CA2434046A1 - Dosage adjustment for antibiotics - Google Patents

Abstract

The present invention concerns adjustement of dosage and adjustement of the frequency of administration of antibiotics that are predominantly excreted b y the biliary tract on the basis of liver function tests with the goal of reducing side effects caused by the antibiotic.

Description

DESCRIPTION
DOSAGE ADJUSTMENT FOR ANTIBIOTICS
BACKGROUND OF THE INVENTION
This application claims the priority of U.S. Provisional Application No.
60/261,437, filed January 11, 2001, the disclosure of which is specifically incorporated herein by reference in its entirety.
1. Field of the Invention 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.

2. Description of Related Art The emergence of multidrug-resistant pathogens is a continuing challenge for the treatment of infectious diseases. For example, strains of Enterococcus faecium that are resistant to vancomycin pose a serious threat to individuals, such as cancer patients and transplant recipients, suffering from numerous irnmunosuppressive conditions. As vancomycin was considered to be the antibiotic of last resort for several pathogens, emergence of strains resistant to vancomycin pose a serious health threat to society. The most serious complications from vancomycin-resistant enterococcal (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). Combination therapies with other known antibiotics have proven futile in treatment of these infections. A new drug, Synercid, belonging to the class of streptogramin antibiotics, was FDA
approved in September 1999, for the treatment of serious or life-threatening infections associated with vancomycin-resistant Enterococcus faeciurn (VREF) bacteremia.
Synercid is a combination of two streptogramins: 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 axed others. Infections by these pathogens are typically seen in hospitalized and immunocompromised individuals.
The approval of Synercid was based on clinical studies conducted worldwide in 2,401 Synercid-treated patients enrolled in five Phase III comparative trials and an Emergency-Use Program. 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. In 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.
In addition to Synercid, it is also desirable to minimize or alleviate side effects caused by other antibiotics. Thus, there is a need for methods of dosage adjustments that minimize side effects caused by antibiotics.
SUMMARY OF THE INVENTION
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. Thus, 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%, 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. For example, 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.
In one embodiment of the present invention the antibiotic is a streptogramin antibiotic.
In a more specific embodiment 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 LV.), Amphoterecin B and lipid formulations of Arnphoterecin B, Clofazimine and the like. However, the skilled artisan will understand that 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.

In some embodiments, the antibiotic is used in combination with other antibiotics. For example, Synercid may be used in conjunction with other antibiotic drugs such as minocycline.
In one embodiment of the present invention 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 measures the extent of biliary tract dysfunction. In specific embodiments the liver function test measures 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.
In one embodiment of this invention the amount of antibiotic comprises a dose of the antibiotic. In another embodiment the amount comprises the frequency of administering the antibiotic.
In other embodiments, the methods of the present invention may be used to reduce and/or prevent side effects in an individual being treated with the antibiotic. In some embodiments 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 HIV 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 mufti-drug resistant. The skilled artisan will recognize that the practice of the methods of the invention are not limited by the type of infection.
In other aspects, the infection may be bacterial. Examples of bacterial infection include enteroccocal infections that may further be vancomycin-resistant. For example, the infection may be caused by Erater~ococcus faecium or Enterococcus aviurn. Other examples of bacterial infection are staphylococcal infections. Fox example 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. In some embodiments of the present invention 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 determining 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.
As used herein the specification and claim(s), the words "a" or "an" when used in conjunction with the word "comprising" may mean one or more.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
1. The Present Invention Side effects caused by antibiotics often pose major problems and may include myalgias, arthralgias, cardiotoxicity, hepatotoxicity, nephrotoxicity, anemia and the like. One of the goals for effective therapy with antibiotics is to find methods that allow administration of antibiotics in dosages and frequencies that minimize or prevent side effects. 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. The inventors contemplate that the methods taught herein can be used to minimize side effects of any antibiotic that is predominantly excreted by the biliary tract.
Thus, dosage adjustment for any antibiotic that is excreted at about 60% or more by the biliary tract axe contemplated.

One such drug is Synercid, which is a streptogramin antibiotic. Synercid-based treatments are currently the only effective treatment for Vancomycin-resistant enterococci (VRE), especially, Enterococcur faecium (VREF) infections. VRE infections occur in seriously immunocompromised patients, such as cancer patients, HIV 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 VREF in vitro in a study by the present inventors. Thus, the efficacy and the tolerability of this regimen against VRE
infections in cancer patients in a prospective, open-label study was evaluated. Fifty-six evaluable patients with VRE infection were entered on quinupristin/dalfopristin 7.5 mg/kg every 8 hours plus minocycline 100 mg every 12 hours for a mean duration of 12 days (range, 2-52 days).
. Fifty-one (91%) infections were caused by VREF. Liver functions tests were performed on all patients before, during and after the end of therapy. All patients were followed until one month after completion of therapy. Thirty-eight (68%) of the 56 patients responded. Ninety percent of them had hematological malignancies, 40 (71%) were neutropenic (<
500 cells/mm3).
The types of infections were bacteremia (71%), urinary tract infection (14%), pneumonia (5%) and wound infection (5%). There were no significant differences in responses related to site of infection or presence of neutropenia. Adverse events included arthralgia/myalgia in 36% of patients, liver ftmction abnormalities in 7%, and leukopenia in 5%. Patients with arthralgia/myalgia had significantly higher levels of alkaline phosphatase during therapy than patients without this adverse event (P = 0.05). Higher levels of alkaline phosphatase are therefore indicators of biliary dysfunction. Other enzymes that are tested for biliary function tests include gamma glutamyl transpeptidase (gamma GT).
In this high risk patient population, treatment of serious VRE infections with quinupristin/dalfopristin and minocycline was effective. The present inventors have shown herein that the associated side effects of arthralgias/myalgias which occurred at a substantial frequency are related to biliary tract dysfunction. The invention also describes that performing 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 ftinction 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. As these patients are severely immunocompromised, the infections they have can be fatal, and therefore there is need to continue the Synercid-based therapy. 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.
2. Infections 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 (Vergis et al., 1997;
Linden et al., 1996).
The most serious complications from VRE infections occur in severely immunocomprornised 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 underlying hematologic malignancy. In that subgroup of patients, VRE bacteremia was associated with an attributable mortality of 37%, and 81% of the patients developed hypoperfusion abnormalities and/or organ dysfwction. Montecalvo et al., (1996), determined that neutropenia is a risk factor for the persistence of VRE bacteremia in irnmunocompromised patients. Similarly, Linden et al., (1996) found that VRE bacteremia in immunocompromised liver transplant patients is associated with a persistence of the infection, more frequent recurrent bacteremia and the need for multiple invasive interventions. In that same study, Linden et al.
attributed the serious morbidity and attributable death in patients with VREF
bacteremia to be partially mediated by the lack of effective antimicrobial therapy.
Among the conventional antimicrobial agents there are no effective regimens available for the treatment of VRE infections. Various regimens have been tried, such as oral novobiocin plus intravenous ciprofloxacin (Linden et al., 1996), doxycycline (Papanicolaou et al., 1996), continuous high dose ampicillin or ampicillin-sulbactam (Mekonen et al., 1995), or chloramphenicol. The results of these studies have been inconclusive in terms of efficacy. In a study involving 100 patients with VRE bacteremia, there was no significant difference in mortality between treated and untreated patients (Lautenbach et al., 1998).
The treatment in that study included the use of ampicillin, imipenem, ciprofloxacin, doxycycline, and chloramphenicol. Chloramphenicol has been proposed as an alternative agent (Horns 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 polyunsaturated macrolactones and the B-group components which are depsipeptides. Several streptogramin antibiotics are known (Table 1), which are known by different names in accordance with their origin, including pristinamycins, mikamycins and virginiamycins.

