Trial Information

Plasma and Abscess Fluid Pharmacokinetics of Cefpirome and Moxifloxacin After Single and Multiple Dose Administration

Title: Plasma and abscess fluid pharmacokinetics of cefpirome and moxifloxacin single dose
and multiple dose administration.

Background: Extensive research in the field of abscess treatment has established a claim
for invasive drainage as the most efficient means of resolving suppurative lesions. In
particular, computer tomography-guided percutaneous abscess drainage has repeatedly been
reported to be advantageous compared to other invasive methods. However, application of the
percutaneous interventional method is subject to some limitations. Coagulation abnormalities
are considered a contraindication, and the absence of a safe anatomic access route, the
presence of fistulas, severe inflammation of organs, or patients with advanced age have
likewise been linked to low success rates of percutaneous abscess drainage. From these
considerations, it becomes evident that percutaneous and surgical abscess drainage alone are
not satisfactory in a number of patients suffering from abscess/infected cyst-related
disease. In some patients antibiotic therapy is administered in bridging them to more stable
conditions that drainage can be performed. Therefore, it is eminent for the overall outcome
of patients to select an appropriate antibiotic. For this purpose, a model was recently
developed to simulate the concentration time-curve of fosfomycin in abscess fluid after a
single dose and after multiple doses.

Cefpirome and moxifloxacin are drugs which may be used in the empiric therapy of purulent
infections. They may be used as monotherapy or they may be combined, e.g. with fosfomycin.
Cefpirome is a 4th class cephalosporin with a broad spectrum (gram positive and gram
negative pathogens), penetrating well into soft tissues. Moxifloxacin is a new
fluoroquinolone with a considerable antimicrobial spectrum, also penetrating excellently
into soft tissues. Based on the experiences with the methods and results obtained from our
recent study on fosfomycin penetration into abscess fluid, the present pilot study will be
set out to gain PK information on the penetration properties of cefpirome and moxifloxacin
into abscess fluid and abdominal cysts.

Aim of the study: To determine pharmacokinetics of cefpirome and moxifloxacin in abscess
(cyst) fluid and plasma after single and multiple doses.

Study design: Pharmacokinetic pilot study. Drug concentrations will be determined in abscess
liquid upon drainage and in plasma over a period of eight hours.

Study population: 20 Patients with an abscess or an abdominal cyst, scheduled for surgical
or computer tomography-guided drainage.

Methods: 1) High pressure liquid chromatography 2) Analysis of computer tomography (CT)
images 3) Pharmacokinetic simulation model

Study drugs: Cefpirome (Cefrom, Aventis): will be administered to patients intravenously as
single or multiple doses of 2 g dissolved in 100 mL of distilled water over 20 minutes.
Moxifloxacin (Avelox, Bayer): will be administered to patients per os as tablet as single or
multiple doses of 400 mg.

Patients: A total of 20 patients will be enrolled in the study. They will be assigned to 2
groups. Group 1: single dose (n = 12), Group 2: multiple doses (n = 8).

Main outcome variable: The cefpirome and moxifloxacin concentrations in abscess fluid will
be measured. Considering plasma PK and the ratio of the surface to volume ratio of the
abscess, the individual concentration-versus-time curve in abscess (cyst) fluid will be
calculated. Individual pharmacokinetic parameters will be determined for abscess (cyst)
fluid after a single dose and at steady state: AUC, AUC0-12/24h, Cmax, Tmax, t1/2ß, Cav(ss).

Additional outcome variables: Plasma (single dose and steady state): AUC, AUC0-12/24h, Cmax,
Tmax, t1/2ß, Cav(ss). Pus and plasma: ratios of AUC and Cav(ss) to MIC, T>MIC The following
parameters will be determined if possible: the diameter of the pericapsular space with
enrichment of contrast agent, the degree of contrast agent enhancement in this zone and the
pus density, rate of drug degradation in pus at body temperature in vitro, pH-value of pus,
pus viscosity and specific weight.

Inconveniences and risks for patients:

The following side effects may occur after administration of cefpirome: Hypersensitivity
reaction, allergic skin reactions, exanthema, urticaria, pruritus, drug fever, anaphylactic
reactions, anaphylactic shock, interstitial nephritis, nausea, vomiting, abdominal pain,
diarrhoea, pseudomembraneous colitis, elevation of liver enzymes and serum creatinine,
thrombocytopenia, eosinophilia, hemolytic anemia, granulocytopenia, agranulocytosis, local
irritation and pain at the site of injection, dysgeusia.

The following side effects may occur after administration of moxifloxacin:

Often or occasionally: Nausea, diarrhea, vomits, dyspepsia, QT-prolongation, elevation of
AST, ALT, bilirubin, gamma GT, amylase, leucocytopenia, decrease of prothrombin,
eosinophilia, thrombocythemia, thrombocytopenia, anemia, abdominal and head pain, dizziness,
dysgeusia; unfrequent: asthenia, candidosis, thoracal and back pain, discomfort, leg pain,
anaphylactic reactions, anaphylactic shock, insomnia, vortex, nervousness, tremor,
paresthesia, discomposure, depression, hallucination, depersonalization, ataxia, xerostomia,
flatulence, obstipation, anorexia, stomatitis, glossitis, tachycardia, edema, hypertension,
palpitations, QT-prolongation, syncope, atrial fibrillation, angina pectoris,
vasodilatation, hypotension, ventricular arrhythmia, torsade de pointe, hyperglycemia,
hyperlipidemia, elevation of prothromin, icterus, arthralgia, myalgia, tendonitis, rash,
pruritus, perspiration, urticaria, xerodermia, amblyopia, tinnitus, vaginitis, hepatitis,
ataxia, tendon rupture, hypernatremia, hypercalcemia, neutropenia, hemolysis, transient loss
of vision.

Total blood loss will be limited to a maximum of 85 mL, which is usually well tolerated by
patients.

Risk/benefit assessment: CT and abscess drainage represent standard diagnosis and
therapeutic procedures. Therefore, any risk associated with CT or abscess drainage is not
ascribed to study procedures. Single and multiple doses of cefpirome (maximum of 14 doses)
and moxifloxacin (maximum of 7 doses) are normally well tolerated and have very few side
effects.

Ongoing therapy will not be affected or changed by study procedures. In summary, the risk
conferred to patients by study procedures appears minimal.