WO2002055731A2 - Ajustement de dosage pour antibiotiques - Google Patents

Ajustement de dosage pour antibiotiques Download PDF

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Publication number
WO2002055731A2
WO2002055731A2 PCT/US2002/000775 US0200775W WO02055731A2 WO 2002055731 A2 WO2002055731 A2 WO 2002055731A2 US 0200775 W US0200775 W US 0200775W WO 02055731 A2 WO02055731 A2 WO 02055731A2
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patients
antibiotic
infection
synercid
liver function
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PCT/US2002/000775
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WO2002055731A3 (fr
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Issam Raad
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Board Of Regents, The University Of Texas System
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Priority to EP02707442A priority Critical patent/EP1360316A2/fr
Priority to CA002434046A priority patent/CA2434046A1/fr
Priority to AU2002241849A priority patent/AU2002241849A1/en
Publication of WO2002055731A2 publication Critical patent/WO2002055731A2/fr
Publication of WO2002055731A3 publication Critical patent/WO2002055731A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates

Definitions

  • the present invention relates generally to the fields of infectious diseases and administration of antibiotics. More particularly, it concerns the adjustment of dosage and/or the adjustment of frequency of administration of antibiotics that are excreted predominantly through the biliary tract on the basis of biliary function tests, with the goal of reducing side effects caused by the antibiotics.
  • Synercid is a combination of two streptogramms: quinupristin and dalfopristin. It has successfully been used to treat infections caused by drug-resistant pathogens such as vancomycin resistant enterococci, methicillin resistant staphloccocus, penicillin resistant pneumococci and others. Infections by these pathogens are typically seen in hospitalized and immunocompromised individuals.
  • drug-resistant pathogens such as vancomycin resistant enterococci, methicillin resistant staphloccocus, penicillin resistant pneumococci and others. Infections by these pathogens are typically seen in hospitalized and immunocompromised individuals.
  • Synercid was found to be effective and generally well-tolerated. Success rates were judged equivalent to the comparator in patients with skin and soft-tissue infection or with nosocomial pneumonia. In particular, patients with severe underlying conditions and a Gram- positive infection, who were left without any other alternative antibacterial treatment due to in vitro resistance of infecting bacteria, previous failure, allergy or intolerance to commercially available antibiotics, were successfully treated with Synercid.
  • a major side effect of Synercid is the occurrence of arthralgias and myalgias. These were reported with an overall incidence of 9.5 percent in the Emergency-Use Program.
  • arthralgias and myalgias were reported with an overall incidence of 9.5 percent in the Emergency-Use Program.
  • cancer patients at least 36% of the patients treated with Synercid develop arthralgias and myalgias. Often the arthralgia and myalgia leads to discontinuation of the drug in these patients. Since the patients treated with Synercid have life-threatening infections there is an urgent need for development of methods that will reduce and/or alleviate the side effects of Synercid that lead to drug discontinuation.
  • the present invention provides methods that overcome existing defects in the art.
  • Provided herein are methods for determining the necessity of and the amount of adjustment of dosage for antibiotics that are predominantly excreted through the biliary tract. These methods reduce or alleviate side effects caused by the antibiotics in individuals in need of the antibiotics.
  • One example of such an antibiotic is Synercid and the major side-effects of Synercid are arthralgias and myalgias.
  • Synercid is used in patients that have resistant infections. So far, no dosage adjustment is performed for Synercid. For example, no dose adjustment has been required for patients with renal impairment and/or patients undergoing peritoneal dialysis; patients with hepatic insufficiencies; patients that are older or pediatric; and/or on basis of patient gender. Thus, all types of patients are typically given the same dosage of this drug regardless of other conditions that may exist.
  • the side effects of Synercid result in the discontinuation of therapy in some patients with acute adverse effects. As most patients that require Synercid therapy are immunocompromised patients, Synercid constitutes a life-saving therapy for these individuals. Discontinuation of the drug due to side effects offers very limited alternative options and is thus often fatal for the patient.
  • the present invention provides methods for reducing side effects in an individual to be treated with an antibiotic that is predominantly excreted through the biliary tract comprising, a) performing a liver function test on the individual; and b) administering to the individual an amount of the antibiotic based on the liver function test.
  • the term "predominantly excreted through the biliary tract” is defined here as an antibiotic that is excreted at about 60% or more through the biliary tract.
  • an antibiotic that is excreted at about 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%o, or even about 99%, including all percentages between the listed percentages, through the biliary tract may be dosage adjusted by the methods of the present invention.
  • the term "about” used in the sentence above is defined to include fractional values of ⁇ 0.1 to + 0.5 of each value for example, ⁇ 0.1, + 0.2, + 0.3, + 0.4 and ⁇ 0.5 as well as the values in between these numbers.
  • the term “about 60%” includes, 59.5%, 59.6%, 59.7%, 59.8%, 59.9%, 60%, 60.1%, 60.2%, 60.3%, 60.4%, and 60.5%, and the values in between these numbers; and the term “about 61%” includes 60.5%, 60.6%, 60.7%, 60.8%, 60.9%, 61%, 61.1%, 61.2%, 61.3%, 61.4%, and 61.5% as well as the values in between these numbers.
