Antimicrob. Agents Chemother. 1983 Foulds 692 9

7/28/2019 Antimicrob. Agents Chemother. 1983 Foulds 692 9

1/9

23(5):692. DOI: 10.1128/AAC.23.5.692.

1983,Antimicrob. Agents Chemother.G McMahon

FM M O'Brien, S L Hayes, D J Weidler andG Foulds, J P Stankewich, D C Marshall,

sulbactam in humans.Pharmacokinetics of

http://aac.asm.org/content/23/5/692found at:Updated information and services can be

These include:

CONTENT ALERTS

morealerts (when new articles cite this article),Receive: RSS Feeds, eTOCs, free email

http://journals.asm.org/site/misc/reprints.xhtmlInformation about commercial reprint orders:http://journals.asm.org/site/subscriptions/To subscribe to to another ASM Journal go to:

onSeptember21,2013byguest

http://aac.asm.org/

Download

edfrom


http://aac.asm.org/

Download

edfrom


http://aac.asm.org/

Download

edfrom


http://aac.asm.org/

Download

edfrom


http://aac.asm.org/

Download

edfrom


http://aac.asm.org/

Download

edfrom


http://aac.asm.org/

Download

edfrom


http://aac.asm.org/

Download

edfrom


http://aac.asm.org/

Download

edfrom
http://aac.asm.org/cgi/alertshttp://aac.asm.org/cgi/alertshttp://aac.asm.org/cgi/alertshttp://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/http://aac.asm.org/cgi/alerts


2/9

V o l . 2 3 , N o . 5N T I M I C R O B I A L A G E N T S AND C H E M O T H E R A P Y , M a y 1 9 8 3 , P . 6 9 2 - 6 9 90 0 6 6 - 4 8 0 4 / 8 3 / 0 5 0 6 9 2 - 0 8 $ 0 2 . 0 0 / 0C o p y r i g h t C 1 9 8 3 , A m e r i c a n S o c i e t y f o r M i c r o b i o l o g y

P h a r m a c o k i n e t i c s o f S u l b a c t a m i n HumansGEORGE FOULDS,l* JOSEPH P . STANKEWICH,2 DAVID C . MARSHALL,t MARK M. O ' B R I E N , tSHERRARD L . HAYES, DONALD J . WEIDLER,' AND F . GILBERT McMAHON4

C e n t r a l R e s e a r c h D i v i s i o n ' a n d Q u a l i t y C o n t r o l D i v i s i o n , 2 P f i z e r I n c . , G r o t o n , C o n n e c t i c u t 0 6 3 4 0 ; D i v i s i o n o fC l i n i c a l P h a r m a c o l o g y , U n i v e r s i t y o f M i a m i , M i a m i , F l o r i da 3 3 1 0 3 '; a n d C l i n i c a l R e s e a r c h C e n t e r , I n c . ,New O r l e a n s , L o u i s i a n a 7 0 1 1 2 4R e c e i v e d 1 2 N o v e m b e r 1 9 8 2 / A c c e p t e d 1 8 F e b r u a r y 1 9 8 3

S u l b a c t a m , a new 3 - l a c t a m a s e i n h i b i t o r , h a s p h a r m a c o k i n e t i c c h a r a c t e r i s t i c s i nh u m a n s s i m i l a r t o t h o s e o f a m p i c i l l i n a n d a m o x i c i l l i n . I t s h a l f - l i f e i n h u m a n s i sa p p r o x i m a t e l y 1 h . I n a t w o - c o m p a r t m e n t p h a r m a c o k i n e t i c m o d e l , t h e a p p a r e n tv o l u m e o f d i s t r i b u t i o n f o r t h e c e n t r a l compartment i s a p p r o x i m a t e l y 1 2 l i t e r s , a n dh a l f o f t h e d o s e i s f o u n d i n t h e c e n t r a l c o m p a r t m e n t i n t h e p o s t d i s t r i b u t i v e p h a s e .A p p r o x i m a t e l y 75% o f a p a r e n t e r a l d o s e i s e x c r e t e d u n c h a n g e d i n u r i n e . T h eL c o a d m i n i s t r a t i o n o f s u l b a c t a m w i t h a m p i c i l l i n , p e n i c i l l i n G , or c e f o p e r a z o n e h a se s s e n t i a l l y n o e f f e c t u p o n t h e k i n e t i c s o f e i t h e r t h e , B - l a c t a m a n t i b i o t i c o rs u l b a c t a m .S i n c e t h e i n t r o d u c t i o n o f P - l a c t a m a n t i b i o t i c s ,m a n y o r g a n i s m s p r e v i o u s l y s u s c e p t i b l e t o t h ep e n i c i l l i n s h a v e d e v e l o p e d r e s i s t a n c e . T h i sr e s i s t a n c e i s o f t e n d u e t o t h e p r e s e n c e o f a 1 B -l a c t a m a s e , a n e n z y m e t h a t i s c a p a b l e o f h y d r o -l y z i n g t h e 1 - l a c t a m r i n g o f p e n i c i l l i n s , t h e r e b yd e s t r o y i n g t h e i r a n t i b i o t i c a c t i v i t y ( 1 6 , 1 8 ) . O n e

w a y t o r e s t o r e t h e s u s c e p t i b i l i t y o f r e s i s t a n ts t r a i n s o f b a c t e r i a t o t h e a n t i b i o t i c i s t o c o a d m i n -i s t e r a 1 3 - l a c t a n i a s e i n h i b i t o r , t h a t i s , a c o m -p o u n d w h i c h w i l l i n a c t i v a t e t h e e n z y m e . S u c h ac o m p o u n d i s s u l b a c t a m ( C P - 4 5 , 8 9 9 , p e n i c i l l a n i ca c i d s u l f o n e ) , a c o m p e t i t i v e a n d n o n c o m p e t i t i v e1 - l a c t a m a s e i n h i b i t o r ( 4 , 1 4 , 1 5 ) p r e s e n t l y u n d e rc l i n i c a l i n v e s t i g a t i o n . A l t h o u g h i t h a s r e l a t i v e l yl i t t l e i n t r i n s i c b i o l o g i c a l a c t i v i t y , s u l b a c t a m h a sb e e n s h o w n t o e x t e n d t h e i n v i t r o s p e c t r u m o f , B -l a c t a m a n t i b i o t i c s t o a n u m b e r o f r e s i s t a n t o r g a -n i s m s ( 1 , 8 , 9 , 1 7 ) . T h i s r e p o r t d e s c r i b e s t h ep a r e n t e r a l p h a r m a c o k i n e t i c s o f s u l b a c t a m i n h u -m a n s .S i n c e t h e e f f i c a c y o f s u l b a c t a m r e q u i r e s c o n -c o m i t a n t a d m i n i s t r a t i o n o f a , B - l a c t a m a n t i b i o t i c ,e m p h a s i s h a s b e e n p l a c e d u p o n c o m p a r i s o n s o ft h e p h a r m a c o k i n e t i c s o f s u l b a c t a m w i t h t h o s e o fa n d i n c o m b i n a t i o n w i t h p a r e n t e r a l a n t i b i o t i c ss u c h a s a m p i c i l l i n , p e n i c i l l i n G , a n d c e f o p e r a -z o n e .

MATERIALS AND METHODSA s a y o f s u l b a c t a m : b i o a s s a y . D u r n g t h e s i n g l e - a n dm u l t i p l e - d o s e s t u d i e s i n w h i c h s u l b a c t a m wa s g i v e nt P r e s e n t a d d r e s s : E t h i c o n , S o m m e r v i l l e , N J 0 8 8 7 6 .t P r e s e n t a d d r e s s : U n i v e r s i t y A f f i l i a t e d C i n c i n n a t i C e n t e rf o r D e v e l o p m e n t a l D i s a b i l i t i e s , C i n c i n n a t i , OH 4 5 2 2 9 . P r e s e n t a d d r e s s : 1 6 0 0 S o u t h 4 t h S t r e e t , F o r t P i e r c e , F L3 3 4 5 0 .

