ORIGINAL CONTRIBUTION
Parenteral Cephalothin Therapy for Pelvic Gonococcal Infections Michael C. Tomlanovich, MD Richard M. Nowak, MD Tom Madhavan, MD Keith H. Burch, MD Evelyn J. Fisher, MD Eugene Mezger, MD Edward L. Quinn, MD Wadid Berzi, MD Detroit, Michigan
The efficacy of intravenous cephalothin was studied prospectively in 20 patients with acute pelvic inflammatory disease, all of whom presented with lower abdominal pain, cervical and adnexal tenderness, fever, and leukocytosis. Blood, cervical, and cul-de-sac cultures were obtained on admission. The latter was transported anaerobically and inoculated in routine and prereduced medium. Transgrow medium with trimethoprim was used for endocervical cultures. Neisseria gonorrhoeae was isolated from the endocervix in 15 patients and from the culde-sac and cervix in three. Anaerobic organisms were also isolated from the culde-sac in four patients. All received intravenous cephalothin, 2 gm every four hours for seven days. Clinical improvement was observed in 48 to 78 hours. The cervical cultures were negative for N. gonorrhoeae after 48 hours, at the completion of treatment, and two weeks post-treatment. The drug was well tolerated. It was concluded that cephalothin intravenously is an acceptable alternative antibiotic for the treatment of gonococcal pelvic infection. Tomlanovich MC, Nowak RM, Madhavan T, Burch KH, Fisher EJ, Mezger E, Quinn EL, Berzi W: Parenteral cephalothin therapy for pelvic gonococcal infections. JACEP 7:88-92, March, 1978.
adnexitis, cepha/othins, gonorrhea; gonorrhea, drug therapy.
INTRODUCTION Locally d i s s e m i n a t e d gonococcal infections in women, including endometritis, salpingitis, t u b o - o v a r i a n abscess, oophoritis, and pelvic peritonitis, have been successfully t e a t e d with aqueous penicillin or ampicillin p a r e n t e r a l l y for several years. 1 However, a s s e s s m e n t of a l t e r n a t e antibiotic r e g i m e n s is e s s e n t i a l for the following reasons: 1) p e n i c i l l i n a l l e r g y , 2 2) m i x e d infections w i t h penicillinase-producing organisms, 3 3) r e l a t i v e contraindications to e s t a b l i s h e d a l t e r n a t e r e g i m e n s 4 (eg, use of tetracycline in pregnancy), and 4) the r e c e n t l y recognized problem of p e n i c i l l i n - r e s i s t a n t gonococcal s t r a i n s causing localized and d i s s e m i n a t e d infections. ~-7 Some c e p h a l o s p o r i n s have been used in the From the Divisions of Emergency Medicine and Infectious Disease, and Department of Pathology, Henry Ford Hospital, Detroit, Michigan. Presented at the fifth annual ACEP/EDNA Scientific Assembly in San Francisco, California, November, 1977. The study was supported by a grant from the Eli Lilly Research Laboratories, Indianapolis,Indiana. Address for reprints: Michael C. Tomlanovich, MD, Division of Emergency Medicine, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan 48202. 7:3 (Mar) 1978
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t r e a t m e n t of gonococcal i n f e c t i o n s with acceptable cure r a t e s 2 , s The present study was u n d e r t a k e n to det e r m i n e the efficacy of c e p h a l o t h i n i n t r a v e n o u s l y in the t r e a t m e n t of gonococcal pelvic infections. Also, a n a t t e m p t was made to identify other possible bacterial agents in the etiology of the disease.