  • the antibiotic is a streptogramin antibiotic.
  • the streptogramin antibiotic is Synercid.
  • Some antibiotics that may be dosage and/or frequency adjusted using the methods of the present invention include those that are predominantly excreted through the biliary tract such as Synercid, Nascillin, Cefoperzone, Doxycycline, macrolide antibiotics such as Erythromycin, Clarithromycin, Azithromycin (administered by IN.), Amphoterecin B and lipid formulations of Amphoterecin B, Clofazimine and the like.
  • the methods of the invention are not limited to the listed antibiotics and that any antibiotic that is predominantly excreted by the biliary tract may be dosage adjusted by the methods taught herein.
  • the antibiotic is used in combination with other antibiotics.
  • Synercid may be used in conjunction with other antibiotic drugs such as minocycline.
  • the liver function tests measures the function and/or metabolic ability of the liver of the individual. In another embodiment, the liver function test measures the metabolism of the antibiotic. In other embodiments the liver function test measmes the extent of biliary tract dysfunction. In specific embodiments the liver function test measmes the activity of an enzyme. The enzyme activity measured can be the activity of alkaline phosphatase and/or the activity of gamma-glutamyl transpeptidase (gamma GT). Other liver enzyme activities may also be measured.
  • the amount of antibiotic comprises a dose of the antibiotic. In another embodiment the amount comprises the frequency of administering the antibiotic.
  • the methods of the present invention may be used to reduce and/or prevent side effects in an individual being treated with the antibiotic.
  • the individual can also be further afflicted with cancer, and/or is neutropenic, and/or is immunocompromised and/or is a transplant recipient and/or is a HIN patient.
  • the individuals being treated with the antibiotic may be afflicted with an infection.
  • the infections may be bacteremia, urinary tract infection (UTI), pneumonia, wound infections, bone & joint infections, endocarditis etc.
  • the infection can further be multi-drug resistant. The skilled artisan will recognize that the practice of the methods of the invention are not limited by the type of infection.
  • the infection may be bacterial.
  • bacterial infection include enteroccocal infections that may further be vancomycin-resistant.
  • the infection may be caused by Enterococcus faecium or Enterococcus avium.
  • Other examples of bacterial infection are staphylococcal infections.
  • the infection may be caused by methicillin- resistant Staphylococcus aureus or Staphylococcus pyogenes.
  • the invention also provides a method for dosaging an antibiotic that is predominantly excreted by the biliary tract comprising, a) measuring liver function; and b) adjusting the dosage of the antibiotic based on the liver function measurements.
  • adjusting the dosage comprises the frequency of administering the antibiotic and/or adjusting the amount of antibiotic administered.
  • the invention further provides an improved method for reducing side effects in an individual to be treated with an antibiotic that is predominantly excreted through the biliary tract by dete ⁇ nining the appropriate dosage amount of antibiotics administered to an individual wherein the improvement comprises, a) performing a liver function test on the individual; and b) adjusting the dosage of the antibiotic based on the liver function test.
  • the present invention provides methods for minimizing side effects of antibiotics that are predominantly excreted by the biliary tract by adjusting their dosage and/or frequency of administration. These methods involve performing a biliary function test to analyze the ability of a patient to handle the excretion of an antibiotic and formulating a dosage regimen for administration of the antibiotic based on the biliary function of the patient.
  • One such drug is Synercid, which is a streptogramin antibiotic. Synercid-based treatments are currently the only effective treatment for Nancomycin-resistant enterococci (VRE), especially, Enterococcus faecium (VREF) infections. NRE infections occur in seriously immunocompromised patients, such as cancer patients, HIN patients, transplant patients etc.
  • a Synercid-based therapy comprising a combination of Synercid (quinupristin/dalfopristin) with minocycline, was found to be either synergistic or additive against NREF in vitro in a study by the present inventors.
  • the efficacy and the tolerability of this regimen against NRE infections in cancer patients in a prospective, open-label study was evaluated.
  • Fifty-six evaluable patients with NRE infection were entered on quinupristin/dalfopristin 7.5 mg/kg every 8 hours plus minocycline 100 mg every 12 horns for a mean duration of 12 days (range, 2-52 days).
  • liver function tests that specifically evaluate biliary function on patients treated with Synercid (alone or in combination with other drugs) allows the determination of an amount and dosage of Synercid to be administered so as to decrease or prevent the occurrence of the associated side effects.
  • Some examples of such liver function tests are gamma GT measurements, alkaline phosphatase measurements etc. This is important as many patients have to discontinue Synercid based therapy due to the side effects.
  • the present invention provides methods that reduce or alleviate the side effects which mainly manifest as arthralgias and myalgias in individuals being treated with Synercid, thereby, allowing the continuation of this life saving therapy.