MICROORGANISM ANTIBIOTIC

FUNGI

Micromonospora sp. Vernamycin STREPTOMYCES

S. alborectus Virginiamycin S. griseus (NRRL2426) Viridogrisein S. lavendulae Etamycin S. loidensis (ATCC11415) Vernamycin ~' mitakaensis (ATCC15297)Mikamycin S. ostreogf~iseus (ATCC27455)Ostreogrycin S. p~istinaespiralis(ATCC25486)Pristinamycin S. virginiae (ATCC13161) Virginiamycin A. daghestanicus Etamycin 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 SOS subunit of the ribosome.
Streptogramins axe mainly produced by actinomycetes, including many streptomycetes for example, Streptom~ces alborectus, Str~eptornyces mitakaensis, Streptomyces pristinaespiralis, Streptorrtyces ostreogriseus and Streptomyces virginiae. In addition, streptogramins are also synthesized by eukaryotes such as Micromonospora which synthesizes vernamycins. Some examples are listed in Table 1 above.

Among known streptogramins, pristinamycin (RP 7293), an antibacterial of natural origin produced by Sty~eptornyces pristizzaespiralis, 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 StYeptomyces vizginiae, ATCC 13161 and is also known as Staphylomycine~.
Virginiamycin is used in animal feed to protect animals from infections. Yet other examples of streptogramins include mikamycin, ostreogrycin, viridogrisein, vernamycin and etamycin. The group A and group B components are also used for the treatment of acne.
4. S nercid 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.
Synercid has been shown both in vitro and in clinical infections to be active against most strains of the following microorganisms:
Aerobic grant positive microorga~zisms:
Enterococcus faecium (Vancomycin-resistant and multidrug-resistant strains only) Staphylococcus aureus (methicillin-susceptible strains only) Stf~eptococcus pyogerzes In addition irz vitf°o data shows that Synercid exhibits a minimum inhibitory concentrations (MIC's) of <l .0m g/mL against >90% isolates of the following microorganisms:
Aerobic grain positive nzicroorgahisyrzs:
Cozynebacter ium jeikeiuzn Staphylococcus aur~eus (methicillin-resistant strains) Staphylococcus epidermidis (including methicillin-resistant strains) Streptococcus agalactiae Pharmacology: Synercid is a sterile lyophilized formulation of two semisynthetic pristinamycin (streptogramin) derivatives, quinupristin (derived from pristinamycin I) and S dalfopristin (derived from pristinamycin IIA) in the ratio of 30:70 (w/w).
These two components act synergistically, therefore, Synercid's ifa 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,lOR,13S,1SaS,18R,22S,24aS)-22-[p-(dimethylamino)benzyl]-6 1S ethyldocosahydro-10,23-dimethyl-5,8,12,15,17,21,24-heptaoxo-13-phenyl-18-[[(3S)-3 quinuclidinyithio]methyl]-12H-pyrido [2,1-fJpyrrolo-[2,1-1] [ 1,4,7,10,13,16]
oxapentaazacyclononadecin-9-yl]-3-hydroxypicolinamide. The main component of quinupristin has an empirical formula of CS3H67N9010S, a molecular weight of 1022.24.
Dalfopristin is a slightly yellow to yellow, hygroscopic, powder. The chemical name for dalfopristin is: (3R,4R,SE,l0E,12E,14S,26R,26aS)-26-[[2-(diethylamino)ethyl]sulfonyl]-8,9,14,15,24,25,26,26a-octahydro-14-hydroxy-3-isopropyl-4,12-dimethyl-3H-21,18-nitrilo-1 H,22H-pyrrolo [2,1-c] [ 1, 8,4,19]-dioxadia zacyclotetracosine-1, 7,16,22(4H,17H)-tetrone.
Dalfopristin has an empirical formula of C34HSON409S, a molecular weight of 690.85.

Pharmacokinetics: 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.S mg/kg of Synercid intravenously ql2h or q8h for a total of 9 or 10 doses, respectively. In vitro, the transformation of the parent drugs into their major active metabolites occurs by non-enzymatic reactions and is not dependent on cytochrome-P4S0 or glutathione-transferase enzyme activities.

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, electrophysiologic 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.
In patients with renal insufficiency, i.e., creatinine clearance 6 to 28 mL/min, the AUC of quinupristin and dalfopristin in combination with their major metabolites increased about 40%
and 30%, respectively. In patients undergoing Continuous Ambulatory Peritoneal Dialysis, dialysis clearance for quinupristin, dalfopristin and their metabolites is negligible. The plasma AUC of unchanged quinupristin and dalfopristin increased about 20% and 30%, respectively.
The high molecular wVeight of both components of Synercid indicates that it is unlikely to be removed by hemodialysis.
In patients with hepatic dysfunction (Child-Pugh scores A and B), the terminal half life of quinupristin and dalfopristin was not modified. However, the AUC of quinupristin and dalfopristin in combination with their major metabolites increased about 180%
and 50%, respectively.
I~r vitro combination testing of Synercid with aztreonam, cefotaxime, ciprofloxacin, and gentamicin against Entef°obacteriaceae and Pseudomonas aerugifzosa does not show antagonism. In vitro combination testing of Synercid with prototype drugs of the following classes: aminoglycosides (gentamicin), -lactams (cefepime, ampicillin, and amoxicillin), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline) and also chloramphenicol against enterococci and staphylococci also does not show antagonism. 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.