MATERIALS AND METHODS Study Population P a t i e n t s w i t h suspected pelvic infections were identified from the patient population p r e s e n t i n g to the Division of Emergency Medicine. The d i a g n o s i s of p e l v i c i n f e c t i o n was based on lower abdominal p a i n (less t h a n one week duration), lower abd o m i n a l t e n d e r n e s s , u t e r i n e and/or adnexal tenderness, fever over 38 C (104 F) a n d / o r l e u k o c y t o s i s over 12,000/cu mm. P a t i e n t s with severe u n d e r l y i n g diseases, concomitant infections r e q u i r i n g o t h e r a n t i b i o t i c t r e a t m e n t , previous antibiotic treatm e n t of a n y kind w i t h i n three days, and p r e g n a n t patients were excluded. All the p a t i e n t s were hospitalized because of severity of symptoms.
Laboratory Studies Blood s a m p l e s , e n d o c e r v i c a l swabs, and cul-de-sac aspirates were o b t a i n e d for c u l t u r e . Pelvic specim e n s were collected u n d e r sterile t e c h n i q u e with a n t i s e p t i c p r e p a r a tion of the vulva a n d v a g i n a l vault. E n d o c e r v i c a l swabs were i m m e d i ately inoculated on Transgrow med i u m with t r i m e t h o p r i m . T h e culde-sac aspiration was performed with a sterile spinal needle. If no m a t e r i a l was o b t a i n e d , s t e r i l e n o n b a c t e r i o • static s a l i n e was injected into the cul-de-sac a n d s u b s e q u e n t l y aspirated. Portions of the aspirate were placed in anaerobic prereduced med i u m a n d modified S t u a r t ' s bacterial transport medium. T h e s e s p e c i m e n s were i m m e d i a t e l y t r a n s p o r t e d to the laboratory for culture. The anaerobic culde-sac aspirate was inoculated on roll t u b e s of b r a i n - h e a r t i n f u s i o n a g a r with v i t a m i n K, hemin, and resazurin, a n d also into a chopped m e a t carbohydrate broth. These c u l t u r e s were m a i n t a i n e d a n a e r o b i c a l l y and incubated at 35 C (95 F). The aerobic cul-de-sac a s p i r a t e was i n o c u l a t e d onto chocolate agar, Colombia agar w i t h 10% sheep blood, M c C o n k e y agar, and Transgrow medium. These cultures were incubated at 35 C in a 5% to 10% CO2 atmosphere. Neisseria gonorrhoeae colonies
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were p r e s u m p t i v e l y i d e n t i f i e d by gram stain morphology and positive oxidase r e a c t i o n . Oxidase positive gram negative diplococci were subcultured on chocolate agar. Growth from the pure subcultures u n d e r w e n t c a r b o h y d r a t e u t i l i z a t i o n t e s t i n g on cysteine trypticase agar c o n t a i n i n g 1% glucose, lactose, maltose, or sucrose. The identity of isolates as N. gonorrhoeae was confirmed by the ability to ferment glucose but not the other sugars. The colonies were add i t i o n a l l y confirmed by fluorescent antibody testing (FA N. gonorrhoeae antiserum, Difco Laboratories).
Treatment and Follow-up Patients were admitted with w r i t t e n informed consent to the Infectious Diseases Service and treated for s e v e n d a y s w i t h i n t r a v e n o u s cephalothin (2 gm over a 20-minute period every four hours). Clinical exa m i n a t i o n s were performed daily to evaluate the clinical response and to observe for a n y drug intolerance or adverse reactions. Hematologic, hepatic, and r e n a l function studies were performed before, during, and after the c o m p l e t i o n of t r e a t m e n t . Follow-up cervical cultures were obtained after 48 hours, at the completion of t r e a t m e n t , and two weeks following discharge. A b n o r m a l laboratory studies were repeated and followed.
several nongonococca] aerobes were found in the peritoneal specimens inc l u d i n g Lactobacillus sp, Staphylococcus aureus, b e t a Streptococcus ( n o n - g r o u p A), a n d a l p h a Streptococcus (non-Group D). Aerobes were the exclusive peritoneal isolate in four p a t i e n t s and all were associated w i t h gonococcal e n d o c e r v i c a l infection.