  • Vancomycin was a drug of last resort for resistant gram positive infections. The emergence of vancomycin resistance in the 1980's has been a cause of high concern. It has been demonstrated that vancomycin resistance is a significant independent predictor of increased morbidity and mortality in enterococcal bacteremia (Nergis et al, 1997; Linden et al, 1996). The most serious complications from NRE infections occur in severely immunocompromised patients, particularly cancer patients who are either neutropenic or have underlying hematologic malignancies (Linden et al, 1996; Edmond et /., 1996; Montecalvo et al, 1996). Edmond et ⁇ /.
  • Chloramphenicol has been proposed as an alternative agent ( ⁇ orris et al, 1995); however, more recently it was shown to have no significant impact on mortality, even in uncomplicated cases with catheter-related VRE bacteremia (Lautenbach et al, 1998). 3. Streptogramin antibiotics
  • Streptogramins comprise a homogenous group of antibiotics, consisting of a combination of two types of chemically different molecules; the A-group components which are polyunsatmated macrolactones and the B-group components which are depsipeptides.
  • streptogramin antibiotics are known (Table 1), which are known by different names in accordance with their origin, including pristinamycins, mikamycins and virginiamycins.
  • the A and B components have a synergistic antibacterial activity which can be as much as 100 times that of each separate component.
  • the bactericidal activity is more effective against Gram-positive bacteria such as staphylococci and streptococci.
  • the A and B components inhibit protein synthesis by binding to the 50S subunit of the ribosome.
  • Streptogramins are mainly produced by actinomycetes, including many streptomycetes for example, Streptomyces alborectus, Streptomyces mitakaensis, Streptomyces pristinaespiralis, Streptomyces ostreogriseus and Streptomyces virginiae.
  • streptogramins are also synthesized by eukaryotes such as Micromonospora which synthesizes vemamycins. Some examples are listed in Table 1 above.
  • pristinamycin RP 7293
  • an antibacterial of natural origin produced by Streptomyces pristinaespiralis was isolated for the first time in 1955.
  • Pristinamycin is used in Europe as an oral antibiotic and is marketed under the name Pyostacine® and consists mainly of pristinamycin IA and pristinamycin IIA.
  • Another antibacterial of the streptogramin class namely virginiamycin, has been prepared from Streptomyces virginiae, ATCC 13161 and is also known as Staphylomycine®.
  • Virginiamycin is used in animal feed to protect animals from infections.
  • streptogramins include mikamycin, ostreogrycin, viridogrisein, vernamycin and etamycin.
  • the group A and group B components are also used for the treatment of acne.
  • Synercid® (also called RP 59500 or RP 57669/RP 54476) is an antibacterial agent that belongs to the class of macrolides-lincosamides-streptogramins. This injectable streptogramin is approved for the treatment of patients with serious or life-threatening infections, for example, those associated with vancomycin-resistant Enterococcus faecium (VREF) bacteremia; and complicated skin and skin structure infections caused by Staphylococcus aureus (methicillin susceptible) or Streptococcus pyogenes. Synercid has been approved for marketing in the United States for this indication under FDA's accelerated approval regulations that allow marketing of products for use in life-threatening conditions when other therapies are not available.
  • VREF vancomycin-resistant Enterococcus faecium
  • Aerobic gram-positive microorganisms Enterococcus faecium (Vancomycin-resistant and multidrug-resistant strains only)
  • Aerobic gram-positive microorganisms Aerobic gram-positive microorganisms:
  • Staphylococcus aureus (methicillin-resistant strains)
  • Staphylococcus epidermidis (including methicillin-resistant strains)
  • Synercid is a sterile lyophilized formulation of two semisynthetic pristinamycin (streptogramin) derivatives, quinupristin (derived from pristinamycin I) and dalfopristin (derived from pristinamycin IIA) in the ratio of 30:70 (w/w). These two components act synergistically, therefore, Synercid' s in vitro microbiologic activity is greater than that of the individual components.
  • the metabolites of quinupristin and dalfopristin also contribute to the antimicrobial activity of Synercid.
  • the site of action of quinupristin and dalfopristin is the bacterial ribosome. Dalfopristin has been shown to inhibit the early phase of protein synthesis while quinupristin inhibits the late phase of protein synthesis.
  • Quinupristin is a white to very slightly yellow, hygroscopic powder. It is a combination of three peptide macrolactones.
  • the main component of quinupristin (>88.0%) has the following chemical name: N-[(6R,9S,10R,13S,15aS,18R,22S,24aS)-22-[p-(dimethylamino)benzyl]-6- ethyldocosahydro-10,23-dimethyl-5,8,12,15,17,21,24-heptaoxo-13-phenyl-18-[[(3S)-3- quinuclidinyIthio]methyl]-12H-pyrido[2,l-f]pyrrolo-[2,l-l] [1,4,7,10,13,16] oxapentaazacyclononadecin-9-yl]-3-hydroxypicolinamide.
  • the main component of quinupristin has an empirical formula of C53H67N9
  • Dalfopristin is a slightly yellow to yellow, hygroscopic, powder.
  • the chemical name for dalfopristin is: (3R,4R,5E,10E,12E,14S,26R,26aS)-26-[[2-(diethylamino)ethyl]sulfonyl]-
  • Dalfopristin has an empirical formula of C34H50N4O9S, a molecular weight of 690.85.