a l o n e , s u l b a c t a m l e v e l s i n s e r u m a n d u r i n e w e r ea s s a y e d b y a m i c r o b i o l o g i c a l c y l i n d e r p l a t e t e c h n i q u e ,e s s e n t i a l l y d e s c r i b e d i n t h e U n i t e d S t a t e s P h a r m a c o -p o e i a XX ( 2 0 ) . T h e a s s a y e m p l o y e d C o m a m o n a s t e r r i -g e n a ATCC 8 4 6 1 a t a c o n c e n t r a t i o n o f a p p r o x i m a t e l y1 0 7 o r g a n i s m s p e r m l o f A n t i b i o t i c M e d i u m A (BBLM i c r o b i o l o g y S y s t e m s ) a s t h e t e s t m e d i u m . A s i n g l es e e d e d 1 2 - m l a g a r l a y e r i n p l a s t i c p e t r i d i s h e s ( 2 0 b y1 0 0 mm) w a s u s e d t o e n h a n c e s e n s i t i v i t y .T h e s e r u m s a m p l e s w e r e a n a l y z e d a g a i n s t a s t a n -d a r d c u r v e p r e p a r e d i n p o o l e d h u m a n c o n t r o l s e r u m .T h e s t a n d a r d c u r v e r a n g e d f r o m 1 t o 3 . g / m l w i t h al i m i t o f d e t e c t i o n o f a p p r o x i m a t e l y 0 . 5 , u g / m l . Whenn e c e s s a r y , t h e s e r u m s a m p l e s w e r e d i l u t e d w i t hp o o l e d h u m a n c o n t r o l s e r u m t o a p p r o x i m a t e l y 2, u g / m l . T h e s t a n d a r d c u r v e ( 1 . 4 t o 4 . 0 , u g / m l ) f o r t h ea n a l y s i s o f u r i n e s a m p l e s w a s p r e p a r e d i n 1% p o t a s s i -um p h o s p h a t e b u f f e r ( p H 6 . 0 ) . A l l u r i n e s a m p l e s w e r ed i l u t e d a m i n i m u m o f 1 0 - f o l d w i t h 1% p o t a s s i u mp h o s p h a t e b u f f e r ( p H 6 . 0 ) t o e l i m i n a t e a n y s am p l ei n t e r f e r e n c e a n d , i f n e c e s s a r y , a d d i t i o n a l l y t o a p p r o x i -m a t e l y 2 , g / m l . T h e r e s u l t i n g l i m i t o f d e t e c t i o n i nu n d i l u t e d u r i n e w a s a p p r o x i m a t e l y 7 , u g / m l .E a c h s t a n d a r d c u r v e s a m p l e w a s p l a t e d i n t r i p l i c a t eo n e a c h o f n i n e a g a r p l a t e s . T h e s e r u m a n d u r i n es p e c i m e n s w e r e p l a t e d i n t r i p l i c a t e o n e a c h o f t h r e ea g a r p l a t e s . T h e t e s t a g a r p l a t e s w e r e t h e n i n c u b a t e d a t3 2 t o 3 5 C f o r a p p r o x i m a t e l y 1 8 h . T h e r e s u l t i n g z o n e so f i n h i b i t i o n w e r e r e a d b y a n a u t o m a t e d z o n e r e a d e r ,a n d t h e c a l c u l a t i o n s w e r e p e r f o r m e d b y a P D P - 8 Ec o m p u t e r h a r d - w i r e d t o t h e r e a d e r ( 6 ) . A l i n e a r r e g r e s -s i o n a n a l y s i s w a s p e r f o r m e d o n t h e l o g o f t h e c o n c e n -t r a t i o n o f s t a n d a r d s v e r s u s t h e z o n e d i a m e t e r . I n a l lb i o a s s a y s d e s c r i b e d i n t h i s p a p e r , s a m p l e s f o r w h i c ht h e i n i t i a l a s s a y i n d i c a t e d a v a l u e o u t s i d e t h e r an g e o ft h e s t a n d a r d c u r v e w e r e r e d i l u t e d , t o b r i n g t h e c o n c e n -t r a t i o n w i t h i n t h e r a n g e o f t h e s t a n d a r d c u r v e , a n dt h e n w e r e r e a s s a y e d .F r e s h s u l b a c t a m s t a n d a r d s w e r e p r e p a r e d i n c o n t r o ls e r u m o r 1% pH 6 . 0 b u f f e r a n d a n a l y z e d o n e a c h t e s td a y a s c o n t r o l s f o r t h e s e r u m a n d u r i n e a s s a y s , r e s p e c -t i v e l y . T h e m e a n r e c o v e r y f o r 1 4 f o r t i f i e d u r i n e c o n -

6 9 2


3/9

SULBACTAM PHARMACOKINETICS I N HUMANS 6 9 3t r o l s o v e r 8 a s s a y d a y s w a s 9 8 . 4 % w i t h a r e l a t i v es t a n d a r d d e v i a t i o n o f 1 . 4 % . T h e m e a n r e c o v e r y f o r 2 2f o r t i f i e d s e r u m c o n t r o l s o v e r 1 1 a s s a y d a y s w a s 9 9 . 5 %w i t h a r e l a t i v e s t a n d a r d d e v i a t i o n o f 2 . 3 % .A s s a y o f s u l b a c t a m : G C - M S . D u r i n g s t u d i e s i n w h i c hs u l b a c t a m w a s c o a d m i n i s t e r e d w i t h a n a n t i b i o t i c , t h em e t h y l e s t e r o f s u l b a c t a m w a s p r e p a r e d a n d a n a l y z e db y g a s c h r o m a t o g r a p h y w i t h m a s s s p e c t r o m e t r y d e t e c -t i o n ( G C - M S ) . To 0 . 5 0 m l o f s e r u m o r 3 0 , u l o f u r i n e ,1 0 0 , u o f a s o l u t i o n o f t h e s o d i u m s a l t o f p e n i c i l l a n i ca c i d ( C P - 1 2 , 9 4 3 ) , e q u i v a l e n t t o 0 . 0 4 mg o f f r e e a c i d p e rm l , w a s a d d e d a s a n i n t e r n a l s t a n d a r d . T h e m i x t u r ew a s a c i d i f i e d w i t h 0 . 5 m l o f 0 . 2 5 N H C I a n d e x t r a c t e dw i t h 5 m l o f e t h y l a c e t a t e . T h e e x t r a c t s w e r e m e t h y l a t -e d w i t h d i a z o m e t h a n e ( 1 1 ) . A f t e r m e t h y l a t i o n , t h ee x t r a c t s w e r e r e d u c e d i n v o l u m e t o 0 . 5 m l a n d s t o r e di n a f r e e z e r u n t i l t h e y w e r e i n j e c t e d i n t o t h e g a sc h r o m a t o g r a p h . P o r t i o n s ( 1 t o 5 p l ) o f t h e e x t r a c t sw e r e i n j e c t e d i n t o a F i n n i g a n 3 2 0 0 g a s c h r o m a t o g r a p h -m a s s s p e c t r o m e t e r w i t h c h e m i c a l i o n i z a t i o n a n d s p e -c i f i c i o n m o n i t o r i n g u n d e r t h e f o l l o w i n g c o n d i t i o n s :c o l u m n , 1 . 5 m b y 2 . 2 mm, 3% O V - 1 o n GCQ 6 0 / 8 0 ;c o l u m n t e m p e r a t u r e , 1 7 0 C ; s o u r c e t e m p e r a t u r e ,1 6 5 C ; c a r r i e r g a s , m e t h a n e ; i o n s o u r c e p r e s s u r e , 7 5 0p . m ; a t t e n u a t i o n , 1 0 - 8 ; f i l t e r , 0 . 5 . D e t e c t i o n w a s b ys p e c i f i c i o n m o n i t o r i n g : s u l b a c t a m ( m l e 2 0 6 ) a n d C P -1 2 , 9 4 3 ( m l e 2 4 4 ) .T h e r e t e n t i o n t i m e f o r t h e s u l b a c t a m p e a k ( m l e 2 0 6 )w a s a p p r o x i m a t e l y 6 0 s . T h e r e t e n t i o n t i m e f o r t h ei n t e r n a l s t a n d a r d p e a k ( p e n i c i l l a n i c a c i d , m l e 2 4 4 ) w a sa p p r o x i m a t e l y 2 5 s . S t a n d a r d c u r v e s p r e p a r e d b yf o r t i f i c a t i o n o f b l a n k s e r u m o r u r i n e w i t h a s o l u t i o n o fs u l b a c t a m i n e t h y l a c e t a t e ( 1 m g / 1 0 m l ) w e r e p r e p a r e di n p a r a l l e l w i t h t h e s a m p l e s . Q u a n t i t a t i o n w a s b yc o m p a r i s o n o f l o g R ( t h e r a t i o o f p e a k h e i g h t o fs u l b a c t a m t o p e a k h e i g h t o f t h e i n t e r n a l s t a n d a r d ) w i t ht h e l e a s t - s q u a r e s r e g r e s s i o n o f l o g c o n c e n t r a t i o n o fs t a n d a r d s v e r s u s l o g R o f s t a n d a r d s . S t a n d a r d c u r v e sw e r e i r j e c t e d a f t e r e v e r y s e t o f 1 0 t o 2 0 s a m p l e s . T h eGC-MS a s s a y w a s l i n e a r o v e r t h e r a n g e o f 0 . 1 , u g / m l t og r e a t e r t h a n 4 0 0 , L g / m l . T o e x a m i n e t h e r e p r o d u c i b i l i t ya n d p r e c i s i o n o f t h e a s s a y , t r i p l i c a t e s a m p l e s i n d o gs e r u m a n d u r i n e w e r e p r e p a r e d a n d a s s a y e d . T h ec o r r e l a t i o n c o e f f i c i e n t s o f l o g p e a k h e i g h t v e r s u s l o gc o n c e n t r a t i o n w e r e g r e a t e r t h a n 0 . 9 9 7 0 . T h e r e l a t i v es t a n d a r d d e v i a t i o n s w e r e b e t w e e n 2 . 1 a n d 8 . 9 % o . C o m -p a r i s o n o f p e a k h e i g h t s o f d r u g e x t r a c t e d f r o m d o gs e r u m , p l a s m a , a n d u r i n e a n d h u m a n s e r u m w i t h p e a kh e i g h t s o f d r u g p r e p a r e d i n e t h y l a c e t a t e i n d i c a t e d t h a tt h e e x t r a c t i o n p r o c e d u r e r e c o v e r e d e s s e n t i a l l y a l l o ft h e s u l b a c t a m a n d t h a t t h e a p p a r e n t e x t e n t o f r e c o v e r yw a s c o n s t a n t o v e r t h e r a n g e o f 0 . 1 t o g r e a t e r t h a n 1 0 0, u g / m l i n a l l m e d i a t e s t e d . F o r e x a m i n a t i o n o f i n t e r f e r -e n c e b y 3 - l a c t a m a n t i b i o t i c s , s t a n d a r d c u r v e s o f h u -man s e r u m f o r t i f i e d w i t h b e t w e e n 0 . 2 a n d 1 0 , u g o fs u l b a c t a m p e r m l , a l o n e a n d i n c o m b i n a t i o n w i t h 5 0 -, g / m l c o n c e n t r a t i o n s o f a m p i c i l l i n , a m o x i c i l l i n , p e n i -c i l l i n G , c e f o p e r a z o n e , o r c e p h a l o t h i n , w e r e a s s a y e df o r s u l b a c t a m . No s i g n i f i c a n t c h a n g e w a s p r o d u c e d i ne i t h e r t h e s l o p e o r i n t e r c e p t o f t h e s t a n d a r d c u r v e s b yt h e a d d i t i o n o f t h e a n t i b i o t i c . A l l o f t h e c o r r e l a t i o nc o e f f i c i e n t s w e r e a b o v e 0 . 9 9 6 . A d d i t i o n a l l y , a s s a y s o fa m p i c i l l i n a t 5 0 , u g / m l , c e f o p e r a z o n e a t 1 0 0 F g / m l ,c e f a z o l i n a t 1 0 0 , u g / m l , o r c e p h a l o t h i n a t 5 0 , g / m lp r o d u c e d n o d e t e c t a b l e r e s p o n s e c o r r e s p o n d i n g t oe i t h e r s u l b a c t a m o r t h e i n t e r n a l s t a n d a r d ( p e n i c i l l a n i ca c i d ) .