Results of Treatment All p a t i e n t s were hospitalized a n d received i n t r a v e n o u s cephalothin, 12 gm a day for seven days. The clinical response was excellent with freedom from fever, abdominal pain, and other systemic symptoms. Transient elevation of liver enzymes was n o t e d i n five p a t i e n t s (25%) and t h r o m b o p h l e b i t i s was o b s e r v e d in two p a t i e n t s (10%). Two p a t i e n t s reported mild pelvic discomfort after the c o m p l e t i o n of t r e a t m e n t . Two weeks after discharge from the h o s p i t a l , p e l v i c e x a m i n a t i o n revealed a n o n t e n d e r cervix a n d adn e x a a n d absence of m i l d nonspecific discharge in 17 p a t i e n t s who r e t u r n e d for follow-up. Microbiological studies done at 48 hours, at the completion of treatm e n t , a n d two weeks post-therapy were all negative for N. gonorrhoeae. However, a repeat cul-de-sac aspiration was not performed.
DISCUSSION RESULTS (Table 1) Demonstration of N. gonorrhoeae N. gonorrhoeae was recovered from the endocervix from 15 of 20 patients (75%). G r a m negative intracellular diplococci were seen on smear in two-thirds of these patients who had positive endocervical cultures for N. gonorrhoeae. Three of these pat i e n t s were also f o u n d to have N. gonorrhoeae in the cul-de-sac aspirate. In two patients, N. gonorrhoeae was the exclusive peritoneal isolate.
Demonstration of Anaerobes and Aerobes Of the 20 peritoneal specimens obtained, anaerobic organisms were found in four (20%) and exclusively in one (5%). These were demonstrable both by g r a m s t a i n and culture. The organisms included Peptostrep-
tococcus sp, Fusobacteriurn sp, Peptococcus asaccharolyticus, a n d Peptostreptococcus anaerobius. Two of these p a t i e n t s had a n e g a t i v e endocervical culture for N. gonorrhoeae a n d t h e r e m a i n i n g two h a d a gonococcal cervical infection. Also,
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The presence of acute pelvic infection is w e l l documented with abd o m i n a l p a i n (the m o s t c o m m o n symptom), lower a b d o m i n a l tenderness, fever, leukocytosis, a n d exquisite t e n d e r n e s s on m a n i p u l a t i o n of the cervix on pelvic e x a m i n a t i o n 2 Prompt t r e a t m e n t is i m p o r t a n t for both the cure and the control of gonorrhea. A presumptive diagnosis of infection by e x a m i n a t i o n of gram stained smears at the time of initial e v a l u a t i o n m u s t be confirmed by culture if the m a x i m u m gonococcal isolations are to b e obtained. 1° Hence, the speed a n d efficiency of culture diagnosis t a k e s o n c a r d i n a l importance.
Culture Techniques A selective m e d i u m for the cult i v a t i o n of gonococci a n d m e n i n gococci was reported by Thayer and M a r t i n in 1964.11 This m e d i u m was improved by the same investigators in 1966.12 The T h a y e r - M a r t i n selective m e d i u m is r e c o m m e n d e d for p r i m a r y isolation of the gonococcus from the sites where these organisms
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Table 1 RESULTS
Endocervical Culture for Case No. IV. gonorrhoeae
Aerobes
Anaerobes
neg beta Streptococcus (non Group A) neg
neg neg
3 5
neg neg
neg
Staphylococcus aureus
Peptostreptococcus sp.