  • Quinupristin and dalfopristin are the main active components circulating in plasma in human subjects. Quinupristin and dalfopristin are converted to several active major metabolites: two conjugated metabolites for quinupristin (one with glutathione and one with cysteine) and one non-conjugated metabolite for dalfopristin (formed by drug hydrolysis). Pharmacokinetic profiles of quinupristin and dalfopristin in combination with their metabolites provide doses of 7.5 mg/kg of Synercid intravenously ql2h or q8h for a total of 9 or 10 doses, respectively.
  • Synercid is a major inhibitor of cytochrome P450 3A4 isoenzyme. Synercid can also interfere with the metabolism of other drug products that are associated with QTc prolongation. However, electrophysio logic studies show that Synercid does not itself induce QTc prolongation.
  • Fecal excretion constitutes the main elimination route for both parent drugs and their metabolites (75 to 77% of dose).
  • Urinary excretion accounts for approximately 15% of the quinupristin and 19% of the dalfopristin dose.
  • Preclinical data in rats have demonstrated that approximately 80% of the dose is excreted in the bile and in man, biliary excretion is probably the principal route for fecal elimination.
  • the pharmacokinetics of the Synercid were not modified in older individuals or by gender differences.
  • the mode of action differs from that of other classes of antibacterial agents such as -lactams, aminoglycosides, glycopeptides, quinolones, macrolides, lincosamides and tetracyclines. No cross resistance was seen between Synercid and these agents when tested by the minimum inhibitory concentration (MIC) method.
  • MIC minimum inhibitory concentration
  • Indications for Use Use of Synercid for treating resistant infections such as in VREF- infected patients has been allowed under an investigator sponsored-IND program ("compassionate use program') in the US (Cerwinka et al, 1995) and under a similar Compassionate Use Program in other countries including France, Israel and the UK (Lynn et al, 1994).
  • Patients are treated for a variety of infections, including post-operative wounds, intra- abdominal infections, peritonitis, urinary tract infection, suppurative phlebitis, osteomyelitis, bacteremia of unknown origin and endocarditis.
  • infections including post-operative wounds, intra- abdominal infections, peritonitis, urinary tract infection, suppurative phlebitis, osteomyelitis, bacteremia of unknown origin and endocarditis.
  • liver function tests in accordance to methods of the present invention can be performed on all these patient types prior to the appropriate dosage adjustment.
  • Synercid based treatments due to the Emergency/Compassionate Use clause of Synercid, however, it will be understood that this is just a guideline and that the Synercid based therapy may be performed on any patient regardless of the guidelines if determined essential by a trained physician:
  • Patients that are treated with Synercid generally have a culture of the infection site which is positive for the causative pathogen prior to treatment. Treatment is generally not initiated without positive cultures. In general, the patient must meet at least one of the following inclusion criteria; the infection must be caused by a pathogen with resistant or intermediate in vitro susceptibility to all clinically appropriate antibiotics.
  • the infection must be caused by a pathogen with resistant or intermediate in vitro susceptibility to all clinically appropriate antibiotics.
  • Vcomycin-resistant Enterococcus faecium which has been shown to have a vancomycin sensitivity of intermediate or resistant via one of the following inclusion criteria: 1.
  • Disk Diffusion zone size 16 mm or less and/or 2. MIC of 8 ⁇ g/ml or higher.
  • Patients with an infection due to a non-VREF organism including infections with but not limited to staphylococci
  • MRSA Maltostrehalose, MRSE
  • streptococci other enterococci and Legionella sp.
  • streptococci other enterococci and Legionella sp.
  • streptococci other enterococci and Legionella sp.
  • streptococci other enterococci and Legionella sp.
  • the infection type includes intra-abdominal infections, skin and skin-structure infections, urinary tract infections, central catheter related bacteremia, endocarditis, bone and joint infections, bacteremia with an unknown source, respiratory tract infections, and all other types of infections.
  • Radiological evidence such as a CT scan or ultrasound
  • abdominal wall rigidity localized or diffuse
  • mass or ileus evidence of systemic inflammatory response (except if patient is neutropenic), i.e. at least one of the following: fever*, elevated white blood cell count, hypotension, tachycardia, tachypnea, hypoxia or altered mental status
  • culture of intra-abdominal fluid or abdominal soft tissue positive for the causative pathogen i.e. at least one of the following: fever*, elevated white blood cell count, hypotension, tachycardia, tachypnea, hypoxia or altered mental status
  • culture of intra-abdominal fluid or abdominal soft tissue positive for the causative pathogen i.e. at least one of the following: fever*, elevated white blood cell count, hypotension, tachycardia, tachypnea, hypoxia or altered mental status
  • Patients with skin and skin-structure infections generally have the following criteria: seropurulent drainage or at least three of the following: tenderness to palpation, erythema, induration, fluctuance; and/or properly collected culture of drainage or material biopsied or aspirated from the site of infection positive for the causative pathogen.