S t u d i e s w e r e c o n d u c t e d t o d e t e r m i n e t h e s t a b i l i t y o fs u l b a c t a m i n f r o z e n h u m a n s e r u m a n d u r i n e . F o r t i f i e ds u l b a c t a m s a m p l e s w e r e p r e p a r e d i n p o o l e d h u m a nc o n t r o l u r i n e a n d p o o l e d h u m a n c o n t r o l s e r u m a t 3 0 2a n d 2 . 0 , u g o f s u l b a c t a m p e r m l , r e s p e c t i v e l y , a n d w e r ea s s a y e d . T h e s a m p l e s w e r e t h e n s u b d i v i d e d , f r o z e n a ta p p r o x i m a t e l y - 6 0 C , a n d a s s a y e d p e r i o d i c a l l y . S u l -b a c t a m i n h u m a n s e r u m r e t a i n e d f u l l a c t i v i t y w h e ns t o r e d a t - 6 0 C f o r 6 w e e k s . S u l b a c t a m i n h u m a nu r i n e r e t a i n e d a t l e a s t 9 4 % o f i n i t i a l a c t i v i t y . A d d i t i o n -a l s t a b i l i t y s t u d i e s s h o w e d t h a t h u m a n s e r u m s a m p l e sf o r t i f i e d w i t h 2 o r 2 0 ; . g o f s u l b a c t a m p e r m l r e t a i n e d9 6 o r 9 8 % o f t h e i r i n i t i a l a c t i v i t y a f t e r 1 3 d a y s o fs t o r a g e a t - 2 0 C . H o w e v e r , s a m p l e s f o r t i f i e d w i t h 2 ,5 , o r 1 0 j . L g o f s u l b a c t a m p e r m l l o s t a p p r o x i m a t e l y 2 4 %o f t h e i r a c t i v i t y u p o n s t o r a g e a t - 1 0 C f o r 3 7 d a y s .T h e s e r e s u l t s i n d i c a t e t h a t s a m p l e s o f h u m a n s e r u m t ob e a s s a y e d f o r s u l b a c t a m s h o u l d b e s t o r e d a t o r b e l o w- 2 0 0 C .

A s s a y o f a m p i c i l l i n , p e n i c i l l i n G , a n d c e f o p e r a z o n e .A m p i c i l l i n , p e n i c i l l i n G , a n d c e f o p e r a z o n e c o n c e n t r a -t i o n s i n s e r u m a n d u r i n e w e r e d e t e r m i n e d b y a m i c r o -b i o l o g i c a l c y l i n d e r p l a t e t e c h n i q u e e s s e n t i a l l y i d e n t i c a lt o t h a t d e s c r i b e d i n t h e U n i t e d S t a t e s P h a r m a c o p o e i aXX ( 2 0 ) . T h e o r g a n i s m u s e d f o r t h e s e a s s a y s w a sM i c r o c o c c u s l u t e u s ATCC 9 3 4 1 a t a c o n c e n t r a t i o n o fa p p r o x i m a t e l y 1 0 7 o r g a n i s m s p e r m l i n A n t i b i o t i cM e d i u m C (BBL M i c r o b i o l o g y S y s t e m s ) f o r a m p i c i l l i na n d p e n i c i l l i n G o r M e d i u m A f o r c e f o p e r a z o n e . As i n g l e s e e d e d a g a r l a y e r o f a p p r o x i m a t e l y 1 2 m l i np l a s t i c p e t r i d i s h e s ( 2 0 b y 1 0 0 mm) w a s u s e d t oi m p r o v e s e n s i t i v i t y . C o m p e n s a t o r y s t a n d a r d c u r v e sf o r e a c h a n t i b i o t i c w e r e p r e p a r e d i n p o o l e d c o n t r o lh u m a n s e r u m . F o r a s s a y s o f d r u g i n u r i n e , s t a n d a r dc u r v e s w e r e p r e p a r e d i n 1% p o t a s s i u m p h o s p h a t eb u f f e r ( p H 6 . 0 ) . E a c h s t a n d a r d c u r v e c o n c e n t r a t i o nw a s p l a t e d i n t r i p l i c a t e o n e a c h o f n i n e a g a r p l a t e s .S e r u m a n d u r i n e s p e c i m e n s w e r e p l a t e d i n t r i p l i c a t e o ne a c h o f - t h r e e a g a r p l a t e s . A f t e r i n c u b a t i o n a t 3 2 t o3 5 C f o r a p p r o x i m a t e l y 1 8 h , z o n e s o f i n h i b i t i o n w e r er e a d b y t h e a u t o m a t e d z o n e r e a d e r a n d c a l c u l a t e d a sd e s c r i b e d a b o v e .A m p i c i l l i n c o n c e n t r a t i o n s i n t h e s e r u m s t a n d a r dc u r v e s r a n g e d f r o m 0 . 0 4 t o 0 . 1 4 , u g / m l , a n d t h e p e n i c i l -l i n G s t a n d a r d c u r v e s r a n g e d f r o m 0 . 0 5 t o 0 . 4 , u g / m l .T h e b u f f e r s t a n d a r d c u r v e s f o r a s s a y o f u r i n e s a m p l e sr a n g e d f r o m 0 . 0 3 t o 0 . 1 2 , u g o f a m p i c i l l i n p e r m l o r 0 . 0 3t o 0 . 2 0 , u g o f p e n i c i l l i n G p e r m l . I f n e c e s s a r y , s e r u ms a m p l e s w e r e d i l u t e d t o a p p r o x i m a t e l y t h e m i d p o i n t o ft h e a p p r o p r i a t e s t a n d a r d c u r v e w i t h p o o l e d h u m a nc o n t r o l s e r u m . A l l u r i n e s a m p l e s w e r e d i l u t e d a m i n i -m u m o f 1 0 - f o l d w i t h t h e 1% p h o s p h a t e b u f f e r t oe l i m i n a t e a n y s a m p l e i n t e r f e r e n c e s . T h e y w e r e t h e nd i l u t e d f u r t h e r , i f n e c e s s a r y , t o b r i n g t h e e x p e c t e da s s a y c o n c e n t r a t i o n n e a r t h e m i d p o i n t o f t h e s t a n d a r dc u r v e . D u r i n g t h e s t u d y o f t h e i n t e r a c t i o n o f a m p i c i l l i no r p e n i c i l l i n G a n d s u l b a c t a m i n h u m a n s ( d e s c r i b e db e l o w ) , t h e m e a n r e c o v e r i e s o f a m p i c i l l i n i n f o r t i f i e ds e r u m a n d u r i n e c o n t r o l s w e r e 9 8 a n d 1 0 0 % , r e s p e c -t i v e l y , w i t h r e l a t i v e s t a n d a r d d e v i a t i o n s o f 1 . 7 a n d2 . 7 % , r e s p e c t i v e l y . T h e m e a n r e c o v e r i e s f o r t h e p e n i -c i l l i n G s e r u m a n d u r i n e c o n t r o l s w e r e 1 0 0 a n d 97%w i t h r e l a t i v e s t a n d a r d d e v i a t i o n s o f 4 . 3 a n d 1 . 8 % ,r e s p e c t i v e l y .F o r t h e a s s a y o f c e f o p e r a z o n e , t h e s t a n d a r d c u r v e sr a n g e d f r o m 1 . 5 t o 6 p L g / m l i n s e r u m a n d 0 . 3 t o 1 . 2, u g / m l i n u r i n e . T h e l i m i t s o f s e n s i t i v i t y w e r e a p p r o x i -

