Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

46th Interscience Conference on Antimicrobial Agents and Chemotherapy

San Francisco, California / September 27-30, 2006

The challenge of multidrug-resistant “superbugs” that can survive treatment with broad-spectrum antibiotics once reserved for the most difficult pathogens is increasing. Individually, many treatment-resistant infections can be controlled with an appropriately selected antibiotic delivered in a sufficient dose but, collectively, the superbugs present a growing spectrum of resistance mechanisms that complicate empiric therapy even in institutions with effective surveillance programs. New antibiotic development has focused on creating treatments that can circumvent more than one mechanism of resistance, preserving potency against multi-resistant bacteria even when the pathogen is unknown. Tigecycline is a prototype of this new approach. Resistant infections are continuing to show a high rate of susceptibility to this agent, even though it has now been widely available in many parts of the world for more than a year. A broad array of clinical studies and experience presented here at ICAAC addressed the established and potential applications of this therapy.

Canadian Study Confirms Broad Spectrum Activity

One of the most compelling sets of data demonstrating the activity of tigecycline against multiple superbugs was generated by a study in Canada. Led by Dr. George G. Zhanel, Health Sciences Centre, University of Manitoba, Winnipeg, the study evaluated susceptibility in up to 300 isolates from each of 19 medical centres. Using conservative breakpoints, essentially all isolates of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) were susceptible to tigecycline. Very high rates of susceptibility were observed in extended-spectrum beta-lactamase (ESBL)-producing bacteria as well as other pathogens that are sometimes challenging, such as Klebsiella pneumoniae and Stenotrophomonas maltophilia. The isolates for this study were drawn from blood, urine, wounds and the respiratory tract.

“Tigecycline possesses a high level of activity against resistant organisms,” stated Dr. Zhanel, who compared this agent to piperacillin/tazobactam, cefazolin, ceftriaxone, cefepime, gentamicin, ciprofloxacin, levofloxacin, meropenem and vancomycin. In this study, the only pathogen to which tigecycline exhibited substantially less susceptibility than one or more comparators was Pseudomonas aeruginosa. Although susceptibility to meropenem was also 100% for S. aureus and Escherichia coli, this agent was ineffective against MRSA (vs. 100% for tigecycline) and less effective against both Enterococcus species (55.4% vs. 79.3%) and S. maltophilia (4.7% vs. 72%). The only other 100% susceptibility seen in this series was for vancomycin and piperacillin/tazobactam against S. aureus, vancomycin against MRSA and levofloxacin against Acinetobacter species.

Similar findings were reported in the US where a longitudinal analysis of tigecycline activity was conducted in S. aureus, Acinetobacter and Enterobacteriaceae with multi-drug resistance. Susceptibility of isolates collected at 83 geographically diverse sites in 2003 and 2004 was compared to that of isolates collected at 73 sites in 2005 and 2006. There were 47 sites that provided isolates in both periods. A subgroup analysis was conducted on those isolates defined as multidrug-resistant by lack of susceptibility to at least three agents.

N

o Change in Susceptibility Observed over Time

“Non-susceptibility, including in multidrug-resistant strains, was not encountered during either of the study periods,” reported Dr. Michael Cohen, Focus Bio-Inova, Herndon, Virginia. This included 100% susceptibility of all S. aureus isolates, whether or not they were treatment-resistant, in the first and second periods of surveillance. In the Acinetobacter species, the susceptibility of the isolates increased from 96.9% overall and from 91.7% in the multidrug-resistant subgroup during the first period of surveillance to 100% in the second. The authors attributed this to the stability of the activity of tigecycline against Acinetobacter. For the Enterobacteriaceae, the susceptibilities remained stable overall (99% in 2003 to 2005 and 99.1% in 2005 to 2006) and for the multidrug-resistant subgroup (97.7% in 2003 to 2004 and 96.7% in 2005 to 2006).

So far, the potency of tigecycline against resistant bacteria has been durable. In a surveillance of more than 38,000 clinical isolates collected from 213 sites in 30 countries over a two-year period, there was essentially no change in susceptibility of any of the bacteria when analyzed by 50% inhibitory concentrations (IC50) or 90% inhibitory concentrations (IC90). Perhaps due to chance, the minimum inhibitory concentrations (MIC) actually decreased over time for S. pneumoniae, an outcome now being evaluated in more detail. In the TEST (Tigecycline Evaluation Surveillance Trial) program, this increased susceptibility of S. pneumoniae was the only change in which susceptibility differed by more than a single dilution when results from 2004, 2005 and 2006 were compared.

