limited (16% susceptibility) [49].
In a study of respiratory tract isolates from 25 medical centers in Canada, 7566 unique patient isolates of H. influenzae and 2314 unique isolates of M. catarrhalis were tested. β-lactamase production was noted in 22.5% of the H. influenzae isolates and in 92.4% of the M. catarrhalis isolates. The MIC90 of tigecycline was 4 µg/mL for all isolates, with a range of ⩽0.06 µg/mL to ⩾8 µg/mL [50].
The activity of tigecycline was tested in a worldwide collection of 1215 strains of H. influenzae, 495 strains of M. catarrhalis, and 17 strains of Neisseria meningitidis. All isolates were uniformly susceptible to tigecycline, even those that produced β-lactamase [51].
The in vitro activity of tigecycline was evaluated with 195 clinical isolates of S. maltophilia collected in the Hospital Clínico San Carlos in Spain. All isolates were reported to be susceptible to minocycline, and 98% were susceptible to trimethoprim-sulfamethoxazole. Tigecycline exhibited good activity, with MICs that were 2 dilutions higher than that of minocycline and 3–4 dilutions lower than that of tetracycline. Tigecycline inhibited 94.4% of the isolates tested at a concentration of 4 µg/mL. Tigecycline was more active than amikacin, ceftazidime, and ticarcillin-clavulanate [33].
In another survey of bacterial resistance to antibiotics, antimicrobial susceptibility testing was performed of 595 Acinetobacter isolates collected from 52 sentinel clinical laboratories located in the United Kingdom. Widespread resistance to cephalosporins, aminoglycosides, and ciprofloxacin was noted. Carbapenems, colistin, sulbactam, minocycline, and tigecycline were reported to be active against >80% of the isolates. The relative activities, in descending order, were minocycline, tigecycline, and tetracycline. Tigecycline was noted to be less active than minocycline, but both antibiotics were able to overcome most bacterial resistance mechanisms [34].
The activity of tigecycline against 90 isolates of Eikenella corrodens collected in Madrid was compared with that of other antibiotics. All isolates were inhibited by tigecycline at concentrations between ⩽0.06 and 4 µg/mL. The tigecycline MIC90 for the isolates was 2 µg/mL, and the MIC90 values for ampicillin, amoxicillin-clavulanate, cefotaxime, imipenem, chloramphenicol, and ciprofloxacin were 1, ⩽0.5/0.25, 0.5, ⩽0.12, ⩽2, and 0.5 µg/mL, respectively [35].
The AcrAB multidrug efflux pump is associated with reduced in vitro activity of tigecycline against P. mirabilis [52]. Strains of P. aeruginosa are also less susceptible to tigecycline [14]. Experiments using mutant bacteria exhibiting drug efflux mediated by the MexAB-OprM and MexCD-OprJ efflux pumps suggest that, although glycylcyclines are subject to efflux from P. aeruginosa, they are generally inferior substrates to the tested efflux pumps, compared with narrower-spectrum tetracyclines. This fact is demonstrated by the observation that the MICs of doxycycline and minocycline increased to a greater degree than did those of tigecycline against the MexAB-OprM– and MexCD-OprJ–overexpressing mutant P. aeruginosa strains [53].
Activity against anaerobic bacteria. In a study that evaluated in vitro activity against anaerobes, tigecycline was tested against 831 isolates constituting all of the species within the B. fragilis group. The isolates were collected during 1998–2000 from various geographically diverse US medical centers. At a concentration of 8 µg/mL, tigecycline was found to be more active than clindamycin, minocycline, trovafloxacin, and cefoxitin and less active than imipenem or piperacillin-tazobactam against all isolates tested [54].
Activity against atypical organisms. In another study, the susceptibilities of Mycoplasma hominis, Mycoplasma pneumoniae, and Ureaplasma urealyticum were determined by agar dilution. M. pneumoniae was susceptible to tigecycline at an MIC90 of 0.25 µg/mL, making tigecycline more active than either tetracycline or minocycline when tested against these 30 isolates. M. hominis was also susceptible to tigecycline (MIC90 against 29 isolates, 0.5 µg/mL). U. urealyticum was less susceptible to tigecycline (MIC90 against 25 isolates, 8 µg/mL) than it was to tetracycline (MIC90, 1 µg/mL) or minocycline (MIC90, 0.25 µg/mL) [55].