  • UTI urinary tract infections
  • Acute Uncomplicated LM wherein patients meet four of the following criteria: at least two of the following symptoms: dysuria, urgency, frequency, suprapubic pain; no urinary symptoms in the four weeks prior to this episode; pyuria: which is dipstick positive for leukocyte esterase or WBC in microscopic examination > 10 leukocytes/nim 3 (unspun urine) unless neutropenic; and midstream urine culture growing at least 10 3 cfu/mL of the causative pathogen of unspun urine; (2) Acute Uncomplicated Pyelonephritis, wherein patients generally meet some of the following criteria: fever, chills, flank pain, other diagnosis excluded, no history or clinical evidence of urological abnormalities; pyuria which is dipstick positive for leukocyte esterase or WBC in microscopic examination > 10 leukocytes/mm 3 (unspun urine) unless neutropenic; and/or midstream urine culture
  • UTI patients may also have some of the following symptoms: dysuria, urgency, frequency, suprapubic pain, fever, chills, flank pain.
  • the patients may also have pyuria which is dipstick positive for leukocyte esterase or WBC in microscopic examination > 10 leukocytes/mm 3 (unspun urine) unless neutropenic.
  • the midstream urine culture growing at least 10 5 cfu/ml of the causative pathogen in unspun urine for a Complicated LM patient or 10 4 cfu/ml of the causative pathogen for a patient in the LM in Men category or for catheter associated LM, a specimen taken directly from the catheter growing at least 10 2 cfu/ml of the causative pathogen.
  • Asymptomatic Bacteriuria Patients with Asymptomatic Bacteriuria generally meet three of the following criteria: no symptoms of UTI infection; pyuria which is dipstick positive for leukocyte esterase or NrBC in microscopic examination > 10 leukocytes/mm 3 (unspun urine) unless neutropenic and two consecutive midstream urine cultures growing at least 10 5 cfu/ml of the causative pathogen of unspun urine > 24 hours apart.
  • Patients with Catheter-Related Bacteremia generally meet the following four criteria: presence of a percutaneous inserted or tunneled central venous or arterial catheter; at least one of the following three criteria of no other apparent origin than a catheter infection: fever or hypothermia ( ⁇ 35.6°C) observed on two or more occasions over a 12-hour period, chills, leukocytosis with > 10 10 PM ⁇ /L (10,000 PM ⁇ /mm 3 ), unless neutropenic; one or more blood cultures positive for the causative pathogen with no-apparent source other than the catheter; and if catheter is removed prior to treatment, semi-quantitative catheter culture positive (> 15 cfu, 'Maki technique") with isolation of an identical causative pathogen from the catheter and from the bloodstream.
  • Patients with Endocarditis generally have the following criteria for either definite, probable or possible endocarditis ("Non Reyn” criteria modified by E.A. Blumberg et al, 1992).
  • Patients with definite endocarditis have culture of a valvular vegetation, of a vegetation that has embolized, or of an intracardiac abscess positive for the causative pathogen.
  • Patients with probable endocarditis have either, persistently positive blood counts, and one of the following: a new murmur due to vascular insufficiency, or predisposing heart disease and vascular phenomena; or they may have all of the following: intermittently positive blood cultures (i.e. not meeting definition for persistently positive); fever; new regurgitant murmur or echocardiographic evidence of endocarditis; and vascular phenomena.
  • Patients with possible endocarditis can have either, persistently positive blood cultures, and one of the following: predisposing heart disease, or vascular phenomena or all of the following: intermittently positive blood cultures (i.e. not meeting definition for persistently positive); fever, predisposing heart disease, vascular phenomena.
  • Blood cultures at least 2 cultures of samples of > 0 mL of blood each, drawn from two different access sites following application of antiseptic solution, with at least 5 minutes
  • Persistently positive blood cultures all of 2, all of 3, or more than 66% of > 3 cultures of separate blood cultures positive for the causative pathogen.
  • Vascular phenomena petechiae, conjunctival hemorrhages, Roth's spots, Osier's nodes,
  • Predisposing heart disease definite valvular or congenital heart disease or a cardiac prosthesis excluding permanent pacemakers.
  • Bone and Joint infections include those with the following types of bone and joint infections: (1) Osteomyelitis. These patients generally meet one of the following two criteria: positive bone biopsy culture for the causative pathogen, or radiological evidence of osteomyelitis plus positive blood cultures for the causative pathogen. The following may conditions also be present: focal pain, swelling, erythema, induration, draining sinus- fever, chills, increased WBC (>10,000/mm 3 or > 15% bands). (2) Septic arthritis. These patient generally have: painful / tender joint or loss of joint function; Fever; and/or positive synovial fluid culture for the causative pathogen from the infected joint. (3) Prosthetic joint infections.
  • Mediastinitis These patients generally have: pathogens isolated from blood culture and/or culture of mediastinal tissue or fluid obtained during surgery or needle aspiration; fever; chest pain or sternal instability or mediastinal widening on x-ray examination.