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. Listed below are some of the different types of patients and infections that may be treated with Synercid and therefore be amenable to dosage adjustment to reduce or alleviate side effects by the methods of this inventions. Thus, 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.
The following criteria are used as general indications for 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:
i. Microbiological Criteria:
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 ih vitro susceptibility to all clinically appropriate antibiotics. One example of this is Vancomycin-resistant Ehterococcus faecium (VREF) 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 of 16 mm or less and/or 2. MIC of S ~g/ml or higher.
Patients with an infection due to a non-VREF organism including infections with but not limited to staphylococci (MRSA, MRSE), streptococci, other enterococci and Legionella sp. may also be treated with Synercid. Another inclusion criteria is documented intolerance or absolute contraindication of a patient to all available clinically appropriate antibiotics. Yet another inclusion criteria is a documented treatment failure with all available clinically appropriate antibiotics of the patient.
Generally, all types of infection can be treated with Synercid and hence all such patients are amenable to dosage adjustment using methods of the invention. 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.
ii. Site-specific Infection Criteria:
Patients with infra-abdominal infections can be treated with Synercid and the following three criteria are generally considered, at least one of the following:
radiological evidence (such as a CT scan or ultrasound) of infra-abdominal infection, 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, tacliycardia, tachypnea, hypoxia or altered mental status; and culture of infra-abdominal fluid or abdominal soft tissue positive for the causative pathogen.
*Fever is defined herein as rectal temperature > 3S°C or oral temperature > 37.5°C on two or more occasions during a 12-hour period.
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.
Patients with urinary tract infections (IJTI) generally fit into one of the following four UTI groups: (1) 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/nima (unspun urine) unless neutropenic; and midstream urine culture growing at least 103 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~ (unspun urine) unless neutropenic; and/or midstream urine culture growing at least 104 cfu/mL of the causative pathogen of unspun urine; (3) Complicated UTI and (4) UTI in men, wherein patients with complicated UTI may have four of the following criteria or UTI in men may have at least one of the following factors associated with complicated UTI including: presence of an indwelling or intermittent urinary catheter > 100 mL of residual urine retained after voiding, obstructive uropathy due to bladder outlet obstruction, a calculus or, other causes, vesico-ureteral reflux or other urologic abnormalities including, surgically created ileal loops, azotemia due to intrinsic renal disease, renal transplantation. Further 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/mm3 (unspun urine) unless neutropenic. The midstream urine culture growing at least 105 cfu/ml of the causative pathogen in unspun urine for a Complicated LM patient or 104 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 10z cfu/ml of the causative pathogen.
Patients with Asymptornatic l3acteriuria generally meet three of the following criteria: no symptoms of UTI infection; pyuria which is dipstick positive for leukocyte esterase or VrBC in microscopic examination > 10 leukocytes/mm3 (unspun urine) unless neutropenic and two consecutive midstream urine cultures growing at least 105 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 > 101° PMN/L (10,000 PMN/mm3), 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 ("Von 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.
5. Definition of terms 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 (preferably 15-30 minutes) intervals between drawings.
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.
T~asczzlar plzenofnena: petechiae, conjunctival hemorrhages, Roth's spots, Osler's nodes, Janeway lesions, aseptic meningitis, glomerulonephritis, pulmonary, coronary or peripheral emboli.
Predisposing heart disease: definite valvular or congenital heart disease or a cardiac prosthesis excluding permanent pacemakers.
Patients with 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/mm3 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.
These patients generally have fever; pain, dysfunction or weakening of the joint; and/or positive culture of needle aspirate from the joint space or intraoperative culture for the causative pathogen. (4) 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/mm3 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 culture for the causative pathogen and/or radiological evidence of purulent collection in the pleural cavity.
Patients who do not qualify for any of the above categories default into the other infections category. These types of infections include but are not limited to intravascular, deep wound other than abdominal or CNS infections.
Uses of Other Drugs with Synercid: Some selected drugs that are predicted to have plasma concentrations increased by Synercid are:
Antihistamines: astemizole, terfenadine Anti-HIV (NNRTIs and Protease inhibitors): 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 Arthralgias/Myalgias: Episodes of arthralgia and myalgia, some of which tend to be severe, are the major side effects seen in patients treated with Synercid. In several of these patients, treatment discontinuation resolves these symptoms. The etiology of the myalgias and arthralgias are not very well understood.

Dosage and Administration: 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. If necessary, central venous access (e.g., PICC) can be used to administer Synercid to decrease the incidence of venous irritation.

Infection Dose Vancomycin-Resistant 7.5 mg/kg q8h EnterococcuS faecium Complicated Skin and 7.5 mg/kg ql2h Skin Structure Infection The minimum recommended treatment duration for Complicated Skin and Skin Structure Infections is seven days. For Vancomycin-Resistant En.te~ococcus faecium infection, the treatment duration varies and is determined based on the site and severity of the infection.
6. Liver Function Tests Liver Function tests (LFTs) 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. In context of this invention, 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. One example of such an antibiotic is Synercid.
Transaminases, or aminotransferases, 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. For example, 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. Alternatively, 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.
Patients whose LFTs show a predominant rise in the transaminases have liver diseases which are characterized by hepatocellular damage. Examples include viral hepatitis, drug or toxin induced injury, or hepatic ischemia. 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 HCV). 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 intracellular 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.
From the above discussion, it is clear that bilirubin 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.
They 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.
In relation to the present invention 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 biliany tract. Thus, 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.
From the art, as practiced so far, no dosage adjustment of Synercid is performed for different patient types. For example, the same dosage of Synercid is prescribed currently for in patients, with renal impairment and/or patients undergoing peritoneal dialysis; in patients with hepatic insufficiencies; in patients that are older; in pediatric patients;
and/or on basis of patient gender. The present inventors have shown that 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. Based on the results of these liver function tests, especially biliany function tests such as alkaline phosphatase or gamma glutamyl transpeptidase (gamma GT), 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.
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. However, one of skill in the art will recognize that while 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.