The in vitro activities of tigecycline, tetracycline, doxycycline, and minocycline were studied with 76 clinical isolates of rapidly growing mycobacteria (Mycobacterium fortuitum group [n = 26], Mycobacterium abscessus [n = 20], Mycobacterium chelonae [n = 26], Mycobacterium immunogenum [n = 1], and the Mycobacterium smegmatis group [n = 1 isolate each of M. smegmatis sensu stricto, Mycobacterium wolinskyi, and Mycobacterium goodie]), and 45 isolates representing 5 species of slowly growing nontuberculous mycobacteria (Mycobacterium avium complex [n = 11], Mycobacterium lentiflavum [n = 10], Mycobacterium kansasii [n = 11], Mycobacterium marinum [n = 11], Mycobacterium xenopi [n = 1], and Mycobacterium simiae [n = 1]). All of the rapidly growing mycobacterial isolates were highly susceptible to tigecycline, with an MIC90 of 0.25 µg/mL for M. abscessus and <0.12 µg/mL for M. chelonae and the M. fortuitum group. The measured tigecycline MICs were the same regardless of resistance or susceptibility to tetracycline, and tigecycline was 4–11-fold more active than tetracycline. No slowly growing nontuberculous mycobacteria were susceptible to tigecycline. Minocycline was more active against M. marinum and M. kansasii than was tigecycline. The authors concluded that tigecycline offers exciting therapeutic potential for the rapidly growing mycobacteria, especially for M. chelonae and M. abscessus, against which the activities of currently available agents are limited [39].
In another investigation, 37 isolates of M. marinum were collected from geographically diverse US clinical laboratories. The most potent agent was trimethoprim-sulfamethoxazole, with 91.9% of isolates categorized as susceptible. Tigecycline was noted to have an MIC90 of 3 µg/mL (upper limit, 24 µg/mL), compared with an MIC90 of 2 µg/mL for minocycline [40].
Edelstein et al. [56] reported that, in a guinea pig model of legionnaires disease, tigecycline is as effective as erythromycin against intracellular Legionella pneumophila and in preventing death due to pneumonia. Although these findings require confirmation in human clinical trials, in this animal model, tigecycline monotherapy was associated with persistence of L. pneumophila in the lungs at the end of therapy, suggesting that it may have limited efficacy in more difficult-to-treat infections. On the basis of their findings, they predicted that tigecycline should be effective for the treatment of mild legionnaires disease, but that prolonged therapy (14–21 days) would be required for a cure, under the assumption that human pharmacokinetics are similar to guinea pig pharmacokinetics. However, because tigecycline was associated with residual bacterial concentrations in the lungs, it may not be the drug of choice to treat severe legionnaires disease, especially for those patients who require hospitalization or are in an immunocompromised state [56].
Pharmacokinetics And Pharmacodynamics Of Tigecycline
Tigecycline is administered parenterally as a 1-h infusion twice daily and is available only as an injectable formulation. Most of the pharmacokinetic studies of tigecycline have been single-dose studies conducted among healthy subjects. The most common adverse events associated with the administration of tigecycline are dose related and include nausea, vomiting, and headache [10, 57–59]. In studies of single- and multiple-dose tigecycline pharmacokinetics conducted in the United States and Europe, the half-life of tigecycline ranged from 37 to 67 h, and the systemic clearance of tigecycline ranged from 0.2 to 0.3 L/h/kg. Tigecycline had a large volume of distribution (7–10 L/kg), indicating extensive distribution into the tissues. Food increased the maximum tolerated single dose from 100 mg to 200 mg, but the duration of infusion did not affect tolerability [58].