V O L . 2 3 , 1 9 8 3


4/9

A N T I M I C R O B . A G E N T S C H E M O T H E R .m a t e l y 0 . 7 . g / m l i n s e r u m a n d , b e c a u s e o f t h e 1 0 - f o l dd i l u t i o n i n b u f f e r , 2 a g / m l i n u r i n e . F o r a t y p i c a lc e f o p e r a z o n e s t u d y t h e m e a n r e c o v e r y f o r 1 7 s e r u mc o n t r o l s o v e r 6 a s s a y d a y s w a s 1 0 1 % w i t h a r e l a t i v es t a n d a r d d e v i a t i o n o f 3 . 2 % o . T h e m e a n r e c o v e r y f o r 1 3u r i n e c o n t r o l s o v e r 6 a s s a y d a y s w a s 1 0 1 % w i t h ar e l a t i v e s t a n d a r d d e v i a t i o n o f 2 . 3 % .S i n c e a p r i m a r y p u r p o s e o f t h i s w o r k w a s t o e x a m -i n e t h e i n f l u e n c e o f s u l b a c t a m o n t h e k i n e t i c s o f , B -l a c t a m a n t i b i o t i c s , t h e p o s s i b l e i n t e r f e r e n c e o f s u l b a c -t a m i n t h e a b o v e a s s a y s w a s i n v e s t i g a t e d . E v e n w h e ns u l b a c t a m w a s a d d e d a t 1 0 t i m e s t h e l e v e l s o f a m p i c i l -l i n a n d p e n i c i l l i n G t o c o n t r o l s a m p l e s i n s e r u m , n oi n t e r f e r e n c e w a s d e t e c t e d i n e i t h e r o f t h e s e a s s a y s .S u l b a c t a m a l s o h a d n o e f f e c t o n t h e a s s a y s f o r c e f o p e r -a z o n e , e v e n w h e n t h e s u l b a c t a m c o n c e n t r a t i o n s w e r et w i c e t h o s e o f t h e c e f o p e r a z o n e . A d d i t i o n a l l y , 5 0 F g o fs u l b a c t a m p e r m l a l o n e p r o d u c e d n o r e s p o n s e i n t h ea s s a y f o r c e f o p e r a z o n e . T h e s e r e s u l t s w e r e e x p e c t e ds i n c e M . l u t e u s i s n o t k n o w n t o p r o d u c e a n y , B -l a c t a m a s e e n z y m e s .A s t u d y w a s c o n d u c t e d t o d e t e r m i n e t h e s t a b i l i t y o fc e f o p e r a z o n e i n h u m a n s e r u m a n d u r i n e u n d e r s e v e r a ls t o r a g e c o n d i t i o n s . C e f o p e r a z o n e s am p l e s w e r e p r e -p a r e d i n p o o l e d h u m a n c o n t r o l u r i n e a n d p o o l e dh u m a n c o n t r o l s e r u m a t 3 0 0 a n d 6 0 p , g o f c e f o p e r a z o n ep e r m l , r e s p e c t i v e l y , a n d w e r e a s s a y e d . T h e s a m p l e sw e r e t h e n s u b d i v i d e d i n t o i n d i v i d u a l t u b e s , s t o r e d a t 5 ,- 2 0 , o r - 6 0 C , a n d a s s a y e d p e r i o d i c a l l y . C e f o p e r a -z o n e i n s e r u m r e t a i n e d a t l e a s t 9 5 % o f i n i t i a l a c t i v i t ya f t e r 3 m o n t h s a t - 2 0 C a n d 1 0 l o o f i n i t i a l a c t i v i t ya f t e r 3 m o n t h s a t - 6 0 C . C e f o p e r a z o n e i n u r i n e w a sc o m p l e t e l y s t a b l e f o r 3 m o n t h s e v e n w h e n o n l y r e f r i g -e r a t e d a t 5 C , b u t t h e c e f o p e r a z o n e s e r u m s a m p l e sw e r e r e l a t i v e l y u n s t a b l e u n d e r t h i s c o n d i t i o n .A l l c l i n i c a l s a m p l e s f o r b i o a s s a y w e r e s t o r e d i n aR e v c o f r e e z e r a t - 6 0 0 C b e f o r e b e i n g a s s a y e d . A l lb i o a s s a y s w e r e c o m p l e t e w i t h i n 6 w e e k s . S a m p l e s f o rGC-MS a s s a y o f s u l b a c t a m w e r e s t o r e d a t - 2 0 C a n da s s a y e d w i t h i n 8 w e e k s o f r e c e i p t .Human s t u l e s . ( i ) S i n g l e d o s e . T o a s s e s s s i n g l e - d o s ep h a r m a c o k i n e t i c s , h e a l t h y m a l e v o l u n t e e r s w e r e g i v e nd o s e s o f 1 2 5 t o 1 , 0 0 0 mg o f s u l b a c t a m b y i n t r a m u s c u -l a r ( i . m . ) i n j e c t i o n o r 3 0 - m i n i n t r a v e n o u s ( i . v . ) i n f u -s i o n . S a m p l e s o f s e r u m a n d u r i n e f r o m e a c h v o l u n t e e rw e r e a s s a y e d f o r i n t a c t s u l b a c t a m b y b i o a s s a y .

( U ) M u l t i p e d o s e . T o a s s e s s t h e p o s s i b l e i n c r e a s e i nd r u g c o n c e n t r a t i o n s d u r i n g a m u l t i p l e - d o s e r e g i m e n ,h e a l t h y m a l e v o l u n t e e r s r e c e i v e d e i t h e r i . m . o r 3 0 - m i ni . v . d o s e s o f , 5 0 0 mg o f s u l b ac t a m e v e r y 6 h f o r 3 d a y s .S a m p l e s o f s e r u m w e r e o b t a i n e d a f t e r t h e f i r s t d o s ea n d a f t e r t h e s e c o n d d o s e o n d a y 3 . T h e s e r u m s a m p l e sw e r e a s s a y e d f o r s u l b a c t a m b y b i o a s s a y .I n t e r a c t i o n s t u d i e s . To a s s e s s t h e p o s s i b l e p h a r m a -c o k i n e t i c i n t e r a c t i o n o f s u l b a c t a m w i t h p e n i o i l l i n Ga n d a m p i c i l l i n , s i x h e a l t h y m a l e v o l u n t e e r s r e c e i v e d5 0 0 mg o f s u l b ac t am a l o n e , 5 0 0 mg o f p e n i c i H l i n Ga l o n e , a n d t h e c o m b i n a t i o n b y 3 0 - m i n i n f u s i o n s i n at h r e e - w a y c r o s s o v e r e x p e r i m e n t . S i m i l a r l y , a n o t h e rs e t o f s i x v o l u n t e e r s r e c e i v e d 5 0 0 mg o f s u l b ac t a ma l o n e , 5 0 0 mg o f p e n i c i l l i n G a l o n e , a n d t h e c o m b i n a -t i o n b y i . m . i n j e c t i o n . A t h i r d s e t o f s i x v o l u n t e e r sr e c e i v e d 5 0 0 mg o f s u l b a c t a m a l o n e , 5 0 mg o f a m p i c i l -l i n a l o n e , a n d t h e c o m b i n a t i o n b y i . v . b o l u s . A f t e re a c h d o s e , s e r u m a n d u r i n e s a m p l e s f r o m e a c h s u b j e c tw e r e a s s a y e d f o r s u l b a c t a m ( G C - M S ) , a m p i c i l l i n , o rp e n i c i l l i n G , a s a p p r o p r i a t e .

