Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-09-24
2002-10-22
Dees, Jose G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S011400, C530S317000
Reexamination Certificate
active
06468967
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to improved methods of administering lipopeptide antibiotics, such as daptomycin, with potent bactericidal activity against gram-positive bacteria, including antibiotic-resistant strains. The present invention also relates to improved methods of administering quinopristin/dalfopristin, which also has potent bactericidal activity against gram-positive bacteria, including antibiotic-resistant strains.
BACKGROUND OF THE INVENTION
The rapid increase in the incidence of gram-positive infections—including those caused by resistant bacteria—has sparked renewed interest in the development of novel classes of antibiotics. One such class is the lipopeptide antibiotics, which includes daptomycin. Daptomycin has potent bactericidal activity in vitro against clinically relevant gram-positive bacteria that cause serious and life-threatening diseases. These bacteria include resistant pathogens, such as vancomycin-resistant enterococci (VRE), methicillin-resistant
Staphylococcus aureus
(MRSA), glycopeptide intermediary susceptible
Staphylococcus aureus
(GISA), coagulase-negative staphylococci (CNS), and penicillin-resistant
Streptococcus pneumoniae
(PRSP), for which there are very few therapeutic alternatives (see Tally et al., 1999, Exp. Opin. Invest. Drugs 8:1223-1238, hereafter “Tally”). Daptomycin provides a rapid, concentration-dependent bactericidal effect and a relatively prolonged concentration-dependent post-antibiotic effect in vivo.
Daptomycin is described in Baltz in
Biotechnology of Antibiotics
, 2nd Ed., ed. by W. R. Strohl (New York: Marcel Dekker, Inc.), 1997, pp. 415-435, hereafter “Baltz.” Daptomycin is a cyclic lipopeptide antibiotic that can be derived from the fermentation of
Streptomyces roseosporus
. It is comprised of a decanoyl side chain linked to the N-terminal tryptophan of a cyclic 13-amino acid peptide (see FIG. 1a, Baltz et al., supra). The compound is currently being developed in both intravenous and oral formulations to treat serious infections caused by bacteria, including, but not limited to, methicillin resistant
Staphylococcus aureus
(MRSA) and vancomycin resistant enterococci (VRE).
Daptomycin's mechanism of action is distinct from that of other classes of antibiotics, which include &bgr;-lactams, aminoglycosides, glycopeptides and macrolides. Without wishing to be bound by any theory, daptomycin is believed to kill gram-positive bacteria by disrupting multiple aspects of bacterial plasma membrane function while not penetrating into the cytoplasm. The antibacterial mechanisms of daptomycin may include inhibition of peptidoglycan synthesis, inhibition of lipoteichoic acid synthesis and dissipation of bacterial membrane potential (see, e.g., Baltz, supra).
The efficacy and safety of daptomycin has been examined in nonclinical studies and in Phase I and Phase II clinical trials. Daptomycin was well tolerated in human volunteers when given intravenously at 1 or 2 mg/kg every 24 hours. See Baltz, supra, and references therein. Furthermore, a single dose of daptomycin was well-tolerated over a dose range of 0.5 to 6 mg/kg. See Baltz, supra, and Woodworth et al., 1992, Antimicrob. Agents Chemother. 36:318-25. However, prolonged treatment with 3 mg/kg daptomycin every 12 hours was shown to cause occasional adverse effects (Baltz, supra). Transient muscular weakness and pain were observed in two of five human patients who had been treated with 4 mg/kg daptomycin every 12 hours for 6 to 11 days (Tally, supra). In the two subjects who experienced muscular weakness and pain, creatine phosphokinase (CPK) levels had increased one to two days prior to the muscular weakness. Treatment was discontinued three to four days after the initial elevation in CPK was observed. One to two days after discontinuation of daptomycin treatment, CPK levels peaked at levels in excess of 10,000 U/L in one subject and at 20,812 U/L in the second subject (Tally, supra). Based upon these studies and the rationale that higher doses of daptomycin were required for efficacy against many types of bacterial infection, clinical studies of daptomycin were discontinued (Baltz, supra).
