Slide 18.

Tigecycline has been shown to be active against a wide variety of pathogens.¹ Specifically, tigecycline has broad-spectrum in vitro activity against the following organisms (note that some of the organisms listed below have not been included on the slide):

Gram-positive Bacteria: S. aureus, S. epidermidis, E. faecalis, E. faecium, E. avium, E. casseliflavus, E. gallinarum, S. agalactiae, S. anginosus group, and S. pyogenes

Gram-negative Bacteria: C. freundii, E. cloacae, E. aerogenes, E. coli, K. oxytoca, K. pneumoniae, and Stenotrophomonas maltophilia

Anaerobes: B. fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus, B. distasonis, B. ovatus, C. perfringens, P. micros, Prevotella spp.

Although this list is not all inclusive, it shows the broad spectrum of activity against pathogens that is displayed by tigecycline.

Reference

• Tygacil [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals; 2004.

Slide 30.

Tigecycline has been evaluated in 4 large-scale, phase III, double-blind, randomized, multicenter, active-comparator clinical studies in hospitalized patients with complicated skin and skin structure infection (cSSSI) or complicated intra-abdominal infection (cIAI).¹

In these studies, tigecycline monotherapy was shown to be as effective as the combination of vancomycin plus aztreonam for treating cSSSI for the primary efficacy end point of clinical response (cure/failure).* In patients with cSSSI, cure was considered the resolution of all signs and symptoms of infection or improvement to such an extent that no further antibacterial therapy was necessary. Pooled data from both cSSSI studies demonstrated that the cure rates in clinically evaluable patients were similar for tigecycline-treated patients and vancomycin-plus-aztreonam–treated patients (87% vs 89%, respectively).¹

Similarly, tigecycline monotherapy was shown to be as effective as imipenem-cilastatin for treating cIAI for the primary efficacy end point of clinical response (cure/failure).* In patients with cIAI, cure was considered the resolution of the intra-abdominal infectious process, resulting from tigecycline or imipenem-cilastatin and initial intervention (operative and/or radiographically controlled drainage procedures). Pooled data from both cSSSI studies demonstrated that the cure rates in microbiologically evaluable patients were similar for tigecycline-treated patients and imipenem-cilastatin–treated patients (86% vs 86%, respectively).¹

It should be noted that majority of patients evaluated had complicated appendicitis – all had operation or drainage procedures

E. coli was the most commonly isolated aerobe, followed by Klebsiella spp., in both trials. Oliva et al. (2005) reported identification of six ESBL-producing E. coli and seven ESBL-producing K. pneumoniae isolates before therapy in their study.

*Tigecycline met the statistical criteria for noninferiority at the 15% level (cure versus failure) at test-of-cure assessments in both the cSSSI studies (P < 0.0001) and the cIAI studies (P < 0.0001).^1,2

References

• Data on file, Wyeth Pharmaceuticals Inc.

• Temple, RJT. Active Control Non-Inferiority Studies: Theory, Assay Sensitivity, Choice of Margin. Available at: www.fda.gov/ohrms/dockets/ac/02/slides/3837s1_02_Temple/sld001.htm. Accessed May 11, 2005.

N/V – more than twice the rate for comparators in complicated skin and soft-tissue infections

Acinetobacter

Acinetobacter species are aerobic gram-negative bacteria that are widely distributed in soil and water and can occasionally be cultured from skin, mucous membranes, secretions, and the hospital environment.Acinetobacter baumannii is the species most commonly isolated.

A baumannii has been isolated from blood, sputum, skin, pleural fluid, and urine, usually in device-associated infections.

Acinetobacter encountered in nosocomial pneumonia often originates in the water of room humidifiers or vaporizers. In patients with acinetobacter bacteremia, intravenous catheters are almost always the source of infection. In patients with burns or with immune deficiencies, acinetobacter acts as an opportunistic pathogen and can produce sepsis. Acinetobacter strains are often resistant to antimicrobial agents, and therapy of infection can be difficult. Susceptibility testing should be done to help select the best antimicrobial drugs for therapy. Acinetobacter strains respond most commonly to gentamicin, amikacin, or tobramycin and to newer penicillins or cephalosporins.

The efficacy and safety of ertapenem 1 g parenterally once a day was

evaluated in seven large, statistically powered, double-blind, randomized

clinical studies

Furthermore, ertapenem was highly effective in patients with a range of disease severity within each indication, including elderly patients and patients with severe infections.

One could make a theoretic argument that moxi is the superior FQ, but clinical data aren’t as convincing

What happened to gemifloxacin?

Derived from fermentation product of Streptomyces roseosporus

Fist discovered by Eli Lilly

Dose-range studies showed increased activity with higher doses, but at 12 hrs dosing – there were many adverse effects including muscle weakness, severe myalgia, and increases in CPK – Lilly suspended development unti Cubist pharmaceuitcals obtained rights to develop and manufacture dapto.

Once daily administration was evaluated to maximize efficacy and minimize adverse effects

Daptomycin demonstrates rapid-concentration dependent bactericidal action.

Pharmacodynamic studies indicated that C_max and AUC were the pharmacokinetic parameters that predicted efficacy. AUC/MIC and C_max/MIC correlated better with efficacy than duration of time above the MIC, which is consistent with the concentration-dependent bactericidal activity of daptomycin.

Post-antibiotic effect (PAE) is the suppression of bacterial growth that persists after exposure of the microorganism to an antibiotic. Long PAE has been speculated to predict suppression of bacterial growth in vivo during periods of low drug concentration. Following exposure to daptomycin concentrations ranging from 0.25 to 16 µg/mL, a PAE in vitro of up to 6 hours was shown, as measured by viable cell counts against Staphylococcus aureus and Enterococcus faecalis. In similar experiments using bioluminescence measurements of bacterial adenosine triphosphate (ATP) rather than viable cell counts, PAEs of 6.3 to 6.7 hours for strains of both S. aureus and E. faecalis were demonstrated. In vivo experiments (Safdar et al., 2004) have indicated a PAE of 5-10 hours against Streptococcus pneumoniae and S. aureus.

Exact mechanism of action is not completely understood

In viable bacteria, the polarized state of the cytoplasmic membrane results from the maintenance of ion and proton gradients across the bilayer of the plasma membrane. One of the most prominent gradients involves potassium (K+), with high intracellular and low extracellular concentrations

During step 1 – lipohilic tail of dapto-molecule is inserted into the cytoplasmic membrane

Step 2 – oligomerization of daptomycin occures resulting in formation of ion channels, larger nonspecific pores, or irregular aggregate structures

Required Slide

The prescribing information states that daptomycin has activity in vitro against these microorganisms. Because treatment of clinical infections due to these pathogens has not been established in adequate and well-controlled clinical trials, the prescribing information states that the ”in vitro data are available, but their clinical significance is unknown.” Daptomycin is also active in vitro against other clinically relevant Gram-positive bacteria — only organisms relevant to complicated skin and skin structure infections are listed in the prescribing information.

Novel lipopeptide antimicrobial agent with rapid concentration-dependent bactericidal activity

Active against a variety of aerobic and facultative gram-positive organisms