3 2
neg neg
neg neg
neg neg neg
neg neg neg neg neg neg neg
N. gonorrhoeae
Fusobacterium sp.
neg
neg neg
2 3 4 6 2 6 1 7 4 4 5
neg neg neg neg neg neg neg neg neg neg neg
2 3 3
neg neg neg
2 5
neg neg
1 2
neg pos
3 4
pos pos
5 6 7 8 9 10 11 12 13 14 15
pos neg pos pos pos neg pos pos pos po s neg
Lactobacillus sp. alp ha Streptococcus
16 17 18
pos pos neg
(non-Group D) neg neg neg
19 20
pos pos
neg neg
N. gonorrhoeae N. gonorrhoeae
are o u t n u m b e r e d by o t h e r m o r e r a p i d l y g r o w i n g b a c t e r i a l flora (eg cervix). O v e r g r o w t h by g r a m positive, o t h e r g r a m n e g a t i v e bacteria, and y e a s t is p r e v e n t e d in most cases by this m e d i u m because of added antibiotics (vancomycin, colistin, and nystatin). T r a n s g r o w m e d i u m (modifled T h a y e r - M a r t i n m e d i u m ) h a s been shown to be a valuable tool for transp o r t a t i o n of s u s p e c t e d g o n o c o c c a l specimens ~3 and was used with considerable success in our study. Microbiologic Studies As noted in our study, N. Gonorrhoeae was recovered from the endocervix in 75% of p a t i e n t s and from the cul-de-sac in 15%. Cul-de-sac cult u r e s w e r e p o s i t i v e in 42% w i t h 37.5% growing more t h a n one organism (Table 2). T h e s e b a c t e r i o l o g i c r e s u l t s fall into five categories: 1) patients with positive gonococcal endocervical culture and negative cul-de-sac c u l t u r e (8 of 15); 2) p a t i e n t s with positive gonococcal endocervical c u l t u r e s a n d gonococcal cul-de-sac cultures (3 of 15); 3) p a t i e n t s with pos7:3 (Mar) 1978
Response to Therapy Clinical (sx improved Bacteriologic in days) (repeat cultures)
Cul-de-sac Cultures
Peptococcus asacchrolyticus neg neg
Peptostreptococcus anaerobius neg neg
itive gonococal endocervical cultures and mixed (gonococci and other organisms) cul-de-sac cultures (1 of 15); 4)
p a t i e n t s with positive gonococcal culde-sac cultures (3 of 15), and 5) patients with negative endocervical cultures and
Table 2 PERITONEAL ISOLATES AND ASSOCIATED ENDOCERVICAL CULTURES Case No.
Endocervical Culture
7 8 12 2
N. gonorrhoeae N. gonorrhoeae N. gonorrhoeae N. gonorrhoeae
4
N. gonorrhoeae
14 15
N. gonorrhoeae
18
negative
negative
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Cul-de-sac Culture
N. gonorrhoeae N. gonorrhoeae N. gonorrhoeae Fusobacterium sp. beta Streptococcus (Non-Group A) Staphylococcus aureus Peptostreptococcus sp. Lactobacillus sp. alpha Streptococcus (NonGroup D) Peptococcus asacchrolyticus Peptostreptococcus anaerobius
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positive nongonococcal cul-de-sac cultures (2 of 5). Our findings suggest the followi n g s e q u e n c e of e v e n t s in t h e pathogenesis of pelvic i n f l a m m a t o r y disease. First, gonococcal cervicitis is associated w i t h gonococcal endometritis/salpingitis without bacterial i n v o l v e m e n t of the p e r i t o n e a l cavity. Second, further gonococcal s p r e a d to the pelvic p e r i t o n e u m occurs. Third, t h e r e is a d d i t i o n a l p e r i t o n e a l bact e r i a l c o n t a m i n a t i o n by s e c o n d a r y invaders from the vaginal flora. Fourth, there is progression of this superinfection with consequent peritoneal gonococcal supression. F i n a l l y , there is locally o v e r w h e l m i n g superinfection w i t h t o t a l e l i m i n a t i o n of