In the above-described clinical trials and in a series of toxicology studies in animals, skeletal muscle was found to be the primary target tissue of daptomycin toxicity. Repeated daily intravenous administration in toxicological studies of high doses of daptomycin in rats and dogs (75 mg/kg/day in rats and 40 mg/kg/day in dogs) caused mild myopathy in the skeletal muscle (Tally, supra). It was also found that increases in CPK levels are a sensitive measure of myopathy, and thus can be used to measure daptomycin's effects upon muscle tissue. See Tally et al. supra.
Although low doses of daptomycin do not cause muscle toxicity and are effective in treating many gram-positive bacterial infections, certain types of gram-positive bacterial infections, such as deep-seated infections or those caused by certain antibiotic-resistant bacterial strains, may require higher doses of daptomycin for effective treatment. For instance, certain vancomycin-resistant strains of bacteria exhibit a two- to four-fold higher daptomycin minimum inhibitory concentration (MIC) than most vancomycin-susceptible strains. Accordingly, there is a great need to develop methods for administration of effective amounts of daptomycin that will also minimize adverse skeletal muscle effects.
A non-lipopeptide streptogramin antibiotic combination, quinupristin/dalfopristin, has also shown activity against gram-positive organisms, including antibiotic-resistant bacteria such as methicillin-resistant
Staphylococcus aureus
, glycopeptide intermediary
S. aureus
, and glycopeptide-resistant
Enterococcus faecium
(Rubinstein et al., 1999, J. Antimicrob. Chemother. 44, Topic A, 37-46, hereafter “Rubinstein”). Quinupristin/dalfopristin has been shown to be effective in treatment of nosocomial pneumonia, emergency use studies, complicated skin and skin structure infection and bacteremia (Rubinstein, supra). Approximately 13% of the patients treated with 7.5 mg/kg quinupristin/dalfopristin every 8 or 12 hours experienced arthralgia or myalgia, which included muscle pain, and approximately 5% of patients exhibited increased CPK levels (Rubinstein, supra). Therefore, it would appear that quinupristin/dalfopristin also causes muscle toxicity.
The aminoglycosides, which make up another class of antibiotics, are also toxic at high doses. They have been administered as a high dose at less frequent intervals rather than at lower doses at more frequent intervals in order to reduce their toxicity (Barclay et al., 1994, Clin. Pharmacokinet. 27:32-48). However, aminoglycosides differ from daptomycin in a number of ways, specifically in the fact that the sites of toxicity are distinct. Aminoglycosides are toxic to the kidney and central nervous system whereas skeletal muscle is the site of toxicity for daptomycin. The mechanisms of toxicity for aminoglycosides and daptomycin are also distinct. In addition, aminoglycosides are structurally dissimilar to daptomycin, act only on gram-negative bacteria, have a different mechanism of antibacterial action from daptomycin and exhibit different mechanisms of resistance. Thus, the possibility that less frequent administration of aminoglycosides results in lower toxicity to the patient does not predict that the same would be true for daptomycin.
SUMMARY OF THE INVENTION
The present invention addresses the problem of skeletal muscle toxicity at high doses of lipopeptide antibiotics such as daptomycin, as well as quinupristin/dalfopristin. The invention provides methods for administering the antibiotic that minimizes skeletal muscle toxicity while simultaneously maintaining a sufficient efficacy level.
The process of the invention is characterized by administering less frequent doses comprising a higher concentration of an antibiotic. This protocol is both safer and more efficacious than administering more frequent doses of the antibiotic at lower concent
Oleson, Jr. Frederick B.
Tally Francis P.
Brown Karen E.
Choi Frank
Cubist Pharmaceuticals, Incorporated
Dees Jos,e G.
Fish & Neave
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