  • Patients with bacteremia of unknown source can be those where bacteremia includes as at least one positive blood culture for the causative pathogen, bacteremia of an unknown source is defined as bacteremia without an identifiable primary source of infection at the time of study entry.
  • Patients with respiratory infections that are treated with Synercid include the following types of conditions: (1) Pneumonia. These patients normally have infiltrate on chest x-ray; at least one of the following: new or worsening cough, sputum changes, fever, auscultatory findings such as rales or evidence of consolidation, leukocytosis; (WBC> 10,000/mm 3 or > 15% bands); and/or positive sputum culture for the causative pathogen or one positive blood culture for the causative pathogen in the absence of another source of bacteremia. (2) Pleurisy. These patients can have positive pleural fluid cultme for the causative pathogen and/or radiological evidence of purulent collection in the pleural cavity.
  • infections category Patients who do not qualify for any of the above categories default into the other infections category.
  • infections include but are not limited to intravascular, deep wound other than abdominal or CNS infections.
  • Antihistamines astemizole, terfenadine
  • Anti-HIN delavirdine, nevirapine, indinavir, ritonavir
  • Antineoplastic agents vinca alkaloids (e.g., vinblastine), docetaxel, paclitaxel
  • Benzodiazepines midazolam
  • diazepam Calcium channel blockers dihydropyridines (e.g., nifedipine), verapamil, diltiazem
  • Cholesterol-lowering agents HMG-CoA reductase inhibitors (e.g., lovastatin)
  • GI motility agents cisapride
  • Immunosuppressive agents cyclosporine, tacrolimus
  • Steroids methylprednisolone Other: carbamazepine, quinidine, lidocaine, disopyramide
  • Synercid is generally administered by intravenous infusion in 5% Dextrose in Water solution over a 60-minute period. The recommended dosage for the treatment of infections is described in Table 2.
  • An infusion pump or device may be used to control the rate of infusion.
  • central venous access e.g., PICC
  • PICC central venous access
  • Infections is seven days.
  • the treatment duration varies and is determined based on the site and severity of the infection.
  • Liver Function tests are among the most commonly used investigations in clinical medicine.
  • the standard LFTs include an analysis of serum aminotransferase, alkaline phosphatase and bilirubin. These tests reflect activities of liver enzymes in liver injury.
  • liver function test results are used to determine the dose an antibiotic that is predominantly excreted through the biliary tract administered to a patient in need thereof. This adjustment of dosage reduces and/or alleviates side effects caused by the antibiotics.
  • an antibiotic is Synercid.
  • Transaminases catalyze the transfer of an amino group from an amino acid to ketoacid thereby forming a new amino acid. They are present in highest concentrations in cells from the liver, heart, skeletal muscle and erythrocytes. In hepatocytes, alanine transaminase (ALT) is present in higher concentrations than aspartate transaminase (AST) and therefore with liver injury, ALT exceeds AST (alcoholic liver disease is a notable exception). These enzymes become elevated as hepatocytes become necrotic or partially damaged; however, the magnitude of elevation correlates poorly with disease severity.
  • patients with mild viral hepatitis may have transaminase levels measured in the thousands for several weeks, yet there may be insufficient cellular injury to cause jaundice or prolongation of the prothrombin time.
  • patients with severe alcoholic hepatitis or autoimmune chronic active hepatitis rarely have transaminase values in excess of 500 despite the presence of life-threatening disease.
  • Transaminases are useful as a screening test for the presence of many liver diseases, however notable exceptions are methotrexate induced damage, and alcoholic liver disease which may progress with little change in the LFTs.
  • the AST or ALT are also useful to follow the activity of certain diseases to help judge the need for therapy or the response to therapy (e.g. steroids for autoimmune chronic active hepatitis or interferon for chronic HCN).
  • the transaminases are not useful indicators of prognosis since viable cells may leak transaminases and because it is the extent of hepatic regeneration that more accurately reflects outcome.
  • Alkaline phosphatase represents a group of membrane associated enzymes which become elevated in response to increased intraceUular concentrations of bile acids. This is secondary to increased pressures within the biliary ductal system as a result of either cholestasis or obstruction. Since alkaline phosphatase is present in other cells outside the liver, a hepatic origin can be confirmed by demonstrating an associated increase in the 5' nucleotidase or gamma- glutamyl transpeptidase (GGT). An elevation of the alkaline phosphatase is a sensitive indicator of intrahepatic cholestasis/obstruction or extrahepatic obstruction, whereas bilirubin will become elevated only when the process is advanced.
  • Conditions commonly associated with a predominant elevation of the alkaline phosphatase include: extrahepatic obstruction, infiltrative liver diseases such as amyloidosis or neoplasia, granulomatous hepatitis (especially TB and sarcoid), certain drug reactions, and other chronic cholestatic conditions such as primary biliary cirrhosis and primary sclerosing cholangitis.
  • Bilirubin is a breakdown product of heme which is released as senescent erythrocytes are hemolyzed by the reticuloendothelial system. After uptake by the liver, bilirubin is conjugated with UDPG which enhances its water solubility and enables biliary excretion. The capacity of the liver to take up, conjugate and excrete bilirubin is large and a considerable increase in bilirubin load is required before this hepatic reserve is exceeded. Similarly, extensive parenchymal injury, widespread canalicular dysfunction or almost complete obstruction must be present before the serum bilirubin rises.
