UROPHARMACOLOGY
PROSTATIC TISSUE LEVELS OF OFLOXACIN J. AAGAARD, M.D. J. KNES, B.S. E O. MADSEN, M.D., PH.D.
From the Urology Section, William S. Middleton Memorial Veterans Hospital, and Department of Surgery, University of Wisconsin, School of Medicine, Madison, Wisconsin
ABSTRACT--The prostatic tissue levels oJ ofloxacin were determined in 20 patients undergoing transurethral resection oJ the prostate. Ofloxacin was administered in two separate dosages oJ 300 mg PO Jrom twenty-two to two hours preoperatively. The ofloxacin plasma concentrations ranged Jrom 3.73 to 1.85 Izg/mL at the time oJ surgery, and the tissue concentrations ranged Jrom 4.55 to 1.94 I~g/mL. The ofloxacin tissue/plasma ratios ranged Jrom 0.9 to 1.2. These findings indicate that ofloxacin may be useJul in prophylaxis prior to transurethral prostatic surgery and also in the treatment oJ bacterial prostatitis.
Ofloxacin is a new synthetic carboxyquinolone antimierobial agent with potent baeterioeidal activity against a broad spectrum of microorganisms. Minimum inhibitory concentrations (MICs) in tests against a variety of laboratory strains range from 0.05-50 /zg/mL. An estimated 50 percent of men will experience symptoms of prostatitis sometime in their lives 1 although actual chronic bacterial prostatitis is only rarely diagnosed. Organisms of acute and chronic bacterial prostatitis are gram-negative rods (Enterobaeteriaeeae or pseudomonas sp), enteroeoeei, and gram-positive cocci. In chronic bacterial prostatitis, antibiotic-susceptible strains of bacteria have been isolated even after prolonged antibiotic treatment and multiple episodes of symptomatic baeteriuria. This may be due to inadequate prostate tissue antibiotic concentrations. 2 The purpose of this study was to determine whether clinically useful levels of ofloxacin could be achieved in human prostatic tissue with therapeutic doses, and to evaluate the safety of orally administered ofloxaein.
380
Material and Methods Male patients twenty-one dergoing transurethral resec were enrolled in the study. ministered in two separate PO before scheduled surger 3 ofloxacin fourteen and two gery; Group B received dos hours prior to surgery; Grou seven hours prior to surger 2 twenty-two and ten hours t were included in the stud, formed consent was obtaine. cluded if they had signific~ cardiovascular, hematologic chiatric, respiratory, or m, they had experienced an a seven days of study entry, c lergy to quinolones. Blood chemistry tests al done pre- and post-surgery. tion including vital signs an tests were done twenty-re
UROLOGY
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O C T O B E R 1991
/
VOLU1
and prostatic tissue concentrations of ofloxacin ]ollowing oral administration Group B (n = 5)
Group C (n = 7)
Group D (n = 5)
Plasma
Prostate
Plasma
Prostate
Plasma
Prostate
3.73 2.71 3.25 4.34 3.12
3.69 2.46 3.15 3.60 2.68
1.99 3.91 3.19 3.30 2.46 2.24 1.34
1.45 2.63 2.89 4.48 3.39 2.10 1.18
4.11 1.54 1.23 1.54 1.43
3.44 3.12 1.68 1.26 0.97
dose of drug. Each pales taken simultaneously luring surgery for high ttography (HPLC) deterconcentration. For each ,priate samples obtained, was determined, and the ~tio concentrations were ~up.
300 m9 Io.o.
B. 1 , d .
4.55 4.5
4
3.5
! 3 u 2.5
,~sults e: range 58-87, m e a n 71 a the study. J prostatic tissue concen!or each subject are pretn plasma concentrations 85/Lg/mL for groups A to iod of approximately 2.0 ~r dosing. The means of atration for each group t/~g/mL, decreasing with igure 1 the m e a n plasma, ltrations for each group s h o w s ' t h e m e a n tissue/ group ranged from 0.9 to :ted adverse events that possibly drug related, one ing six hours which rerochlorperazine adminisand one episode of tranat r e s o l v e d w i t h no
2
t.5
1.94
I
A C~,~
I
;
I
B C16-4)
C C19--0
o C~Z-1~
I::X~
~'oup~ +
(hrG,
ple.unla.
bef'oro I~url~rV~ X
prorate
FIGURE 1. Mean ofloxacin concentrations in plasma and prostate. Ofl~c~n
30D I ~
p.o.