N. gonorrhoeae. The b a c t e r i o l o g y of p e l v i c inf l a m m a t o r y disease has been somew h a t v a r i a b l e in d i f f e r e n t studies. E s c h e n b a c h et al TM s t u d i e d 204 w o m e n w i t h p e l v i c i n f e c t i o n to further d e l i n e a t e the causes of this disease. Gonococci were r e c o v e r e d from the endocerviX in 90 p a t i e n t s (44%). N. gonorrhoeae was found in the peritoneal e x u d a t e in 8 of 21 pat i e n t s with, and 0 of 33 without, cerv i c a l gonococcal infection. A m o n g p a t i e n t s w i t h severe disease, o t h e r bacteria were recovered from the p e r i t o n e u m in 5 of 16 w i t h and 19 of 20 w i t h o u t g o n o c o c c a l c e r v i c i t i s . Mixed anaerobic and aerobic bacter i a l p e r i t o n e a l infection was common in nongonococcal pelvic disease. The most frequent species recovered were Bacteroides fragilis, peptostreptococci, and peptococci. They described two different clinical and b a c t e r i a l etiologic forms of pelvic i n f l a m m a t o r y d i s e a s e : gonococcal t u b o p e r i t o n e a l i n f e c t i o n in p a t i e n t s w i t h c e r v i c a l gonococcal infection, and polymicrobial nongonococcal tuboperitoneal infection in p a t i e n t s w i t h o u t gonococcal cervicitis. However, ~the clinical diagnosis was l i m i t e d to p a t i e n t s who had pain in the lower abdomen of < three weeks' duration." Inclusion of p a t i e n t s w i t h such v a r i a b l e d u r a t i o n of s y m p t o m s will produce b a c t e r i o l o g i c r e s u l t s t h a t m a y be compatible with different pathogenic stages of the same disease r a t h e r t h a n the two different etiologic forms of diseases. Chow et al, 15 in a n a l y z i n g the value of cul-de-sac cultures and the i m p o r t a n c e of gonococci a n d o t h e r b a c t e r i a in pelvic i n f l a m m a t o r y disease, studied 20 p a t i e n t s with simultaneous cul-de-sac, cervical, and blood cultures w i t h aerobic and fast i d i o u s a n a e r o b i c t e c h n i q u e s . Cul-
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de-sac cultures were positive in 18 of 20 patients, while all eight n o r m a l control subjects yielded negative results. A n a e r o b i c b a c t e r i a (predomin a n t l y peptococci a n d p e p t o s t r e p tococci) were p r e s e n t in ten p a t i e n t s (59%) a n d were the exclusive isolates in three patients. N. gonorrhoeae was isolated only once from the cul-de-sac d e s p i t e its p r e s e n c e in 13 c e r v i c a l specimens (65%). However, selective m e d i u m for N. gonorrhoeae was not r o u t i n e l y used in cul-de-sac cultures. The authors concluded t h a t culdocentesis is a reliable technique for the bacteriologic diagnosis of acute pelvic i n f l a m m a t o r y disease. The gonococcus m a y be i m p o r t a n t in initiating a c u t e pelvic i n f e c t i o n a n d appears to pave the w a y for secondary i n v a d e r s from t h e v a g i n a l flora to g a i n a c c e s s to t h e u p p e r g e n i t a l tract. Successful t r e a t m e n t m a y be d e p e n d e n t on bacteriologic identific a t i o n of these s e c o n d a r y i n v a d e r s via culdocentesis and subsequent use of appropriate antibotics. Monif et al 1~ cultured N. gonorrhoeae from the cul-de-sac in 11 of 17 p a t i e n t s w i t h b a c t e r i o l o g i c a l docum e n t e d gonococcal cervicitis/endometritis. N. gonorrhoeae was t h e only p e r i t o n e a l i s o l a t e in five p a t i e n t s . The presence of o t h e r a e r o b e s and a n a e r o b e s as well as N. gonorrhoeae was documented in six patients. In t h e r e m a i n i n g six p a t i e n t s , o n l y nongonococcal aerobic and anaerobic o r g a n i s m s were isolated. After a review of o t h e r bacteriologic s t u d i e s and an a n a l y s i s of his results, Monif concluded t h a t anaerobic superinfections follow i n i t i a l infection w i t h N. gonorrhoeae l a t e r in the course of pelvic i n f l a m m a t o r y disease.
