We are all aware of the crisis and implication of infections due to multidrug-resistant gram-negative bacilli. Unfortunately, serious infections caused by pathogens resistant to all available antimicrobial agents are becoming more common and represent significant dilemmas of management. Compounding this is awareness of a dry antimicrobial pipeline for the near future. At the 2010 ICAAC, a few agents were presented, which may offer some hope for the future, however distant. The following are few of these agents.
Abstract A1-027. Phase 1 Single Ascending Dose Study of a Broad-Spectrum Fluorocycline, TP-4341
Study objectives were exploration of safety, tolerability, plasma pharmacokinetics (PK) and urinary excretion of single ascending doses of TP-434 IV. Fifty-six healthy adult volunteers were recruited. Each of the 7 dose groups consisted of 8 subjects (6 randomized to receive TP-434 and 2 randomized to receive matching placebo). Results: No serious adverse events were reported. Gastrointestinal adverse effects were observed at 2 mg/kg or greater. No clinically significant safety laboratory values or significant changes in ECG readings were observed in any dose group. Conclusions: Pharmacokinetics, safety, and tolerability data indicate TP-434 may be of use at dose regimens up to and including 2 mg/kg per day and are consistent with the potential use of once-daily doses in the treatment of important bacterial infections.
Tetraphase Pharmaceuticals, Inc. has built an antimicrobial portfolio by capitalizing on a new synthetic chemistry technology that enables codification of the core tetracycline scaffold. The compound, which is now in phase I/II development is TP-434, a fluorocycline that has a broad-spectrum in vitro antimicrobial activity against most major pathogens except Pseudomonas aeruginosa. The spectrum includes problematic multidrug-resistant and methicillin-resistant Staphylococcus aureus, streptococci, enterococci, Enterobacteriaceae strains containing extended-spectrum β-lactamases, Proteus and Acinetobacter. The spectrum is therefore similar to tigecycline, but TP-434's minimum inhibitory concentrations are lower. In addition, the company is developing an oral formulation, which will be useful for either initial oral therapy or switch therapy.
Abstract A1-658. Pharmacokinetics (PK) and Safety of ACHN-490 Injection Administered Intravenously for 5 Days in Healthy Human Subjects2
The safety, tolerability, and pharmacokinetics of ACHN-490 Injection at 15 mg/kg once daily for 5 consecutive days was explored in a randomized, double-blind, placebo-controlled study. Nephrotoxicity and ototoxicity were evaluated by serum urea nitrogen, serum creatinine, electronystagmography, pure tone audiometry, modified Romberg, and otoacoustic emissions testing. Results: Eight subjects received either ACHN-490 Injection or placebo. Seven subjects received 5 doses and one received 3 doses (early withdrawal for personal reasons). All adverse events were mild to moderate. No evidence of ototoxicity or nephrotoxicity was observed throughout the treatment period. Long-term safety follow-up is ongoing. After 5 days of repeated once-daily intravenous dosing of ACHN-490 Injection, the area under the plasma concentration-time curve, plasma clearance, and steady state volume of distribution of ACHN-490 averaged 239 hr μg/mL, 1.1 mL/min per kilogram, and 0.24 L/kg, respectively. The t1/2was approximately 3 hours. The peak (Cmax) and trough (Cmin) was 113 and 0.4 μg/mL, respectively. Conclusions: ACHN-490 injection was well tolerated and exhibited pharmacokinetics supportive of once-daily, high-dose, short-course therapy. The lack of appreciable drug accumulation after once-daily dosing for up to 5 days is consistent with the apparent elimination half-life of approximately 3 hours.
ACHN-490 is a neoglycoside, a next-generation aminoglycoside, in clinical development with activity against multidrug-resistant gram-negative and select gram-positive pathogens. It is not affected by most of the aminoglycoside-modifying enzymes, which affect presently available aminoglycosides. It is active against Enterobacteriaceae resistant to other antibiotic classes, including those that produce extended-spectrum beta-lactamase, K. pneumoniae carbapenemase, or metallo-β-lactamases. Optimal dosing of ACHN-490, based on pharmacokinetics and pharmacodynamics, favors once-daily, high-dose, short-course therapy. Epithelial lining fluid studies and a possible ventilation associated pneumonia study are planned; the results of these studies will no doubt provide information regarding the potential benefit of this agent. In a previous clinical study, ACHN-490 Injection was well tolerated when administered at 15 mg/kg once-daily for 3 consecutive days. The authors concluded that these findings support the continued development of a high-dose once-daily regimen of ACHN-490 Injection in a 5-day regimen.