The clinical efficacy of tigecycline is consistent with the preclinical studies that brought this treatment forward. The compound is the first member of the glycylcycline class of antibiotics, which are structurally related to tetracyclines but have substantially more affinity to bacterial ribosomes. This affinity markedly improves the ability of these antibiotics to inhibit the protein synthesis needed for the bacteria to survive. The change in chemical structure is credited with the ability of glycylcyclines to circumvent both efflux and ribosomal mechanisms of resistance, which are the two major ways in which bacteria defeat tetracyclines. Conversely, glycylcyclines retain major activity against gram-positive, gram-negative, aerobic and anaerobic bacteria.

Even Experimental Resistance Difficult to Induce

“Resistance to tigecycline has been difficult to produce even in the laboratory,” observed Dr. Iciar Rodríguez-Avial, Department of Clinical Microbiology, Hospital Clínico San Carlos, Madrid, Spain. Author of a study evaluating MRSA susceptibility, Dr. Rodriguez-Avial suggested that based on the high barrier to resistance in the laboratory, “it is not surprising that we have not yet seen any substantial change in susceptibility in the clinic.”

In his study, 116 MRSA isolates were collected from blood cultures between 2002 and 2005. Susceptibility was compared among tigecycline, vancomycin, teicoplanin, rifampicin, levofloxacin, gentamicin, linezolid and erythromycin. Clinical and Laboratory Standards Institute (CLSI) breakpoints were employed. For tigecycline, this breakpoint was <0.5 µg/mL. Full susceptibility of all isolates was only observed for tigecycline, vancomycin and teicoplanin, but the MIC was several times lower for tigecycline relative to any of the comparators.

“Tigecycline activity against MRSA was superior to all antimicrobial agents tested, including vancomycin and teicoplanin,” Dr. Rodriguez-Avial reported. “Its high in vitro activity against MRSA should make it a very useful drug for the treatment of difficult Staphylococcal infections.”

Community-acquired MRSA: A Growing Challenge

The activity of this agent includes efficacy against community-acquired MRSA. As resistant infections find their way into the community setting, rapid initiation of appropriate therapy is essential to reduce the risk of significant morbidity or even mortality. In the SENTRY resistance surveillance program, the activity of tigecycline was specifically evaluated in 951 MRSA isolates categorized as community-acquired that were derived from a larger pool of 2898 isolates. The susceptibility of these community-acquired isolates, which represented 33% of the total sample, was almost exactly the same (98.2%) as the susceptibility of the nosocomial MRSA isolates (98.5%). In a subset of community-acquired isolates expressing the Panton-Valentine leukocidin (PVL) gene, susceptibility to tigecycline was 100%.

According to Dr. Ronald N. Jones, JMI Laboratories, North Liberty, Iowa, lead author of the study and the principal investigator of SENTRY, “Tigecycline was very active against MRSA regardless of the origins of infection,” concluding that “tigecycline should represent an excellent option for the treatment of MRSA infections, including patients with PVL-producing, community-acquired MRSA from the outpatient setting.”

Community-acquired Pneumonia

Studies of this novel antibiotic in community-acquired pneumonia (CAP) have reached phase III testing. In a report that combined data from two phase III, multicentre, double-blind studies, it demonstrated a high rate of efficacy relative to levofloxacin, the comparator in both trials. The two studies had very similar designs: in both, patients hospitalized with CAP were randomized to intravenous (i.v.) tigecycline administered in an initial dose of 100 mg followed by 50 mg every 12 hours or to i.v. levofloxacin which was delivered in a dose of 500 mg every 12 hours. One of the studies permitted patients to be switched to oral levofloxacin after at least three days of i.v. therapy.

When the two studies were combined, there were 846 patients available for the intention-to-treat analysis (ITT) and 574 patients had end-of-study cultures to evaluate bacteriological cure. On the ITT analysis, cure was achieved in 81% of patients randomized to tigecycline vs. 79.7% of those randomized to levofloxacin. On the observed analysis, cure was achieved in 89.7% of tigecycline patients vs. 86.3% of levofloxacin patients. Although the advantage of tigecycline did not reach significance, a statistical analysis did confirm non-inferiority. Adverse events were more common with tigecycline, including nausea (24.3% vs. 8.3%; P<0.001), vomiting (16% vs. 5.7%; P<0.001) and abdominal pain (5.7% vs. 2.1%; P<0.05), but elevations of liver enzymes, including ALT (2.8% vs. 7.3%; P<0.01) and AST (2.6% vs. 6.9%; P<0.01), were significantly higher with levofloxacin. Discontinuations due to adverse events were low in both tigecycline (6.1%) and levofloxacin (8.3%) cohorts.