In Japanese men who received a single 100-mg dose of tigecycline administered intravenously over the course of 1 h, the maximum concentration (Cmax) was 0.85–1 µg/mL, the half-life was 16–24 h, and the AUC0–∞ (area under the concentration–time curve from 0 h to infinity) was 4.2–5.8 µg/h/mL [57]. The Cmax and AUC0–∞ both exhibited a linear dose response (from 0.20 ± 0.05 µg/mL to 1.52 ± 0.16 µg/mL and from 0.8 ± 0.36 µg/h/mL to 8.6 ± 1.8 µg/h/mL with 25 and 50 mg, respectively). In these studies, neither administration with food nor the sex of the patient appreciably altered the pharmacokinetic profile [10, 57–59].
In a randomized, double-blind single-dose study, 8 male subjects received 12.5, 25, 50, 75, 100, 200, and 300 mg over the course of 1 h to evaluate dose proportionality and the effect of food on the pharmacokinetics of tigecycline. The Cmax and AUC0–12 were linear and ranged from 0.11 to 2.8 µg/mL and 0.9 to 17.9 µg/h/mL, respectively. Administration with food did not affect the tolerability of tigecycline and did not change the pharmacokinetic profile [58].
Effects of multiple doses on the pharmacokinetics of tigecycline have been evaluated in a multicenter, prospective, open-label study [11]. In that study of complicated skin and skin-structure infections, for patients receiving 25 mg of tigecycline, the mean ± SD values for maximum concentration at steady state (Css,max), area under the plasma concentration–time curve at steady state from 0 to 12 h (AUCss,0–12h), and weight-adjusted systemic clearance were 0.265 ± 0.206 µg/mL, 1.43 ± 0.668 µg/h/mL, and 0.246 ± 0.114 L/h/kg, respectively. In those patients receiving 50 mg of tigecycline, the Css,max, AUCss,0–12h, and weight-adjusted systemic clearance were 0.403 ± 0.182 µg/mL, 2.24 ± 0.894 µg/h/mL, and 0.310 ± 0.124 L/h/kg, respectively [11].
Tigecycline has a variable and large volume of distribution, which has been reported to range from ∼5 to >10 L/kg [57–59]. The volume of distribution of tigecycline was proportional to the dose, from 4.4 ± 0.9 L/kg with a 25-mg dose to 10.8 ± 2.1 L/kg with a 150-mg dose [57]. In a single-dose rat study, excellent overall tissue penetration was noted, with the highest levels in the bone and bone marrow, followed by salivary gland, thyroid, spleen, and kidney [60]. In a rabbit model of meningitis, single doses of tigecycline of >20 mg/kg yielded concentrations in CSF of >1 µg/mL at 3 h that stayed at a steady level or increased at 6 h [61].
The level of tigecycline binding to protein is ∼78%. Tigecycline has a half-life of 36 h in humans, and on the basis of limited data, it does not appear that the either presence of food or the sex and age of the patient markedly changes the pharmacokinetics of tigecycline. The AUC is the pharmacodynamic parameter of tigecycline that appears to best correlate with bacteriologic eradication. Tigecycline is eliminated primarily by the liver via biliary excretion of unchanged drug and via glucuronidation, with <30% of the drug excreted unchanged in the urine. The AUC and Cmax of tigecycline are moderately higher in patients with renal impairment; however, no dosage adjustment is required in patients with renal dysfunction. Currently, data about the pharmacokinetics and safety of tigecycline in patients with hepatic impairment have not been published. Because the majority of tigecycline is eliminated by the liver, clinicians should exercise caution with the use of this agent to treat patients who have severe hepatic dysfunction.
In a recent pooled pharmacokinetic evaluation of tigecycline in healthy adult volunteers and in persons with renal impairment, tigecycline exhibited approximately linear pharmacokinetics across all dose ranges in the multiple-dose studies. Tigecycline exhibited a long half-life, with a high volume of distribution at steady state, indicating extensive tissue distribution. Within the study population, the pharmacokinetics of tigecycline were not changed by severe renal impairment or hemodialysis. Slight trends for differences in pharmacokinetics were noted in this study, possibly as a result of the age, race, and sex of the subjects; however, these differences require further evaluation in larger populations [62, 63].