Biliary Dysfunction Adjusted Dose of Synercid 1. Normal biliary function 7.Smg/kg Q8h (alkaline phosphatase or gamma GT within 1.5X

normal limit) 2. Mild biliary function 7.Smg/kg Ql2h OR Smg/kg Q8h (alkaline phosphatase or gamma GT within(maintaining a daily dose 1.5- of l5mg/kg) 3X normal levels) 3. Moderate biliary functionSmg/kg IV Ql2h (alkaline phosphatase or gamma GT within normal levels) 4. Severe biliary function Smg/kg IV; Q24h or use alternate (alkaline phosphatase or gamma GT withintherapy with other drugs, >5X for example, normal levels) Linezolid 7. Examples The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

1. Patients and Methods Patients: Between February 1994 and November 1998, 56 cancer patients with proven VRE infections were entered on the study. Patients known to have hypersensitivity to streptogramin antibiotics were excluded. All subjects gave written informed consent to participate in the study which was approved by the Institutional Review Board of MD Anderson Cancer Center. To be eligible for the study, the patient had to have 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 intravasculax 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).

The patients' history and physical examination were reviewed prior to entry on the study.
Quinupristin/dalfopristin was administered at a dose of 7.5 mg/kg every 8 hours, and minocycline at a dose of 100 mg every 12 hours, for a period ranging from 2-52 days (mean, 12 days). Therapy was administered via a central venous catheter in most patients. Liver function tests including bilirubin, alkaline phosphatase, alanine aminotransferase, and albumin were determine on all patients within one week before therapy, midterm during therapy, and within one week after completion of therapy. Patients were followed daily until the end of therapy and re-evaluated one month after completion of therapy.
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, quinupristinldalfopristin, and vancomycin was performed by the I~irby/Bauer disk diffusion method and the microdilution method in Mueller-Hinton broth at an inoculum size of 5 x 105 cfu/mL (National Committee for Clinical Laboratory Standards, 1993). The MIC9o 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 I~irby-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, . 1977).
Definitions: 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/mm3.
Statistical Analysis: Either the X2 test of Fisher's Exact Test was used to determine differences in categorical data. Statistical significance was defined as P <
0.05.

2. Results The majority of patients (71%) had bacteremia (Table 4). Fifty-six patients with VRE
were included in the study, 90% of whom had hematological malignancies (Table 5).. The mean age of the patients was 51 years (range, 7-86 years). VREF accounted for 91%
of the infections;
E. faecalis and E. aviuna were each responsible for one infection Three patients were infected with a mixed infection caused by both E. faecium and E. faecalis.

Characteristics of Patients Enrolled in the Study Age, mean (range) (years)51 (7-86) Male/female (n) 28/28 Underlying disease:

Leukemia 43 (77%) Lymphoma/Myeloma 7 ( 13 %) Solid Tumor 6 (11%) Type of infection Bacteremia 40 (71%) Urinary Tract Infection 8 (14%) Pneumonia 3 (5%) Wound Infection 3 (5%) Other 2 (4%) Bone marrow transplant* 15 (27%) (within a year prior to culture) Mean APACHE Score (range)16 (6-25) * Or pure blood stem cell transplant.

Outcome of Quinupristin/Dalfopristin Plus Minocyline Therapy in Neutropenic versus Non-neutropenic Patients NeutropenicNon-neutropenicTotal P value n=40 n= 16 n=56 Clinical and 26(65%) 12 (75%) 36 (68%) 0.47 microbiological response Relapse (% of 4(10%) 3 (25%) 7 (18%) 0.65 respondents) * Neutropenic patients were defined as those with <_500 neutrophils/mm' 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). The relapse rates were 10% and 19%, respectively (P = 0.65). Thirty-two (80%) of the neutropenic patients had bacteremia compared to 8 (50%) of the patients with adequate neutrophils (P = 0.025). As expected, the response rate for the 21 patients with persistent neutropenia during the treatment course was lower (57%) than the response rate for the 35 patients who were non-neutropenic or recovered their neutrophil count (74%; P
= 0.18).
Twenty-six (65%) of the 40 patients with bacteremia responded, 7 of the 8 with urinary tract infections, 2 of the 3 with pneumonia, and 3 of the 5 patients with other sites of infection.
Hence, the response rates were similar for bacteremias compared to other sites of infection (65%
vs 75%, P = 0.417). Four patients had catheter-related bacteremias. Three neutropenic patients responded to therapy and catheter removal, whereas one patient who was not neutropenic failed to respond. In this latter patient, the catheter was exchanged over a guide wire, which may account for the failure.
Most of the organisms causing infection were fully susceptible to quinupristin/dalfopristin (86%) and/or minocycline (82%) (Table 6). Five organisms had intermediate susceptibility to quinupristinldalfopristin and 3 were resistant.
Eight organisms had only intermediate susceptibility to minocycline and two were resistant.

MIC Susceptibility Profiles of Quinupristin/Dalfopristin and Minocycline and Response to Therapy Susceptible Intermediate Resistant Quinupristin/dalfopristin:
MIC9o (pg/mL) _< 1 2 . >_ 4 Number of patients (% of total) 48 (86) 5 (9) 3 (5) Number of responses (% of patients 32 (67) 4 (80) 2 (67) in category) Minocycline:
MIC~o (p.g/mL) < 4 8 >_ 16 Number of patients (% of total) 46 (82) 8 (14) 2 (4) Number of responses (% of patients 32 (70) 5 (63) 1 (50) in category) *Breakpoints are defined by the National Committee for Clinical Laboratory Standards (8, 34).