“There were no significant differences between treatment groups in the microbiologic responses at the patient level or by baseline respiratory pathogen,” reported the study investigators. Although S. pneumoniae was the most common pathogen in this study, there was broad representation, including Chlamydia pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Legionella pneumophilia.

Treating Resistant B. fragilis, E. coli

In a study designed to evaluate tigecycline specifically against Bacteroides fragilis, 397 clinical isolates were evaluated from a single hospital from 2003 to 2005. The activity of tigecycline was compared against metronidazole, chloramphenicol, clindamycin, moxifloxacin, cefoxitin, imipenem, piperacillin/tazobactam and amoxicillin-clavulanate. While imipenem, piperacillin/tazobactam and tigecycline were the most active against the beta-lactam agents, four strains proved to be resistant to imipenem. All of these strains were inhibited by tigecycline at concentrations of 0.5 to 8 µg/mL.

As reported by Dr. Carmen Betriu, Hospital Clínico San Carlos, “Tigecycline exhibited potent activity against most of the B. fragilis group isolates tested.” Dr. Betriu, the senior author of the study, concluded that “tigecycline may be of value in the treatment of mixed anaerobic infections caused by the B. fragilis group.”

In another study led by Dr. Zhanel, the pharmacodynamic activity of tigecycline against multiple drug-resistant ESBL-producing E. coli was evaluated in three isolates, all of which were resistant to levofloxacin and trimethoprim/sulfamethoxazole. One of the isolates was also resistant to aminoglycosides. The study found that tigecycline was bacteriostatic at an AUC:MIC ratio of 4.2, suggesting that “tigecycline represents a potential therapy for infections caused by multiple drug-resistant ESBL E. coli.”

Currently, tigecycline is indicated for the treatment of adults with complicated skin and skin structure infections caused by E. coli, E. faecalis susceptible to vancomycin, S. aureus (methicillin-susceptible and -resistant strains), S. agalactiae, S. anginosus, S. pyogenes and B. fragilis. It is also indicated for the treatment of complicated intra-abdominal infections caused by a broad array of gram-negative, gram-positive and anaerobic pathogens. However, the indications are expanding and the most important use may be as empiric therapy when the pathogen is unknown due to its broad spectrum of activity. Of note, tigecycline has demonstrated decreased in vitro activity against Proteus spp., Providencia spp. and Morganella spp. P. aeruginosa is inherently resistant to the compound.

Stated Dr. Sam K. Bouchillon, Laboratories International for Microbiology Studies, Schaumburg, Illinois, “This is a very useful drug for difficult infections in which the potential pathogens include those with multiple drug resistance. At least, it is very reasonable to start on this drug and then switch to a drug more specific for the infection once the cultures are available.”

Summary

Due to the increasing number of pathogens with high rates of resistance, development of new antibiotics is focusing on the creation of agents that can defeat multiple resistance mechanisms. The prototype agent for this approach, tigecycline, has proven to be versatile in clinical practice in the US and Europe. The difficulty of inducing resistance to this agent in the laboratory appears to persist in clinical application. Surveillance studies in Canada, the US and Europe have yet to demonstrate any significant change in susceptibility of the most difficult-to-treat pathogens. The efficacy of this agent is likely to stimulate other programs to develop antibiotics which overcome multiple mechanisms of resistance in order to stay ahead of the ever increasing problem of resistant bacteria.

Questions and Answers

The following section is based on discussions with Dr. George G. Zhanel, Health Sciences Centre, University of Manitoba, Winnipeg, during the scientific sessions.

Q: Was there variability in susceptibility among the 19 centres for any of the resistant pathogens tested or did the effects of tigecycline remain fairly consistent?

A: There was no variability. All MRSA, MSSA [methicillin-susceptible S. aureus] and VRE, as well as most ESBL, were all susceptible to tigecycline.

Q: Would you consider tigecycline to be a reasonable empiric antibiotic in the ICU while awaiting cultures?

A: Tigecycline is very active against resistant ICU pathogens and thus, yes, would be considered as a reasonable empiric antibiotic in the ICU while awaiting cultures.