Clinical Studies With Tigecycline
Tigecycline has been evaluated in human clinical trials. Tigecycline is currently approved for the treatment of patients with complicated skin and skin-structure infections and complicated intra-abdominal infections [11, 12].
The clinical and microbiological efficacy, pharmacokinetics, and tolerability of 2 different doses of tigecycline were evaluated in a phase 2, randomized, open-label study of complicated skin and skin-structure infection conducted in 14 centers in the United States. Patients in this study received tigecycline (25 or 50 mg) intravenously every 12 h for 7–14 days. The primary end point was the clinically observed cure rate among patients completing the test-of-cure visit. Secondary end points were the clinical cure rate at the end of therapy and bacteriologic response. One hundred sixty patients received at least 1 dose of tigecycline; 109 patients had clinically evaluable results, and 91 patients had microbiologically evaluable results. At the test-of-cure visit, the clinical cure rate in the 25-mg group was 67% (95% CI, 53.3%–79.3%), compared with 74% (95% CI, 60.3%–85.0%) in the 50-mg group. The eradication rate was 56% in the 25-mg group (95% CI, 40.0%–70.4%), compared with 69% (95% CI, 54.2%–82.3%) in the 50-mg group. Nausea and vomiting were noted to be the most common adverse events [11].
In addition, in vitro tests of susceptibility to tigecycline were performed for selected microbes, including S. pyogenes, methicillin-susceptible and methicillin-resistant S. aureus, E. coli, E. faecalis, and E. faecium. Tigecycline MIC90 values for all isolates tested ranged from 0.06 to 0.5 µg/mL. The authors concluded that tigecycline is efficacious, with a favorable pharmacokinetic profile, for treatment of hospitalized patients with complicated skin and skin-structure infections [11].
A multicenter, phase 2, open-label study of hospitalized patients with complicated intra-abdominal infections requiring surgery was done to evaluate the activity of tigecycline. All patients received 100 mg of tigecycline administered intravenously as a loading dose, followed by 50 mg every 12 h for 5–14 days. One hundred eleven patients with perforated and gangrenous appendicitis, complicated cholecystitis, or perforated diverticulitis and peritonitis were enrolled in this study. Sixty-six patients met all of the inclusion criteria and were evaluated. Cure rates at the test-of-cure visit and the end-of-treatment visit were 67% (95% CI, 54.0%–77.8%) and 76% (95% CI, 63.6%–85.5%), respectively. In the intent-to-treat analyses, the cure rate at the test-of-cure visit was 55% (95% CI, 45.2%–64.4%), and the end-of-treatment cure rate was 72% (95% CI, 62.8%–80.2%). Nausea and vomiting were noted to be the most common adverse events. The authors concluded that tigecycline was safe and efficacious for treatment of hospitalized patients with complicated intra-abdominal infections [12].
Conclusions
In conclusion, tigecycline, a new semisynthetic glycylcycline, appears to hold promise as a new antimicrobial agent that can be administered as monotherapy to patients with certain serious bacterial infections. As with all antimicrobials, clinicians need to prescribe tigecycline appropriately, to avoid the emergence of resistant strains. As a single antimicrobial agent, tigecycline confers broad antibiotic coverage against vancomycin-resistant enterococci, methicillin-resistant S. aureus, and many species of multidrug-resistant gram-negative bacteria. Resistance to tigecycline by P. aeruginosa and reduced susceptibility among Proteus species have been noted. Because in vitro activity does not always predict clinical efficacy, the efficacy of tigecycline must be determined from well-designed clinical trials. Tigecycline has been reported to be efficacious and well tolerated in human clinical trials for the treatment of complicated skin and skin-structure infections, complicated intra-abdominal infections, and infections of the lower respiratory tract. Tigecycline is not recommended for the treatment of serious infections caused by P. aeruginosa. The role of tigecycline as part of a combination regimen remains to be evaluated.
Acknowledgments
Potential conflicts of interest. G.A.N. serves as a consultant and is on the speakers' bureau for Wyeth.
- © 2005 by the Infectious Diseases Society of America
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