The response rate for the 39 infections caused by organisms susceptible to both quinupristin/dalfopristin and minocycline was 60% compared to 63% for the 16 infections caused by organisms susceptible to only one drug. One patient had infection caused by an organism that was intermediately susceptible to both drugs and responded to therapy. One patient with E. faecalis bacteremia responded to the combination of quinupristin/dalfopristin with minocycline even though the organism was resistant to quinupristin/dalfopristin but susceptible to minocycline. The patient with E. aviufyz bacteremia failed to respond. The E.
aviuna was susceptible to quinupristin/dalfopristin but not to minocycline.
Finally, all 3 patients with mixed E. faeciufya and E. faecalis bacteremias responded to the combination therapy.
Myalgia and arthralgia were reported. in 36% of patients (Table 7). Myalgias and arthralgias occurred in 40% of leukemic patients but in only 23% of other patients (P = 0.23).
However, patients with arthralgias/myalgias had significantly higher levels of alkaline phosphatase (mean 318.7 IU/1) during midterm therapy cycle as compared to patients without any joint or muscular pain (mean 216.3 IU/1, P = 0.05). In addition, 16.6% of patients with arthralgias/myalgias had more than fivefold the normal levels of alkaline phosphatase which did not occux in any of the other patients who did not develop this adverse event (P = 0.04). Other toxicities were abnormalities in liver function tests of four patients (7%), leukopenia in three (5%) and phlebitis in one (2%). VRE infection was considered as the primary cause of death in 4 (7%) patients and was a contributing cause of death in another 13 (23%).

Incidence of Adverse Events Associated with Quinupristin/Dalfopristin Therapy Adverse event Number of patients (%) n=56 Myalgia/arthralgia 20 (36%) Increased liver function 4 (7%) tests Leukopeiua 3 (5%) Phlebitis 1 (2%) 3. Discussion 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 irmnunocompromised 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 underlying hematologic malignancy. In that subgroup of patients, 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. Similarly, Linden et al. (1996) found that VRE bacteremia in immunocompromised liver transplant patients is associated with a persistence of the infection, more frequent recurrent bacteremia and the need for multiple invasive interventions. In that same study, 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.

15. Among the conventional antimicrobial agents there are no effective regimens available for the treatment of VRE infections. Various regimens have been tried, such as oral novobiocin plus intravenous ciprofloxacin (Linden et al., 1996), doxycycline (Papanicolaou et al., 1996), continuous high dose ampicillin or ampicillin-sulbactam (Mekonen et al., 1995), or chloramphenicol (Lautenbach et al., 1998). The results of these studies have been inconclusive in terms of efficacy. In a study involving 100 patients with VRE bacteremia, there was no significant difference in mortality between treated and untreated patients (Lautenbach et al., 1998). The treatment in that study included the use of ampicillin, imipenem, ciprofloxacin, doxycycline, and chloramphenicol. Chloramphenicol has been proposed as an alternative agent (Morris 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).
Efficacy of quinupristin/dalfopristin: Quinupristin/dalfopristin is a novel streptogramin antibiotic composed of two-semi-synthetic pristinamycin components (quinupristin/dalfopristin). The two components act synergistically to inhibit protein synthesis for most gram-positive pathogens, including vancomycin-resistant E. faecimra (VREF) (Rubinstein and Bompart, 1997). Although highly active ifa vitro, clinical studies have shown that quinupristin/dalfopristin when used alone is associated with limited efficacy in immunocompromised patients. Dever et al. (1996), have studied quinupristindalfopristin in the treatment of VREF infections in 15 patients, most of whom were immunocompromised; 80% of the patients had liver transplant, AIDS, or underlying malignancy. Clinical cure was reported in 38% of the eight evaluable patients. More recently, Wood et al. (1998a), treated 70 patients with VRE infections using quinupristin/dalfopristin. Among the evaluable patients (n = 65), 38%
were neutropenic and 35% had leulcemia. The overall response rate was 49%.
Wood et al.
(1998b), also reported a 14% rate of emergence of resistance to quinupristin/dalfopristin.
Emergence of resistance was associated with clinical and bacteriologic failure.
A clinical and microbiologic cure, at a frequency of 65% in neutropenic patients, was observed in the present invention, including those with associated VRE
bloodstream infections.
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. For example, in a recent analysis of prospective randomized studies of antimicrobial treatment of neutropenic febrile patients 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). A response rate for VRE bacteremia of 65% to the combination of minocycline and quinupristin/dalfopristin in a patient population consisting mostly of leukemia and bone marrow transplant patients therefore seems favorable, especially when compared to a response rate of less than 50% to quinupristin/dalfopristin previously reported by Dever et al.
(1996) and Wood et al. (1998a). In addition, there was no evidence of emergence of resistance to either quinupristin/dalfopristin or minocycline among those patients with recurrence of the VRE
infection.
Rationale for combination therapy: The improved outcome resulting .from the use of the combination of quinupristinldalfopristin and minocycline compared to quinupristin/dalfopristin without minocycline could be related to several factors, for example, Moreno et al. (1994), suggests that tetracyclines could play a role in the treatment of VREF
infections. 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 ira vitro combination of minocycline and quinupristinldalfopristin was found to be either additive or synergistic against VREF organisms, without any evidence of antagonism. Howe et al. (1997), reported that the addition of tetracycline to quinupristin/dalfopristin improved the outcome in a leukemia patient with neutropenia during bone marrow transplant in the immediate post-transplantation period.
Recently, a report by Aeschlimann et al. (1998), showed that the addition of doxycycline to quinupristin/dalfopristin prevented the emergence of resistance to quinupristin/dalfopristin.
Thus, explaining the lack of emergence of resistance to quinupristin/dalfopristin in the present study. Almost all VRE infections (91 %) in the present study were caused by vancomycin-resistant E. faeciuna which, unlike E. faecalis, are highly susceptible to quinupristin/dalfopristin (Williams et al., 1997). However, the addition of minocycline most likely improved the outcome in those patients with VRE infections resistant to quinupristin/dalfopristin. In the present study, 67% of the patients with quinupristin/dalfopristin-resistant E.
faeciunz and all of the patients with quinupristin/dalfopristin-resistant E. faecalis responded to the combination therapy, probably due to the fact that all of the quinupristin/dalfopristin-resistant VRE organisms were susceptible to minocycline. 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).
Role of the catheter: With respect to patients with catheter-related bloodstream infections, the data shows that the catheter needs to be removed in such patients, as it may act as a source of -reinfection. This observation is consistent with the study of Lai (1996), who determined that VRE catheter-related bacteremia should be treated by catheter removal .
Because the majority of VRE bacteremias (90%) in the present study were non-catheter-related, the inventors contemplate determining whether the bacteremia is catheter-related prior to removal of the catheter. Simultaneous blood cultures drawn through the catheter and peripheral vein would be useful in determining whether the catheter is the source of the infection prior to catheter removal. A recent study shows that a catheter infection is suggested if the blood culture drawn through the central line becomes positive at least 2 hours before a blood culture drawn simultaneously through the peripheral vein (Blot et al., 1999).
Occurrence of adverse events: 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%. In a large prospective study by Moellering et al. (1999), quinupristin/dalfopristin was used to treat VREF infections in 396 patients.
Myalgias and arthralgias were the leading adverse events, occurnng at a rate of 6.6 % and 9.1%, respectively.
However, the population studied by Moellering et al. (1999) was mostly non-oncologic, with only 19% of the patients having an underlying malignancy. In a study by Mandler et al., involving 65 patients treated with quinupristin/dalfopristin, arthralgialmyalgia occurred at rate of 26% and was found to be significantly associated with leukemia as a risk factor In the present study, 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. This might explain why arthralgias and myalgias improve with the reduction of the quinupristin/dalfopristin dose to a frequency of every 12 hours. In addition, when quinupristin/dalfopristin was administered at a dose of 7.5 mg/kg every 12 hours to 450 patients none developed arthralgias and myalgias (Nichols et al., 1999) Therefore, given the association between quinupristin/dalfopristin and arthralgia/myalgia in cancer patients with biliary dysfunction and the discomfort produced by it, it would be desirable adjust the dose in accordance with the degree of biliary dysfunction in order to prevent the occurrence of such adverse effects. Quinupristinldalfopristin is also associated with a high frequency of phlebitis if administered through a small peripheral vein. However, as 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.
4. Conclusion Quinupristin/dalfopristin, 7.5 mg/kg every hours administered intravenously in combination with minacycline, 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.