It.T.tL
1.5 "1.4 1,3 1.22
1.1 1.04
I}.9 a,g
a,7
tl.6 0,~;
xament [ghest m e a n plasma con1L, was observed in the gery shortly after the last te tissue concentration of to be similar to that in 2ted simultaneously with re, the m e a n tissue versus
lnm
/
I
(1+-2:3
F I G U R E 2.
B (16-43
t
I O (~2-110
c C~--O
Mean tissue~plasma ratio of ofloxacin.
plasma ratio was approximately equal to 1. Average sustained tissue concentrations greater than 1/~g/g are found as long as ten hours postdosing, indicating that at b.i.d, dosing prostatic
VOLUME XXXVIII, NUMBER 4
381
tissue concentration of ofloxaein in excess of the MICs of most common pathogens would be achieved. This excellent penetration of ofloxacin into the prostate confirms results obtained in similar studies? '4 This study demonstrated that ofloxaein was rapidly absorbed, penetrated prostate tissue, and was well tolerated following oral administration. Therefore, ofloxacin may be useful in prophylaxis prior to transurethral prostatic surgery, possibly as a single, oral preoperative dose given these pharmacokinetic parameters, and may prove to be useful in bacterial prostatitis.
382
Veterans Administra Madison, Wis (Dt References 1. Stamey TA: Pathogenesis and treatment of fections, Baltimore, Williams and Wilkins, 1980 2. Fair WR: Prostatitis, in Brande AI, Davis q (Eds): Infectious Disease and Medical Mierobiolc delphia, W.B. Saunders Company, 1986, pp 109 3. Naber KG, Adams D, and Kees F: In vitro eentrations in serum, urine, prostatic secretion sue of ofloxaein in urological patients, Drugs I (1987). 4. Ito Y, et al: Prostatic tissue ievels of DL-81 apy (Suppl 1) 32:669 (1984).
UROLOGY
/
OCTOBER 1991
/
VOLUME
PROSTATIC TISSUE LEVELS OF OFLOXACIN J. AAGAARD, M.D. J. KNES, B.S. E O. MADSEN, M.D., PH.D.
From the Urology Section, William S. Middleton Memorial Veterans Hospital, and Department of Surgery, University of Wisconsin, School of Medicine, Madison, Wisconsin
ABSTRACT--The prostatic tissue levels oJ ofloxacin were determined in 20 patients undergoing transurethral resection oJ the prostate. Ofloxacin was administered in two separate dosages oJ 300 mg PO Jrom twenty-two to two hours preoperatively. The ofloxacin plasma concentrations ranged Jrom 3.73 to 1.85 Izg/mL at the time oJ surgery, and the tissue concentrations ranged Jrom 4.55 to 1.94 I~g/mL. The ofloxacin tissue/plasma ratios ranged Jrom 0.9 to 1.2. These findings indicate that ofloxacin may be useJul in prophylaxis prior to transurethral prostatic surgery and also in the treatment oJ bacterial prostatitis.
Ofloxacin is a new synthetic carboxyquinolone antimierobial agent with potent baeterioeidal activity against a broad spectrum of microorganisms. Minimum inhibitory concentrations (MICs) in tests against a variety of laboratory strains range from 0.05-50 /zg/mL. An estimated 50 percent of men will experience symptoms of prostatitis sometime in their lives 1 although actual chronic bacterial prostatitis is only rarely diagnosed. Organisms of acute and chronic bacterial prostatitis are gram-negative rods (Enterobaeteriaeeae or pseudomonas sp), enteroeoeei, and gram-positive cocci. In chronic bacterial prostatitis, antibiotic-susceptible strains of bacteria have been isolated even after prolonged antibiotic treatment and multiple episodes of symptomatic baeteriuria. This may be due to inadequate prostate tissue antibiotic concentrations. 2 The purpose of this study was to determine whether clinically useful levels of ofloxacin could be achieved in human prostatic tissue with therapeutic doses, and to evaluate the safety of orally administered ofloxaein.