Abstract F1-1971. Phase I Clinical Trial to Evaluate the Inhaled Safety and Tolerability of the Unique Antimicrobial OligoG Administered to Healthy Subjects3
This study describes a phase I clinical trial examining the safety and tolerability of aerosolized OligoG for potential treatment of cystic fibrosis. Twenty-eight healthy male volunteers (prestudy examined) were chosen. (Cohort 0) 4 subjects [2 OligoG, 2 placebo (0.9% saline)] were given a one-off dose of 6% in 1.5-ml doses (90 mg/d) and observed for 3 days. For the multi-dose cohorts, each consisting of 8 subjects (all dosed for 3 days), 6 of these were randomized to receive active OligoG and 2 were receiving placebo in a dose-escalation manner. Results: No serious adverse effects (AEs) occurred, and mild AEs were reported. These ranged from slight hyperventilation (placebo) to mild dry coughs (both groups), but the occurrence and frequency of AEs did not differ between the 2 groups. Conclusions: OligoG is well tolerated when administered for up to 270 mg/d BID for 3 consecutive days. There were no serious AEs, discontinuations, or significant changes in vital signs, lung function, or serious AEs.
OligoG is an oligosaccharide derived from alginate polysaccharide. It has been shown to decrease viscosity and weaken biofilms via inhibition of polymerase cross-linking. Thus, it may increase pulmonary clearance of sputum and provide increase diffusion of antimicrobials into biofilms of patients with cystic fibrosis infected with Pseudomonas or Burkholderia spp. The drug has Orphan Drug Medicinal Product status in Europe. A randomized clinical trial in cystic fibrosis for 28 days is planned; outcomes to be measured include safety, microbiological effect, pulmonary function, and respiratory symptoms. If successful, this agent may have potential use for other bronchial infections such as bronchiectasis or ventilator-associated tracheobronchitis.
Abstract F1-1626. Antimicrobial Activity of a Novel Polymyxin Analog (CB-182,804) Tested Against Clinical Strains of Gram-Negative Bacilli, Including Colistin-Resistant Organisms4
CB-182,804 is structurally related to polymyxins and has shown rapid bactericidal activity against many gram-negative pathogens, including multidrug-resistant (MDR) organisms. Four hundred fifty-five strains selected from various surveillance programs were susceptibility tested by Clinical and Laboratory Standards Institute broth microdilution methods. Strains with acquired resistance to colistin and/or selected broad-spectrum antimicrobials were included in all organism groups. Results: CB-182,804 was very active against Pseudomonas aeruginosa (MIC50/90, 0.5/2 μg/mL) and Acinetobacter spp. (MIC50/90, 1/4 μg/mL), including MDR strains. CB-182,804 was also active against Escherichia coli (MIC50/90, 1/2 μg/mL) and Klebsiella pneumoniae (MIC50/90, 1/4 μg/mL), including ESBL and serine carbapenemase (KPC-2 or 3) producers. When compared to colistin, CB-182,804 was more active against Pseudomonas (MIC50 comparisons) and slightly less active against Acinetobacter, E. coli and K. pneumoniae. Conclusions: CB-182,804 was very active against colistin-susceptible strains that were resistant to all other currently available antimicrobials for clinical use and may represent and an important therapeutic option for infections caused by pan-resistant gram-negative bacilli. Cross-resistance with colistin was observed.
CB is a polymyxin B analog, which is undergoing phase II development. There were many posters presented at the ICAAC describing preliminary MIC data, mode of action, mutation frequency, pharmacokinetics, and animal models. This abstract presents comparative MIC data for colistin and CB. The primary advantage from an in vitro standpoint is its activity against MDR Pseudomonas. Further studies of pharmacokinetics and safety will provide data regarding future benefit.
1. Sutcliffe J, Ronn M, Leighton A, et al. Tetraphase Pharmaceuticals, Inc., Watertown, MA, A. Leighton Consulting, San Francisco, CA, Cetero Res., Fargo, ND. ICAAC 2010; abstract A1-027.
2. Havrilla NA, Brooks CA, R. T. Cass RT, et al. Achaogen, Inc., South San Francisco, CA, Jasper Clinic, Inc., Kalamazoo, MI. ICAAC 2010; abstract A1-658.
3. Myrvold R, Febbraro R, Smerud K, et al. AlgiPharma AS, Sandvika, Norway, Simbec Res. Ltd, Merthyr Tydfil, United Kingdom, Smerud Med. Res., Oslo, Norway. ICAAC 2010, abstract F1-1971.
4. Sader HS, Rhomberg PR, Jones RN. JMI Lab., North Liberty, IA. ICAAC 2010, abstract F1-1626.