Treatment with Synercid: Improvement of Safety in Comparison with Zyvox in a Prospective, Randomized Trial Resistant gram positive infections, including vancomycin-resistant enterococci (VREF), have become the leading cause of infections in cancer patients. Synercid (quinupristin/dalfopristin) is a novel antibiotic which is active and efficacious in the treatment of these resistant gram positive infections, particularly VREF. However, the use of this drug is limited by a frequent adverse event which is arthralgias/myalgias. In a study of cancer patients at MDACC, 36% of the patients developed arthralgias/myalgias, often necessitating analgesic treatment.
The present inventors contemplate a prospective, randomized trial with the following objectives:
1. To establish the relationship between arthralgias/myalgias and biliary dysfunction through the determination of a more specific blood test for biliary function, which is the gamma GT;
2. To alleviate the adverse events by adjusting the dose of Synercid in accordance to the biliary function test.
3. To compare the adverse events and efficacy of Synercid to another agent active against VRE, Zyvox, which does not cause arthralgias/myalgias. The patients who receive Zyvox would serve as the control group.
Methods: Patients with VRE infections will be randomized to either Synercid or Zyvox.
Biliary Function tests, including gamma GT, will be obtained at the initiation of antibiotic therapy, midcourse, and at the end of therapy. Those patients who develop arthralgias/myalgias will have their dose adjusted in accordance with their biliary function status and gamma GT
levels. Synercid serum levels will be obtained on all patients who receive this agent and will be repeated after adjusting the dose. Patients receiving Zyvox will serve as controls.
Statistics: Reports of Synercid study conducted at MDACC show that adverse events of myalgias and arthralgias occur due to the use of Synercid at a rate of about 36%. Results from early Zyvox clinical trials indicate that adverse events associated with the drug are much lower than those reported with Synercid (8% definitely related). A sample size of 33 in each arm is needed to be able to detect a difference of 36% for Synercid vs. 8% for Zyvox with 80% power and 95% confidence.
If arthralgias/myalgias are shown to resolve with dose adjustment based on biliary function tests, this will have a wide impact on the use of this antibiotic in cancer patients and all hospitalized patients with VRE infection.

********************=x********************
All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure.
While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention.
More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims. . .

REFERENCES
The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.
Aeschlimann, J.R., M. J. Zervos, M. J. Rybak. 1998. Treatment of vancomycin-resistant Enterocaccus faecium with RP 59500 (quinupristin-dalfopristin) administered by intermittent or continuous infusion, alone or in combination with doxycycline, in an in vitro pharmocodynamic infection model with simulated endocardial vegetations.
0 Antimicrob. Agents Chemother. 47:2710-2717.
American Thoracic Society. Official Statement. Hospital-acquired pneumonia in adults:
diagnosis, assessment of severity, initial antimicrobial therapy and preventative strategies. A consensus statement. Respir. Crit. Care Med., 153:1711-1725, 1996.
Aumercier, M., S. Bouhallab, and M. L. Capmau. 1992. P59500: A proposed mechanism for its 5 bactericidal activity. J. Antimicrob. Chemother. 30:9-14.
Baquero, F. 1997. Gram-positive resistance: challenge for the development of new antibiotics. J.
Antimicrob. Chemother. 39:1-6, (suppl A).
Bergeron, M., G. Montay. 1997. The pharmacokinetics of quinupristin/dalfopristin in laboratory animals and in humans. J. Antimicrob. Chemoter. 39: 129-138.
0 Blot, F., G. Nitenberg, E. Chachaty, B. Raynard, N. Germann, S. Antoun, A.
Laplanche, C.
Brun-Buisson, C. Tancrede C. 1999. Diagnosis of catheter-related bacteremia: a prospective comparison of the time to positivity of hub-blood versus peripheral-blood cultures. Lancet 354: 1072-1977.
Blumberg, E.A. et al, Clin. Infect. Dis. 1992; 15:983-90.
5 Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report CDC
Surveillance, 46:891, 1993.
Cerwinka S., Bornpart F., Kreter B. and Savarese J. . Abstract. IBC Bacterial Multidrug Resistance Civetta Jm, Taylor Rw, Kirby Rr. Critical Care, 3rd ed. Philadelphia, Pa:
Lippincott-Raven;
0 1997:2259.
Curbelo, D. E., B. S. Doll, I. Wilets, et al. 1997. Treatment and outcome in 100 patients with vancomycin-resistant enterococcal (VRE) bacteremia. Abstr. J-7. Izz Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC.