  • liver function test is a true liver function test, but is insensitive in that it becomes increased only with advanced hepatocellular disease or high grade obstruction.
  • Other true liver function tests include the serum albumin and the prothrombin time.
  • liver's synthetic function serve as a measure of the liver's synthetic function and are particularly useful in determining the extent of damage in acute or chronic hepatocellular injury.
  • the inventors have demonstrated that recognition of the pattern of abnormal liver function tests permits the diagnosis of the hepatic capability of the individuals liver to handle Synercid or any antibiotic that is secreted at 60% or more through the biliary tract.
  • an accurate dosage scheme for the administration of an antibiotic that is primarily excreted by the biliary tract can be formulated based on the liver function test.
  • the inventors contemplate that adjustment of the dosage of Synercid to the individuals will help reduce or alleviate side effects such as arthralgias and myalgias.
  • Synercid is mainly metabolized and cleared by the liver. Performing a liver function test on patients that are undergoing therapy with Synercid reveals hepatic insufficiencies such as biliary dysfunction.
  • the methods of the present invention may be used to adjust the dosage of Synercid and to decrease or alleviate the serious side effects such as arthralgias and myalgias associated with its used that often lead to discontinuation of the Synercid therapy.
  • Table 3 Listed below in Table 3 is a list of dosages of Synercid depending on the severity of the biliary tract dysfunction as determined by the present invention.
  • Table 3 is a general indicator of the dosage range and adjustment a determination of the exact dose of Synercid or any other antibiotic that is predominantly excreted by the biliary tract, will be made by a trained physician at the time of drug administration to an individual taking into consideration factors such as disease, age, gender and other similar criteria.
  • VRE VRE isolated from at least one culture specimen from the site of infection. Infections were defined according to the criteria of the Centers for Disease Control and Prevention (Garner et al, 1988). Catheter-related bacteremia was defined as the isolation of > 15 colony-forming units of VRE from the intravascular catheter segment and also isolated from a blood culture collected from a peripheral vein, without any other obvious site of infection (Raad and Bodey, 1992).
  • Microbiologic Methods Enterococci were identified initially from culture specimens based on colony morphology and gram stain morphology. They were subcultured for final identification on Vitek GPI medium (BioMeriuex Vitek, Hazelwood, MD). Susceptibility testing to gentamicin, streptomycin, ampicillin, penicillin, chloramphenicol, minocycline, quinupristin/dalfopristin, and vancomycin was performed by the Kirby/Bauer disk diffusion method and the microdilution method in Mueller-Hinton broth at an inoculum size of 5 x 10 5 cfu/mL (National Committee for Clinical Laboratory Standards, 1993).
  • the MIC 9 o was determined after incubation for 24 hours at 35°C using the interpretations of the National Committee for Clinical Laboratory Standards (National Committee for Clinical Laboratory Standards, 1993). Resistance to vancomycin was defined as a zone size of > 16 mm by the Kirby-Bauer method and a MIC > 8 ⁇ g/mL by the microdilution method. Central venous catheters were cultured upon removal by the roll plate semiquantitative culture technique (Maki, et al,A911).
  • a clinical response to treatment is defined as resolution of all signs and symptoms relating to the original infection.
  • a microbiological response is defined as the eradication of VRE from the site of infection at the end of treatment.
  • Relapse is defined as the return of signs and symptoms of infection and isolation of VRE from the site of infection within one month of follow-up from the end of treatment.
  • Treatment failure is defined as no resolution or worsening of signs and symptoms of infection during treatment, coupled with persistent positive cultures for VRE.
  • Neutropenia is defined as an absolute neutrophil count of ⁇ 500 cells/mm 3 .
  • Neutropenic patients were defined as those with ⁇ 500 neutrophils/m ⁇ r at the onset of treatment.
  • the overall response rate to quinupristin/dalfopristin with minocycline was 68% (38/56 patients).
  • the response rate was similar for the 40 neutropenic patients (neutropenic at the onset of treatment) and the 16 patients with adequate neutrophil counts (65% vs 75%, P — 0.47, Table 5).
  • Thirty-two (80%) of the neutropenic patients had bacteremia compared to 8 (50%) of the patients with adequate neutrophils (P 0.025).
  • VRE bacteremia Lack of effective therapy for VRE bacteremia: It has been demonstrated that vancomycin resistance is a significant independent predictor of increased morbidity and mortality in enterococcal bacteremia (Vergis et al, 1997; Linden et al, 1996). The most serious complications from VRE infections occur in severely immunocompromised patients, particularly cancer patients who are either neutropenic or have underlying hematologic malignancies (Linden et al, 1996; Edmond et al, 1996; Montecalvo et al, 1996). Edmond et al. (1996), studied the outcome of VRE bacteremia in a population consisting of mostly (70%) of patients with 5 underlying hematologic malignancy.