380
Material and Methods Male patients twenty-one dergoing transurethral resec were enrolled in the study. ministered in two separate PO before scheduled surger 3 ofloxacin fourteen and two gery; Group B received dos hours prior to surgery; Grou seven hours prior to surger 2 twenty-two and ten hours t were included in the stud, formed consent was obtaine. cluded if they had signific~ cardiovascular, hematologic chiatric, respiratory, or m, they had experienced an a seven days of study entry, c lergy to quinolones. Blood chemistry tests al done pre- and post-surgery. tion including vital signs an tests were done twenty-re
UROLOGY
/
O C T O B E R 1991
/
VOLU1
and prostatic tissue concentrations of ofloxacin ]ollowing oral administration Group B (n = 5)
Group C (n = 7)
Group D (n = 5)
Plasma
Prostate
Plasma
Prostate
Plasma
Prostate
3.73 2.71 3.25 4.34 3.12
3.69 2.46 3.15 3.60 2.68
1.99 3.91 3.19 3.30 2.46 2.24 1.34
1.45 2.63 2.89 4.48 3.39 2.10 1.18
4.11 1.54 1.23 1.54 1.43
3.44 3.12 1.68 1.26 0.97
dose of drug. Each pales taken simultaneously luring surgery for high ttography (HPLC) deterconcentration. For each ,priate samples obtained, was determined, and the ~tio concentrations were ~up.
300 m9 Io.o.
B. 1 , d .
4.55 4.5
4
3.5
! 3 u 2.5
,~sults e: range 58-87, m e a n 71 a the study. J prostatic tissue concen!or each subject are pretn plasma concentrations 85/Lg/mL for groups A to iod of approximately 2.0 ~r dosing. The means of atration for each group t/~g/mL, decreasing with igure 1 the m e a n plasma, ltrations for each group s h o w s ' t h e m e a n tissue/ group ranged from 0.9 to :ted adverse events that possibly drug related, one ing six hours which rerochlorperazine adminisand one episode of tranat r e s o l v e d w i t h no
2
t.5
1.94
I
A C~,~
I
;
I
B C16-4)
C C19--0
o C~Z-1~
I::X~
~'oup~ +
(hrG,
ple.unla.
bef'oro I~url~rV~ X
prorate
FIGURE 1. Mean ofloxacin concentrations in plasma and prostate. Ofl~c~n
30D I ~
p.o.
It.T.tL
1.5 "1.4 1,3 1.22
1.1 1.04
I}.9 a,g
a,7
tl.6 0,~;
xament [ghest m e a n plasma con1L, was observed in the gery shortly after the last te tissue concentration of to be similar to that in 2ted simultaneously with re, the m e a n tissue versus
lnm
/
I
(1+-2:3
F I G U R E 2.
B (16-43
t
I O (~2-110
c C~--O
Mean tissue~plasma ratio of ofloxacin.
plasma ratio was approximately equal to 1. Average sustained tissue concentrations greater than 1/~g/g are found as long as ten hours postdosing, indicating that at b.i.d, dosing prostatic
VOLUME XXXVIII, NUMBER 4
381
tissue concentration of ofloxaein in excess of the MICs of most common pathogens would be achieved. This excellent penetration of ofloxacin into the prostate confirms results obtained in similar studies? '4 This study demonstrated that ofloxaein was rapidly absorbed, penetrated prostate tissue, and was well tolerated following oral administration. Therefore, ofloxacin may be useful in prophylaxis prior to transurethral prostatic surgery, possibly as a single, oral preoperative dose given these pharmacokinetic parameters, and may prove to be useful in bacterial prostatitis.
382
Veterans Administra Madison, Wis (Dt References 1. Stamey TA: Pathogenesis and treatment of fections, Baltimore, Williams and Wilkins, 1980 2. Fair WR: Prostatitis, in Brande AI, Davis q (Eds): Infectious Disease and Medical Mierobiolc delphia, W.B. Saunders Company, 1986, pp 109 3. Naber KG, Adams D, and Kees F: In vitro eentrations in serum, urine, prostatic secretion sue of ofloxaein in urological patients, Drugs I (1987). 4. Ito Y, et al: Prostatic tissue ievels of DL-81 apy (Suppl 1) 32:669 (1984).
UROLOGY
/
OCTOBER 1991
/
VOLUME