T o a s s e s s t h e p o s s i b l e p h a r m a c o k i n e t i c i n t e r a c t i o no f s u l b a c t a m a n d c e f o p e r a z o n e , h e a l t h y m a l e s u b j e c t sw e r e a d m i n i s t e r e d 2 g o f c e f o p e r a z o n e , a l o n e o r i nc o m b i n a t i o n w i t h 1 g o f s u l b a c t a m , b y 1 - h i . v . i n f u s i o no r i . v . b o l u s i n j e c t i o n t w i c e a d a y f o r 5 d a y s . S e r u ma n d u r i n e s a m p l e s w e r e o b t a i n e d o n d a y s 1 a n d 5 a n da n a l y z e d f o r s u l b a c t a m ( G C - M S ) a n d c e f o p e r a z o n e .

. S e r u m c o n c e n t r a t i o n s o f s u l b a c -t a m o r t h e c o a d m i n i s t e r e d I l - l a c t a m a n t i b i o t i c w e r ef i t t e d t o e q u a t i o n 1 b y u s i n g a n i t e r a t i v e l e a s t - s q u a r e sc o m p u t e r p r o g r a m a n d i n t e r p r e t e d a s o n e - o r t w o -c o m p a r t m e n t p h a r m a c o k i n e t i c m o d e l s b y s t a n d a r dm e t h o d s ( 1 0 , 2 1 ) .C t = A e - a + B e - 3 t ( 1 )

I n a l l c a s e s , m o r e c o m p l e x m o d e l s d i d n o t p r o v i d e as u b s t a n t i a l i m p r o v e m e n t i n t h e f i t o f t h e m o d e l t o t h ed a t a . T h e g o o d n e s s o f f i t ( r 2 ) u s u a l l y e x c e e d e d 0 . 9 6 .A r e a s u n d e r t h e s e r u m c o n c e n t r a t i o n v e r s u s t i m ec u r v e s ( A U C s ) f o r c o m p a r i s o n s o f t h e a v a i l a b i l i t y o fd o s e s o f s u l b a c t a m w e r e c a l c u l a t e d b y t h e t r a p e z o i d a lm e t h o d . W h e r e a p p r o p r i a t e , t h e y w e r e e x t r a p o l a t e d t oi n f i n i t y : A U C O , . = A U C O , + C , / , w h e r e 1 i s t h es l o p e o f I n C v e r s u s t i m e f o r t h e l a s t t h r e e t o f i v e t i m ep o i n t s . H a l f - l i v e s w e r e c a l c u l a t e d a s 0 . 6 9 3 / 3 .R e n a l c l e a r a n c e s ( C l r ) w e r e c a l c u l a t e d f r o m A U C O .f r o m t h e b e s t f i t o f t h e d a t a t o t h e c u r v e a f t e r 3 0 - m i ni . v . i n f u s i o n s a n d t h e r e c o v e r y o f d r u g i n u r i n e : C l , =X U l A U C O . , w h e r e Xu i s t h e a m o u n t o f d r u g r e c o v -e r e d i n u r i n e .F u r t h e r m o r e , A U C O , = A 1 / a + B 1 / l , w h e r e A 1 a n dB 1 a r e A a n d B f r o m e q u a t i o n 1 c o r r e c t e d f o r 3 0 - m i ni n f u s i o n .T o t a l c l e a r a n c e ( C I T ) o f d r u g f r o m b l o o d w a s c a l c u -l a t e d f r o m AUC


5/9

SULBACTAM PHARMACOKINETICS I N HUMANS 6 9 55 0

\ * I Mman + S . D .~20

110

' I .

A2

0.5*0 1 2 3 4 5 6T i m e ( h o u r s p o s t d o s )

F I G . 1 . S e r u m c o n c e n t r a t i o n s o f s u l b a c t a m a f t e r 3 0 - m i n i n f u s i o n s t o men ( f o u r s u b j e c t s per d o s e r e g i m e n ) .S . D . , S t a n d a r d d e v i a t i o n .

m i n ( 2 2 ) . T h e p a r a m e t e r s are a l s o s i m i l a r t ot h o s e o f a m p i c i l l i n : t 1 n = 1 . 3 1 ; V , = 1 2 . 3 l i t e r s ;V b = 1 8 . 5 l i t e r s ; f = 0 . 6 6 ( 1 2 ) ; C , , = 2 9 . 0 , u g / m lf o r c o n t i n u o u s i n f u s i o n o f 5 0 0 , u g / h ( 1 9 ) . T h er e s u l t s s h o w t h a t p a r e n t e r a l s u l b a c t a m a c t s l i k ea t y p i c a l p e n i c i l l i n i n h u m a n s . S u l b a c t a m h a sa l s o b e e n a d m i n i s t e r e d t o h u m a n s b y b o l u s i . v .i n j e c t i o n s : 5 0 0 mg p r o d u c e d a p e a k s e r u m c on-c e n t r a t i o n o f a p p r o x i m a t e l y 3 2 , u g / m l .A f t e r i . m . a d m i n i s t r a t i o n o f 5 0 0 mg o f s u l b a c -t a m , t h e mean p e a k s e r u m c o n c e n t r a t i o n wa s 1 3

, g / m l ; 1 , 0 0 0 mg p r o d u c e d a p e a k o f 2 8 p , g / m l( F i g . 2 ) . T h e e l i m i n a t i o n h a l f - l i f e wa s a p p r o x i -m a t e l y 1 . 2 h . C o m p a r i s o n o f AUCs a n d u r i n a r yr e c o v e r i e s w i t h t h o s e o b t a i n e d a f t e r i . v . d o s e si n d i c a t e d t h a t t h e i . m . d o s e was c o m p l e t e l yb i o a v a i l a b l e .T h e o n l y s i d e e f f e c t o b s e r v e d a f t e r t h e paren-t e r a l a d m i n i s t r a t i o n o f s u l b a c t a m t o h u m a n s wasp a i n a t t h e s i t e o f i . m . i n j e c t i o n . T h e p a i ns u b s i d e d r a p i d l y a n d d i s ap p e a r e d c o m p l e t e l yw i t h i n 1 h . I n t h e s e s t u d i e s , a p p r o x i m a t e l y 70%TABLE 1 . P h a r m a c o k i n e t i c p a r a m e t e r s o f s u l b a c t a m i n h u m a n s : t w o - c o m p a r t m e n t o p e n m o d e l , 3 0 - m i n i . v .i n f u s i o n

C b C o S u l b a c t a m C l e a r a n c e ( m l / m i n )u l b a c t a m d o s e N t / v . V D C , , A U C O - . rcoer i n( m n g ) N ( l t e r s ) ( l i t e r s ) ' ( g / m l ) ( I & g . h / n i ) u r i n e ( m i g ) R e n a l T o t a l N o n r e n a l1 2 5 1 0 . 8 9 2 7 . 0 6 d 1 1 . 9 5 . 9 9 8 . 2 2 7 7 . 4 3 5 7 . 1 7 5 . 72 5 0 1 1 . 0 9 5 . 7 9 1 9 . 9 8 0 . 2 9 1 1 . 5 1 9 . 8 1 8 8 . 6 1 5 8 . 8 2 1 0 . 4 5 1 . 65 0 0 4 0 . 9 6 1 2 . 9 6 2 4 . 0 0 0 . 5 4 3 1 . 1 2 8 . 9 3 6 2 . 6 2 1 1 . 8 2 7 0 . 9 7 4 . 61 , 0 0 0 4 0 . 9 5 1 1 . 3 4 e 2 1 . 8 1 0 . 5 2 6 4 . 1 6 6 . 4 7 8 4 . 6 f 2 0 4 . 1 2 5 4 . 0 5 4 . 0