  • VRE bacteremia was associated with an attributable mortality of 37%, and 81% of the patients developed hypoperfusion abnormalities and/or organ dysfunction.
  • Montecalvo et al. (1996) determined that neutropenia is a risk factor for the persistence of VRE bacteremia in immunocompromised patients.
  • Linden et al. (1996) found that VRE bacteremia in immunocompromised 10 liver transplant patients is associated with a persistence of the infection, more frequent recurrent bacteremia and the need for multiple invasive interventions.
  • Linden et al. (1996) attributed the serious morbidity and attributable death in patients with VREF bacteremia to be partially mediated by the lack of effective antimicrobial therapy.
  • Quinupristin/dalfopristin is a novel streptogramin antibiotic composed of two-semi-synthetic pristinamycin components
  • quinupristin/dalfopristin act synergistically to inhibit protein synthesis for most gram-positive pathogens, including vancomycin-resistant E. faecium (VREF) (Rubinstein and Bompart, 1997).
  • VREF vancomycin-resistant E. faecium
  • Neutropenic febrile patients with a documented bacteremia are usually associated with a lower response rate to active antimicrobial combination therapy than neutropenic febrile patients without bloodstream infections.
  • the present inventors observed an overall response rate of 76% to the combination of imipenem plus amikacin, whereas those patients with associated bacteremia had a response rate of 59% to the same regimens (Raad et al, 1998).
  • Minocycline is a tetracycline with superior activity against resistant gram-positive organisms when compared to other tetracyclines because it is less prone to the efflux by these resistant organisms (Minuth et al, 1974; Robertson et al, 1972). Most of the vancomycin resistant enterococcal organisms at the MD Anderson Cancer Center (82%) were found to be susceptible to minocycline. The in vitro combination of minocycline and quinupristin/dalfopristin was found to be either additive or synergistic against VREF organisms, without any evidence of antagonism.
  • the inventors contemplate evaluation of quinupristin/dalfopristin with and without minocycline in immunocompromised cancer patients and comparing its efficacy and safety with other promising agents such as the oxazolidinones (Jones et al, 1996).
  • Myalgias and arthralgias were the leading adverse events associated with the use of quinupristin/dalfopristin and minocycline in the present study, occurring at a frequency of 36%.
  • quinupristin/dalfopristin was used to treat VREF infections in 396 patients.
  • Myalgias and arthralgias were the leading adverse events, occurring at a rate of 6.6 % and 9.1%, respectively.
  • the population studied by Moellering et al. (1999) was mostly non-oncologic, with only 19% of the patients having an underlying malignancy.
  • myalgia/arthralgia was associated with high levels of alkaline phosphatase. Since quinupristin/dalfopristin is primarily eliminated through the bile into the feces (Bergeron and Montay, 1997), biliary tract dysfunction as manifested by high alkaline phosphatase may lead to accumulation of this drug and its metabolites resulting in arthralgias and myalgias. Cancer patients, particularly leukemia patients, tend to have metastatic and infiltrative liver disease with intrahepatic cholestasis resulting in higher frequency of arthralgias and myalgias.
  • Quinupristin/dalfopristin is also associated with a high frequency of phlebitis if administered through a small peripheral vein.
  • the present invention used the central venous catheters for drug delivery, only one patient, who received the drug through a small peripheral catheter, developed phlebitis.
  • Quinupristin dalfopristin 7.5 mg/kg every horns administered intravenously in combination with minocycline, 100 mg every 12 hours, was found to be efficacious in the treatment of VRE infections in cancer patients.
  • the efficacy was maintained in neutropenic patients with VREF bloodstream infections.
  • Arthralgia/myalgia was reported in more than one- third of the patients, occurring mostly in patients with biliary dysfunction, but resolved upon completion of therapy.
  • the present inventors contemplate a prospective, randomized trial with the following objectives:

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Abstract

La présente invention a trait à un ajustement de dosage et à un ajustement de la fréquence d'administration des antibiotiques qui sont excrétés, en majeur partie, par les voies biliaires à partir des examens des fonctions hépatiques, dans le but de diminuer les effets secondaires provoqués par l'antibiotique.
PCT/US2002/000775 2001-01-11 2002-01-11 Ajustement de dosage pour antibiotiques WO2002055731A2 (fr)

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US7879828B2 (en) 2005-03-14 2011-02-01 Wyeth Llc Tigecycline compositions and methods of preparation

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Cited By (5)

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US7879828B2 (en) 2005-03-14 2011-02-01 Wyeth Llc Tigecycline compositions and methods of preparation
US8975242B2 (en) 2005-03-14 2015-03-10 Wyeth Llc Tigecycline compositions and methods of preparation
US9254328B2 (en) 2005-03-14 2016-02-09 Wyeth Llc Tigecycline compositions and methods of preparation
US9694078B2 (en) 2005-03-14 2017-07-04 Wyeth Llc Tigecycline compositions and methods of preparation
US10588975B2 (en) 2005-03-14 2020-03-17 Wyeth Llc Tigecycline compositions and methods of preparation

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