Delden and Iglewski, Cell-to-cell signaling and Pseudonaonas aeruginosa infections, Emerging Infectious Diseases, 4:551-560, 1998.
Dever, L. L., S. M. Smith, D. Dejesus, et al. 1996. Treatment of vancomycin-resistant Enterococcus faeciuna infections with an investigational streptogramin antibiotic (quinupristin/dalfopristin): A report of fifteen cases. Microb. Drug Resist.
2:407-413 Edmond, M.B., J. F. Ober, J. D. Dawson, et al. 1996. Vancomycin-resistant enterococcal bacteremia: Natural history and attributable mortality. Clin. Infect. Dis.
23:1234-1239 Garner, J. S., W. R. Jarvis, G. T. Emori, et al. 1988. CDC Definitions for nosocomial infections.
Am. J. Infect. Control 16: 128-140.
0 Gonzalez, Venzon, Lee, Mueller, Pizzo, Walsh, Risk factors for fungemia in children infected with h~.unan immunodeficiency virus: a case control study, Clin. Infect. Dis., 23:515-521, 1996.
Griswold, M.W., B. M. Lamestro, L. L. Briceland. 1996. Quinupristin-dalfopristin (RP 59500):
An injectable streptogramin combination. Am. J. Health Syst. Pharm. 53:2045-53.
5 Heir, Sundheim, Holck, Resistance to quaternary ammonium compounds in Staphylococcus spp.
Isolated from the food industry and nucleotide sequence fo the resistance plasmid pST827, .T. Appl. Bacteriol., 79:149-156, 1995.
Howe, R. A., M. Robson, A. Oakhill, et al. 1997. Successful use of tetracycline as therapy of an immunocompromised patient with septicaemia caused by a vancomycin-resistant ~.0 enterococcus. J. Antimicrob. Chemother. 40:144-145.
Jones, R, N, D. Johnson, M. E. Erwin. 1996. In vitro antimicrobial activities and spectra of U100592 and U100766, two novel fluorinated oxazolidinones. Antimicrob. Agents Chemother. 40:720-726 Klempner, Lorber, Bartlett, Hospital infections and health-care epidemiology, In: INFECTIOUS
!,5 DISEASES: MEDICAL KNOWLEDGE SELF-ASSESSMENT PROGRAM, 2ND EDITION, American College of Physicians, Philadelphia, PA, pp. 210, 1998.
Koll, B.S., and A. E. Brown. 1993. Then changing epidemiology of infections at cancer hospitals. Clin. Infect. Dis. 17: 5322, (suppl 2).
Lai, K. K. 1996. Treatment of vancomycin-resistant Enterococcus faeciurn infections. Arch.
0 Intern. Med. 156: 2579-2584.
Lautenbach, E., M. G. Schuster, W. B. Bilker, et al. 1998. The role of chloramphenicol in the treatment of bloodstream infection due to vancomycin-resistant enterococcus.
Clin.
Infect. Dis. 27:1259-65 Lecciones, Lee, Navarro, Vascular catheter-associated fungemia in patients with cancer:
5 analysis of 155 episodes, Clin. Infect. Dis. 14:875-883, 1992.

Leu, Kaiser, Mori, Hospital-acquired pneumonia: attributable mortality and morbidity, Ana. J.
Epidemiol., 129:1258-1267, 1989.
Linden, P, K, A. W. Pasculle, R. Manez, et al. 1996. Differences in outcomes for patients with bacteremia due to vancomycin-resistant Enterococcus faecium or vancomycin-susceptible E. faeciuna. Clin. Infect. Dis. 22:663-670.
Maki, D. G., C. E. Weise, and H. W. Sarafin. 1977. A semi quantitative culture method for identifying intravenous catheter infection. N. Engl. J. Med. 296:1305-1309.
Mandler, H. D., E. A. Blumberg, A. E. Fuchs, et al. Arthralgias and myalgias associated with quinupristin/dalfopristin (Synercid) treatment of infections caused by vancomycin 0 resistant Eraterococcus faecium (VREF). abstr. 608 Fr. IrZ Program and abstracts of the 36th annual meeting of the Infectious Diseases Society of America, Denver, Co.
Mekonen, E. T., G. A. Noskin, D. M. Hacekm et al. 1995. Successful treatment of persistent bacteremia due to vancomycin-resistant, ampicillin-resistant Enterococcus faecium.
Microbiol. Drug Resistance 1:249-253.
5 Minuth, J. N., T. M. Holmes, D. M. Musher. 1974. Activity of tetracycline, doxycycline, and minocycline against methicillin-susceptible and resistant staphylococci.
Antimicrob.
Agents Chemother. 6:411-414.
Moellering, R. C., P. K. Linden, J. Reinhardt, et al. 1999. The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant 0 Ente~ococcus faecium. J. Antimicrob. Chemother. 44:251-261.
Montecalvo, M. A., D. K. Shay, P. Patel, et al. 1996. Bloodstream infections with vancomycin-resistant enterococci. Arch. Intern. Med. 156:1458-1462.
Moreno, F., J. H. Jorgensen , M. H. Weiner. 1994. An old antibiotic for a new multiple-resistant Eyaterococcus faecium? Diagn. Microbiol. Infect. Dis. 20:41=43.
5 National Committee for Clinical Laboratory Standards. 1993. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 3rd ed. Approved standard M7-43.
National Committee for Clinical Laboratory Standards, Villanova, Pa.
National Committee for Clinical Laboratory Standards. 1998. Subcommittee on Antimicrobial Susceptibility Testing. Minutes of June 1998 meeting. National Clinical Laboratory 0 Standards, Reston, Va.
Nichols, R. L., D. R. Graham, S. L. Barnere, A. Rodgers, S. E. Wilson, M.
Zervos, D. L. Dunn, B. Kreter for the Synercid Skin and Structure Infection Group. 1999. Treatment of hospitalized patients with complicated Gram-positive skin and skin structure infections:
two randomized, multicentre studies of quinupristin/dalfopristin versus cefazolin, 5 oxacillin or vancomycin. J. Antimicrob. Chemother. 44: 263-273.