Mean ( a l l d o s e s ) 0 . 9 7 1 1 . 7 3 2 2 . 8 2 0 . 5 1 7 5 . 5 % o f d o s e 2 0 3 . 8 2 6 6 . 3 6 5 . 3S . D . ( a l l d o s e s ) 0 . 1 0 3 . 5 6 3 . 0 7 0 . 1 3 5 . 5 % 4 4 . 4 4 7 . 4 1 7 . 7a F r a c t i o n o f d r u g i n c e n t r a l c o m p a r t m e n t i n p o s t d i s t r i b u t i v e p h a s e ( = P / k l o ) .C a l c u l a t e d ( = k o / k l o V B ) .F r o m f i t o f e q u a t i o n 1 t o t h e d a t a a n d c o r r e c t e d f o r 3 0 - m i n i n f u s i o n .d O n e c o m p a r t m e n t ( = 0 ) .I Mean o f t h r e e ; o n e s u b j e c t c o u l d o n l y b e f i t t e d t o a o n e - c o m p a r t m e n t m o d e l .f Mean o f t h r e e ; n o u r i n e s a m p l e w a s o b t a i n e d f r o m o n e s u b j e c t .

V O L . 2 3 , 1 9 8 3


6/9

A N T I M I C R O B . A G E N T S C H E M O T H E R .

E ~ 2 01 1 0. 5

5

82

0 . 50 1 2 3 4 5 6

T i m e ( h o u r s p o s t i n j e c t i o n )F I G . 2 . S e r u m c o n c e n t r a t i o n s o f s u l b a c t a m a f t e r i . m . i n j e c t i o n s t o men ( f o u r s u b j e c t s p e r d o s e r e g i m e n ) .M e a n s t a n d a r d d e v i a t i o n ( S . D . ) o n e - s i d e d w h e r e n e c e s s a r y t o a v o i d c o n f u s i o n .

o f a p a r e n t e r a l d o s e o f s u l b a c t a m w a s e x c r e t e di n t h e u r i n e b e t w e e n 0 a n d 6 h , w i t h a n a d d i t i o n a lr e c o v e r y o f 5% b e t w e e n 6 a n d 1 2 h p o s t d o s e .T h e u r i n a r y r e c o v e r y d a t a a f t e r t h e 3 0 - m i n i . v .i n f u s i o n s w e r e a n a l y z e d i n m o r e d e t a i l ( T a b l e 1 ) .T h e r e n a l c l e a r a n c e w a s a p p r o x i m a t e l y 2 0 4m l / m i n a n d w a s n o t d o s e d e p e n d e n t . T h e t o t a lc l e a r a n c e o f d r u g f r o m t h e s e r u m w a s 2 6 6m i / m n . T h e n o n r e n a l c l e a r a n c e w a s 6 5 m / m i n .M u l t i p l e - d o s e s t u d y . A f t e r m u l t i p l e d o s e s o fs u l b a c t a m b y 3 0 - m i n i . v . i n f u s i o n o r i . m . i n j e c -t i o n s o f 5 0 0 mg e v e r y 6 h f o r 3 d a y s , n os i g n i f i c a n t c h a n g e s w e r e o b s e r v e d i n e i t h e rAUCs o r p e a k s e r u m c o n c e n t r a t i o n s b e t w e e nd o s e 1 a n d d o s e 1 0 ( F i g . 3 ) .C o a d m i n s t r a t i o n s t u d i e s . T h e p h a r m a c o k i n e t -i c i n t e r a c t i o n o f s u l b a c t a m w i t h s e v e r a l 1 - l a c t a ma n t i b i o t i c s w a s e x a m i n e d i n h u m a n s . O n l y m i n o rc h a n g e s i n s e r u m c o n c e n t r a t i o n s o r u r i n a r y r e -c o v e r i e s o f s u l b a c t a m w e r e o b s e r v e d a f t e r a d -m i n i s t r a t i o n o f 5 0 0 mg o f s u l b a c t am a l o n e a n dw i t h 5 0 0 mg o f p e n i c i l l i n G b y 3 0 - m i n i . v .i n f u s i o n o r i . m . i n j e c t i o n o r w i t h 5 0 0 a m p i c i l l i nb y i . v . b o l u s ( F i g . 4 a n d T a b l e 2 ) . S i m i l a r l y , o n l ym i n o r c h a n g e s i n t h e s e r u m c o n c e n t r a t i o n s o ru r i n a r y r e c o v e r i e s o f p e n i c i l l i n G o r a m p i c i l l i nw e r e o b s e r v e d u p o n c o a d m i n i s t r a t i o n o f s u l b a c -t a m ( F i g . 4 a n d T a b l e 2 ) . No s i g n i f i c a n t c h a n g e si n t h e a p p a r e n t v o l u m e s o f d i s t r i b u t i o n o f t h ec e n t r a l c o m p a r t m e n t o r f , w e r e o b s e r v e d , o w i n gd u e t o c o a d m i n i s t r a t i o n o f s u l b a c t a m a n d p e n i -c i l l i n G o r a m p i c i l l i n .

S u l b a c t a m w a s a l s o c o a d m i n i s t e r e d w i t h c e f o -p e r a z o n e . C o a d m i n i s t r a t i o n o f 1 - g d o s e s o f s u l -b a c t a m w i t h 2 - g d o s e s o f c e f o p e r a z o n e , e i t h e rb y 1 - h i n f u s i o n o r i . v . b o l u s i n j e c t i o n , t w i c e a

3 0 0 I V d a f t2 0 o I M d t a b-Donda t1 1 0 - o t

1 t R

2 3Tim ( h o u r s p o s t d o s )

F I G . 3 . Mean s e r u m c o n c e n t r a t i o n s o f s u l b a c t a ma f t e r i . v . o r i . m . a d m i n i s t r a t i o n o f 5 0 0 mg e v e r y 6 h f o r3 d a y s t o t h r e e men p e r d o s e r e g i m e n .

6 % F OU L DS ET A L .


7/9

SULBACTAM PHARMACOKINETICS I N HUMANS 6 9 7

2 0

a . d e w - 01gmpnidin G+ 5 0 0 mg s d b a _ n , I N5 _

2 P G

0 n G + GorI ' 4 ?0 2 4 6 8

1 0

5

2

0 . 5

b . d o s - 5 0 0 m g p e n i c i l n G+ 5 0 0 i gu m e t a n , 3 0 m i nI V h n f u s m

' x P e n G + S u l b e m t a n\ 'Pm G \ %

I 4 I ID 2 4 6 8

3 0

1 0

5-

2 -

Sui.ctun+PenG'1-

0 . 5

0 . 1 2 4 6 b 80 2 4 8 - 8

4 0

2 0

1 0

5

2

0 o 5

9 ' 4 Xa 8 ~ ~ ~ ~ ~ 1 %

Sul % * m

4 6 8

T u n e (ho post d o s )F I G . 4 . I n t e r a c t i o n o f s u l b a c t a m w i t h p e n i c i l l i n G o r a m p i c i l l i n . Mean ( N = 6 ) c o n c e n t r a t i o n s a f t e r 5 0 0 mg o fe a c h c o m p o n e n t wa s a d m i n i s t e r e d a l o n e o r i n c o m b i n a t i o n . ( ) C o n c e n t r a t i o n o f d r u g a l o n e ; ( - - - - )c o n c e n t r a t i o n i n c o m b i n a t i o n .

d a y f o r 5 d a y s , d i d n o t s i g n i f i c a n t l y a f f e c t t h ep e a k s e r u m c o n c e n t r a t i o n , A U C s , or u r i n a r yr e c o v e r i e s o f c e f o p e r a z o n e ( T a b l e 2 ) . F u r t h e r -more, n o m a j o r a c c u m u l a t i o n o f c e f o p e r a z o n e o rs u l b a c t a m was o b s e r v e d d u r i n g e i t h e r s t u d y .