Norris, A.H., J. P. Reilly, P. H. Edelstein, Chloramphenicol for the treatment of vancomycin-resistant enterococcal infections. 1995. Clin. Infect. Dis. 20: 1137-44.
Papanicolaou, G. A, B. R. Meyers, and J. Meyers. 1996. Nosocomial infections with vancomycin-resistant Enterococcus faecimn in liver transplant recipients: risk factors for acquisition and mortality. Clin. Infect. Dis. 23:760-766.
Platt, Bucknall, MIC tests are not suitable for assessing antiseptic handwashes, J. Hosp. Infect., 11:396-397, 1988.
Raad, Darouiche, Dupuis, Central venous catheters coated with minocycline and rifampin for~the prevention of catheter-related colonization and bloodstream infections: a randomized, 0 double-blind trial, Ann. Intern. Med., 127:267-274, 1997.
Raad, I. I. and G. P. Bodey. 1992. Infectious complications of indwelling vascular catheters.
Clin. Infect. Dis. 15:197-210.
Raad, I. L, D. Abi-Said, I~. V. Rolston , et al. 1998. How should imipenem-cilastatin be used in the treatment of fever and infection in neutropenic cancer patients? Cancer 82:2449-58.
5 Raad, Intravascular-catheter-related infections, Lancet, 351:893-898, 1998.
Reiselman, Tarara, Wenzel, Nosocomial bloodstream infections in the critically ill, JAMA, 272:1578-1601, 1994.
Reverdy, Bes, Nervi, Martra, Fleurette, Activity of four antiseptics (acriflavin, benzalkonium chloride, chlorhexidine diglnconate and hexamidine di-isethionate) and of ethidium ~,0 bromide on 392 strains representing 26 Staphylococcus species, Med.
Microbiol. Lett., 1:56-63, 1992.
Robertson, J. M., E. C. R. Reeve. 1972 Analysis of the resistance mediated by several R-factors to tetracycline and minocycline. Genetical Research, 20:239-252 Rubinstein, E, F. Bompart. 1997. Activity of quinupristin/dalfopristin against gram-positive I',5 bacteria: clinical applications and therapeutic potential. J. Antimicrob.
Chemother. 39 (suppl A):139-143 Russell, Plasmids and bacterial resistance to biocides, J. App. Microbiol., 82:157-161, 1997.
Tacconelli, Tumbarello, Pittiruti, Central venous catheter-related sepsis in a cohort of 366 hospitalized patients, Eur. J. Clin. Microbiol. Infect. Dis., 16:203-209,1997.
0 Townsend, Ashdown, Momoh, Grubb, Distribution of plasmid-born resistance to nucleic acid hinging compounds in methicillin resistant Staphylococcus aureus, J. acid hinging compounds in methicillin resistant Staphylococcus aureus, J. Antimicrob.
Claemother.
15:417-434, 1985.

Tumbarello, Tacconelli, Danati, Nosocomial bloodstream infections in HIV-infected patients:
attributable mortality and extension of hospital stay, J. Acquir. Imrnun.
Defic. Syndr-.
Hum. Retrovir~ol., 19:490-497, 1998.
Vergis, E. N., J. W. Chow, M. K, and Haydn, et al. Vancomycin resistance predicts mortality in enterococcal bacteremia. A prospective, multicenter study of 375 patients.
Program and Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada. September 28-October 1, 1997, p 289 (Abstract #
J-6) Wey, Mori, Pfaller, Woolson, Wenzel, Risk factors for hospital-acquired candidemia, Af°clz.
Intern. lVled. 149:2349-2353, 1989.
0 Williams, J. D., J. P. Maskell, A.C. Whiley, et al. 1997. Comparative in-vitro activity of quinupristin/dalfopristin against Enterococcus spp. J. Antimicrob. Chemother.
39 (suppl A):41-46.
Wood CA, Blumberg EA, Fuchs AE, et al. 1998a. Quinupristin/dalfopristin (Synercid) treatment of infections caused by vancomycin-resistant Enterococcus faecium. abstr. 606 Fr. In 5 Program and abstracts of the 36th annual meeting of the Infectious Diseases Society of America, Denver, Ca.
Wood CA, Blumberg EA, Fuchs AE, et al. 1998b. Emergence of resistance to quinupristin/dalfopristin (Synercid) during treatment of infections caused by vancomycin-resistant Enterococcus faecium. abstr. 607 Fr. In Program and abstracts of ~;0 the 36th annual meeting of the Infectious Diseases Society of America, Denver, Co.

Claims (30)

1. A method 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.

2. The method of claim 1, wherein the antibiotic is a streptogramin.

3. The method of claim 2, wherein the streptogramin is Synercid.

4. The method of claim 1, wherein the antibiotic is further used in combination with other antibiotics.

5. The method of claim 1, wherein the liver function test measures the metabolism of the antibiotic.

6. The method of claim 1, wherein the liver function test measures biliary tract dysfunction.

7. The method of claim 1, wherein the liver function test measures the activity of alkaline phosphatase.

8. The method of claim 1, wherein the liver function test measures the activity of gamma-glutamyl transpeptidase.

9. The method of claim 1, wherein the amount comprises a dose of the antibiotic.

10. The method of claim 1, wherein the amount comprises the frequency of administering the antibiotic.

11. The method of claim 1, wherein the individual is afflicted with cancer.

12. The method of claim 1, wherein the individual is neutropenic.

13. The method of claim 1, wherein the individual is immunocompromised.

14. The method of claim 1, wherein the individual is a transplant recipient.

15. The method of claim 1, wherein the individual is afflicted with an infection.

16. The method of claim 15, wherein the infection is further multi-drug resistant.

17. The method of claim 15, wherein the infection is bacterial.

18. The method of claim 17, wherein the bacterial infection is enteroccocal.

19. The method of claim 18, wherein the enteroccocal infection is further vancomycin-resistant.

20. The method of claim 18, wherein the enteroccocal infection is caused by Enterococcus faecium.

21. The method of claim 18, wherein the enteroccocal infection is caused by Enterococcus avium.

22. The method of claim 17, wherein the bacterial infection is staphylococcal.

23. The method of claim 22, wherein the staphylococcal infection is caused by methicillin-resistant Staphylococcus aureus.

24. The method of claim 22, wherein the staphylococcal infection is caused by Staphylococcus pyogenes.

25. 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.

26. The method of claim 25, wherein adjusting the dosage comprises the frequency of administering the antibiotic.

27. The method of claim 25, wherein adjusting the dosage comprises changing the amount of antibiotic administered.

28. 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 determining 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.

29. The method of claim 28, wherein adjusting the dosage comprises the frequency of administering the antibiotic.

30. The method of claim 28, wherein adjusting the dosage comprises changing the amount of antibiotic administered.