DISCUSSIONT h e p h a r m a c o k i n e t i c s o f s u l b a c t a m i n h u m a n s

are s i m i l a r t o t h o s e o f a m p i c i l l i n o r a m o x i c i l l i n ,w i t h a h a l f - l i f e o f a p p r o x i m a t e l y 1 h . The p r i n c i -p a l mode o f e l i m i n a t i o n i s e x c r e t i o n i n u r i n e w i t ha r e n a l c l e a r a n c e o f a p p r o x i m a t e l y 2 0 4 m l / m i n , av a l u e s i m i l a r t o t h a t r e p o r t e d e l s e w h e r e f o rs u l b a c t a m a n d a m p i c i l l i n ( 5 ) . An a d d i t i o n a l s i m i -l a r i t y t o t h e f - l a c t a m a n t i b i o t i c s i s t h e i n c r e a s e

i n t h e h a l f - l i f e o f s u l b a c t a m o f a p p r o x i m a t e l y40% i n h u m a n s d u e t o a p r i o r d o s e o f p r o b e n e c i d( V . A . C a i n e , K . K . H o l m e s , G . F o u l d s , a n dH . H . H a n d s f i e l d , A b s t r . A n n u . M e e t . Am. S o c .M i c r o b i o l . 1 9 8 1 , A 7 2 , p . 1 3 ) , a response s i m i l a rt o t h a t f o r a m p i c i l l i n ( 7 , 1 3 ) o r p e n i c i l l i n G ( 2 ) .T h i s res p o n se s u g g e s t s t h a t s u l b a c t a m i s e x c r e t -e d b y t h e same m e c h a n i s m i n t h e k i d n e y , i . e . ,m a i n l y t u b u l a r s e c r e t i o n ( 3 ) . M u l t i p l e d o s i n g a tr a t e s as h i g h as 5 0 0 mg every 6 h ( i . m . ) o r 1 gt w i c e a d a y ( 1 h i n f u s i o n s o r i . v . b o l u s ) d o e s n o tappear t o l e a d t o a c c u m u l a t i o n o f d r u g a s i n d i -c a t e d b y a n i n c r e a s e i n p e a k s e r u m c o n c e n t r a -t i o n s o r AUCs. C o a d m i n i s t r a t i o n o f s u l b a c t a mappears t o h a v e very l i t t l e e f f e c t on t h e p h a r m a -c o k i n e t i c s o f a m p i c i l l i n , p e n i c i l l i n G , o r c e f o p e r -

c . d o a - S W n i g a n m p i c l l i n+ S 0 0 m g n _ b e t n , I V b o l u s

III sI

E iI

V o w . 2 3 , 1 9 8 3


8/9

TABLE 2 . Mean A U C s , p e a k s e r u m c o n c e n t r a t i o n s , a n d u r i n a r y r e c o v e r i e s o f s u l b a c t a m a n d 3 - l a c t a ma n t i b i o t i c s a f t e r a d m i n i s t r a t i o n a l o n e o r i n c o m b i n a t i o n t o h e a l t h y s u b j e c t sD o s e M e a n v a l u e

N o . o f D r u g P e a kR o u t e D r u g a ( m g ) s u b j e c t s a s s a y e d AU C c o n c n R e c o v e r y

3 0 - m i n i . v . S U L 5 0 0 6 S U L 3 4 . 4 2 3 . 3 7 2 . 9S U L l 5 0 0 S U L 3 6 . 0 2 8 . 4 7 7 . 8PG 5 0 0 1 6 PG 1 8 . 6 2 2 . 5 8 0 . 8PG 5 0 0 6 PG 1 6 . 0 1 6 . 6 8 6 . 1i . m . S U L 5 0 0 6 S U L 3 5 . 5 1 4 . 2 7 6 . 5S U L 5 0 0 1 S U L 4 3 . 1 1 1 . 1 9 7 . 4PG 5 0 0 J 6 PG 1 4 . 6 b 4 . 6 8 7 6 . 9PG 5 0 0 6 PG 1 8 . 2 4 . 6 2 6 8 . 1i . v . b o l u s S U L 5 0 0 6 S U L 2 9 . 6 3 1 . 8 1 0 9 . 5{ S U L 5 0 0 1 S U L 3 6 . 6 3 0 . 4 8 9 . 2AMP 5 0 0 6 AMP 2 4 . 7 2 3 . 2 5 9 . 9AMP 5 0 0 6 AMP 3 0 . 3 2 7 . 6 6 4 . 2

1 - h i . v . , d o s e CF 2 , 0 0 0 2 4 CF 3 8 1 . 0 1 7 6 . 0 1 7 . 81 CF 2 , 0 0 0 2 4 CF 3 7 8 . 0 1 6 8 . 0 1 5 . 5S U L 1 , 0 0 0 S U L 5 3 . 5 3 8 . 3 3 8 . 91 - h i . v . , t . i . d . , c CF 2 , 0 0 0 2 4 CF 4 0 3 . 0 1 5 9 . 0 1 8 . 3d a y J CF 2 , 0 0 0 1 2 4 CF 3 9 0 . 0 1 5 9 . 0 1 5 . 9i - S U L 1 , 0 0 0 1 J S U L 5 0 . 2 3 5 . 2 4 6 . 8i . v . b o l u s , CF 2 , 0 0 0 2 4 CF 4 4 9 . 0 2 6 6 . 0 2 4 . 1d o s e 1 CF 2 , 0 0 0 2 4 CF 4 3 9 . 0 2 5 4 . O d 2 5 . 2S U L 1 , 0 0 0 S U L 6 9 . 9 7 6 . 0 1 0 1 . 0i . v . b o l u s , CF 2 , 0 0 0 2 4 CF 4 3 8 2 7 6 1 5 . 9t . i . d . , d a y 5 I CF 2 , 0 0 0 1 2 4 CF 4 6 1 2 8 2 1 8 . 6i S U L 1 , 0 0 0 1 S U L 6 7 . 3 7 7 . 6 9 2 . 4a S U L , S u l b a c t a m ; P G , p e n i c i l l i n G ; AMP, a m p i c i l l i n ; C F , c e f o p e r a z o n e . B r a c e s i n d i c a t e c o a d m i n i s t r a t i o n o fi n d i c a t e d d o s e .b . d T h e s e p a i r s o f v a l u e s w e r e d i f f e r e n t ( p a i r e d t t e s t , t w o - t a i l e d , P < 0 . 0 5 ) .c t . i . d . , T h r e e d o s e s p e r d a y .

a z o n e , s u g g e s t i n g t h a t c o a d m i n i s t r a t i o n o f s u l -b a c t a m w i l l n o t a f f e c t t h e u s u a l d o s i n g r e g i m e n sf o r t h e s e P - l a c t a m a n t i b i o t i c s .S u l b a c t a m a p p e a r s t o e q u i l i b r a t e r a p i d l y b e -t w e e n t h e s e r u m a n d t h e p e r i p h e r a l c o m p a r t -m e n t . T h e a p p a r e n t v o l u m e o f d i s t r i b u t i o n o f t h ec e n t r a l c o m p a r t m e n t o f 9 t o 1 6 l i t e r s i s i n t h er a n g e o f t o t a l e x t r a c e l l u l a r f l u i d i n h u m a n s ( a p -p r o x i m a t e l y 1 5 l i t e r s ) a n d s u g g e s t s t h a t s u l b a c -t a m i s w i d e l y d i s t r i b u t e d i n t h e e x t r a c e l l u l a rf l u i d . F u r t h e r m o r e , t h e t o t a l a p p a r e n t v o l u m e o fd i s t r i b u t i o n o f b e t w e e n 1 9 a n d 2 8 l i t e r s i s o v e rh a l f t h a t o f t h e t o t a l b o d y f l u i d , a p p r o x i m a t e l y4 0 l i t e r s i n a 7 0 - k g h u m a n , s u g g e s t i n g t h a t s u l -b a c t a m may b e w i d e l y d i s t r i b u t e d i n t o t h e t i s -s u e s .

ACKNOWLEDGMENTSWe a c k n o w l e d g e t h e t e c h n i c a l a s s i s t a n c e o f R . H . A l l e n ,D . R . B r e n n e n , A . H . K e n n e d y , a n d G . H . K e e l e r .

LITERATURE CITED1 . A s w a p o k e e , N . , a n d H . C . N e u . 1 9 7 8 . A s u l f o n e , - l a c t a mc o m p o u n d w h i c h a c t s a s a , - l a c t a m a s e i n h i b i t o r . J . A n t i -b i o t . 3 1 : 1 2 3 8 - 1 2 4 4 .2 . B o g e r , W. P . , J . 0 . B e a t t y , F . W. P i t t s , a n d H . F . F l i p p i n .

1 9 5 0 . I n f l u e n c e o f a new b e n z o i c a c i d d e r i v a t i v e on t h em e t a b o l i s m o f p a r a - a m i n o s a l i c y c l i c a c i d ( P A S ) a n d p e n i -c i l l i n . A n n . I n t e r n . M e d . 3 3 : 1 8 - 3 1 .3 . B r a z e a u , P . 1 9 7 0 . I n h i b i t i o n o f t u b u l a r t r a n s p o r t o f o r g a n i cc o m p o u n d s , p . 8 8 8 - 8 8 9 . I n L . S . Goodman a n d A . G i l m a n( e d . ) , T h e p h a r m a c o l o g i c a l b a s i s o f t h e r a p e u t i c s , 4 t h e d .T h e M a c m i l l a n C o . , New Y o r k .4 . B r e n n e r , D . G . , J . R . K n o w l e s , a n d G . R D e . 1 9 8 1 . P e n i c i l -l a n i c a c i d s u l f o n e : a n u n e x p e c t e d i s o t o p e e f f e c t i n t h ei n t e r a c t i o n o f 6 a - a n d 6 , B - m o n o d e u t e r o a n d o f t h e 6 , 6 -d i d e u t e r o d e r i v a t i v e s w i t h t h e RTEM , - l a c t a m a s e f r o mE s c h e r i c h i a c o l i . B i o c h e m i s t r y 2 0 : 3 6 8 0 - 3 6 8 7 .5 . B r o w n , R . N . , R . W i s e , J . M. A n d r e w s , a n d J . H a n c o x .1 9 8 2 . C o m p a r a t i v e p h a r m a c o k i n e t i c s a n d t i s s u e p e n e t r a -t i o n o f s u l b a c t a m a n d a m p i c i l l i n a f t e r c o n c u r r e n t i n t r a v e -n o u s a d m i n i s t r a t i o n . A n t i m i c r o b . A g e n t s C h e m o t h e r .2 1 : 5 6 5 - 5 6 7 .6 . D a r d a s , R . B . , J . H . P e r r y , Z . A . C o l e S , a n d C . G . I w a n -i c k i . 1 9 7 3 . A u t o m a t e d p l a t e d i f f u s i o n z o n e m e a s u r e m e n ta n d c o m p u t e r i z e d d a t a h a n d l i n g . B u l l . P a r e n t e r a l D r u gA s s o c . 2 7 : 1 8 5 - 1 9 4 .7 . E i c k h o f f , T . C . , J . W. K i d a k , M. F n l a n d , a n d C . W U c o x .1 9 6 5 . S o d i u m a m p i c i l l i n : a b s o r p t i o n a n d e x c r e t i o n o fi n t r a m u s c u l a r a n d i n t r a v e n o u s d o s e s i n n o r m a l y o u n gm e n . Am. J . M e d . S c i . 2 4 9 : 1 6 3 - 1 7 1 .8 . E n g l s h , A . R . , J . A . R e t s e m a , A . E . G i r a r d , J . E . L y n c h ,a n d W. E . B a r t h . 1 9 7 8 . C P - 4 5 , 8 9 9 , a b e t a - l a c t a m a s e i n h i b -i t o r t h a t e x t e n d s t h e a n t i b a c t e r i a l s p e c t r u m o f b e t a - l a c -t a m s : i n i t i a l b a c t e r i o l o g i c a l c h a r a c t e r i z a t i o n . A n t i m i c r o b .A g e n t s C h e m o t h e r . 1 4 : 4 1 4 - 4 1 9 .9 . F u , K . P . , a n d H . C . N e u . 1 9 7 9 . C o m p a r a t i v e i n h i b i t i o n o fP - l a c t a m a s e s b y n o v e l P - l a c t a m c o m p o u n d s . A n t i m i c r o b .

6 9 8 FOULDS E T A L . A N T I M I C R O B . A G E N T S C H E M O T H E R .


9/9

SULBACTAM PHARMACOKINETICS I N HUMANS 6 9 9A g e n t s C h e m o t h e r . 1 5 : 1 7 1 - 1 7 6 .1 0 . G I b a l d i , M . , a n d D . P e r r i e r . 1 9 7 5 . P h a r m a c o k i n e t i c s .M a r c e l D e k k e r , I n c . , New Y o r k .1 1 . G r u n w a l d , C . , M. V e n d r e l l , a n d B . B . S t o w e . 1 9 6 7 . E v a l u -a t i o n o f gas a n d o t h e r c h r o m a t o g r a p h i c s e p a r a t i o n s o fi n d o l i c m e t h y l e s t e r s . A n a l . B i o c h e m . 2 0 : 4 8 4 - 4 9 4 .

1 2 . J u s k o , W. J . , G . P. L e w i s , a n d G . W. S c h m i t t . 1 9 7 3 .A m p i c i l l i n a n d h e t a c i l l i n p h a r m a c o k i n e t i c s i n n o r m a l a n da n e p h r i c s u b j e c t s . C l i n . P h a r m a c o l . T h e r . 1 4 : 9 0 - 9 9 .1 3 . K a m p n a n n , J . , F . L i n d a h l , J . M. H a n s e n , a n d K . S e r s -b a e k - N i e l s e n . 1 9 7 3 . E f f e c t o f p r o b e n e c i d o n t h e e x c r e t i o no f a m p i c i l l i n i n h u m a n b i l e . B r . J . P h a r m . 4 7 : 7 8 2 - 7 8 6 .1 4 . K e m a l , C . , a n d J . R . K n o w l e s . 1 9 8 1 . P e n i c i l l a n i c a c i ds u l f o n e : i n t e r a c t i o n w i t h RTEM P - l a c t a m a s e f r o m E s c h e -r i c h i a c o l i a t d i f f e r e n t p H v a l u e s . B i o c h e m i s t r y 2 0 : 3 6 8 8 -3 6 9 5 .1 5 . L a b i a , R . , V . L e l i e v r e , a n d J . P e d u z z i . 1 9 8 0 . I n h i b i t i o nk i n e t i c s o f t h r e e R - f a c t o r - m e d i a t e d , - l a c t a m a s e s b y a new1 - l a c t a m s u l f o n e ( C P - 4 5 , 8 9 9 ) . B i o c h i m . B i o p h y s . A c t a6 1 1 : 3 5 1 - 3 5 7 .1 6 . N e u , H . C . 1 9 5 4 . T h e r o l e o f b e t a - l a c t a m a s e s i n t h e

r e s i s t a n c e o f g r a m - n e g a t i v e b a c t e r i a t o p e n i c i l l i n a n dc e p h a l o s p o r i n d e r i v a t i v e s . I n f e c t . D i s . R e v . 1 1 : 1 3 3 - 1 4 9 .1 7 . R e t s e m a , J . A . , A . R . E n g l i s h , a n d A . E . G i r a r d . 1 9 8 0 .C P - 4 5 , 8 9 9 i n c o m b i n a t i o n w i t h p e n i c i l l i n o r a m p i c i l l i na g a i n s t p e n i c i l l i n - r e s i s t a n t S t a p h y l o c o c c u s , H a e m o p h i l u si n f l u e n z a e , a n d B a c t e r o i d e s . A n t i m i c r o b . A g e n t s Chemo-t h e r . 1 7 : 6 1 5 - 6 2 2 .1 8 . R i c h m o n d , M. H . , a n d R . B . S y k e s . 1 9 7 3 . T h e P - l a c t a -m a ses o f g r a m - n e g a t i v e b a c t e r i a a n d t h e i r p o s s i b l e p h y s -i o l o g i c a l r o l e . A d v . M i c r o b i o l . P h y s i o l . 9 : 3 1 - 8 8 .1 9 . T a u n o , S . B . , L . D . J o h n s o n , J . L . B r o d i e , a n d W. M. M.K i r b y . 1 9 6 6 . C o m p a r a t i v e b l o o d l e v e l s o f h e t a c i l l i n , a m p i -c i l l i n a n d p e n i c i l l i n G . N . E n g l . J . M e d . 2 7 5 : 6 3 5 - 6 3 9 .2 0 . U n i t e d S t a t e s P h a r m a c o p o e i a . 1 9 8 0 . 2 0 t h e d . Mack P u b -l i s h i n g C o . , E a s t o n , P a .2 1 . W a g n e r , J . G . 1 9 7 5 . F u n d a m e n t a l s o f c l i n i c a l p h a r m a c o -k i n e t i c s . D r u g I n t e l l i g e n c e P u b l i c a t i o n s , I n c . , H a m i l t o n ,H i .2 2 . Z a r o w n y , D . , R . O g v i v l e , D . T a m b l y n , C . M a c L e o d , a n d J .R u e d y . 1 9 7 4 . P h a r m a c o k i n e t i c s o f a m o x i c i l l i n . C l i n .P h a r m . T h e r . 1 6 : 1 0 4 5 - 1 0 5 1 .

V O L . 2 3 , 1 9 8 3

Documents

Antimicrob. Agents Chemother. 1983 Foulds 692 9