Treatment Various r e g i m e n s are employed in the t r e a t m e n t of pelvic i n f l a m m a t o r y d i s e a s e . T h e 1974 r e c o m m e n d a t i o n s by t h e C e n t e r for Disease Control ~7 call for the administ r a t i o n of 1 g m of o r a l p r o b e n e c i d and 4.8 million units of i n t r a m u s c u lar procaine penicillin G or a single dose of 3.5 gm of oral a m p i c i l l i n with probenecid. Both are followed by 500 mg of oral ampicillin taken four times a day for t e n days. In p a t i e n t s who are allergic to penicillin, an alt e r n a t e r e g i m e n is 1.5 gm of oral tetracycline hydrochloride followed by 500 mg t a k e n four times a day for t e n days. H o s p i t a l i z e d p a t i e n t s are t r e a t e d with 20 million u n i t s of int r a v e n o u s aqueous c r y s t a l l i n e penic i l l i n G d a i l y u n t i l " c l e a r cut improvement," followed by 500 mg of
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o r a l a m p i c i l l i n t a k e n four t i m e s a day to complete ten days of therapy. Since it is impossible to distinguish gonococcal from nongonococcal pelvic infection p r i o r to b a c t e r i o l o g i c results, some p h y s i c i a n s also use an aminoglycoside in addition to penicillin as i n i t i a l therapy, s For s e v e r a l r e a s o n s , i n c l u d i n g the a p p e a r a n c e of penicillinase prod u c i n g gonococci a n d m i x e d infections not c o m p l e t e l y r e s p o n s i v e to penicillin (eg, N. gonorrhoeae and C. trachomatis), K a r n e y a n d Holmes~S felt t h a t a r e - e x a m i n a t i o n of current g o n o r r h e a t h e r a p y g u i d e l i n e s was necessary. They t r e a t e d a large patient population randomly with e i t h e r t e t r a c y c l i n e or spectinomycin and observed a m i n i m u m 94% cure r a t e for u n c o m p l i c a t e d a n o g e n i t a l g o n o r r h e a w i t h e i t h e r d r u g . However, t h e s e l e c t i n g out of e x i s t e n t strains ofN. gonorrhoeae r e s i s t a n t to m a x i m a l doses of t e t r a c y c l i n e would p r e c l u d e its w i d e s p r e a d use. Subsequently, they concluded t h a t future research concerning g o n o r r h e a therapy should e v a l u a t e the efficacy of other a n t i m i c r o b i a l a g e n t s including cephalosporins. Phillips et a119 s t u d i e d the in vitro activity of various cephalosporins a g a i n s t gonococci, a n d f o u n d t h a t cephalosporins were effective against both penicillin sensitive and penicillin r e s i s t a n t (ie, penicillinase produci n g ) gonococci. A g a i n s t p e n i c i l l i n s e n s i t i v e gonococci, c e f u r o x i m e , cefamandole, cefoxitin, cephalothin, cefazolin, c e p h r a d i n e , c e p h a l e x i n , and cephaloridine were found to be effective. A g a i n s t penicillin r e s i s t a n t gonococci, c e f u r o x i m e , c e f o x i t i n , cefazolin, cefamandole, cephalothin, cephaloridine, cephalexin, a n d cephr a d i n e w e r e e f f e c t i v e . T h e y concluded that clinical trials with cephalosporins m a y be worthwhile. Prior to our study, K a p l a n and Acosta s reported good clinical results (over 90% b a c t e r i a l : cures) in pelvic i n f l a m m a t o r y disease using 3 gm of i n t r a m u s c u l a r cephacetrile or cephaloridine daily for a n a v e r a g e of four days. The present study suggests t h a t cephalothin given p a r e n t e r a l l y in the dose of 12 gm/day for one week is an acceptable a l t e r n a t i v e regimen in h o s p i t a l i z e d p a t i e n t s w i t h acute pelvic i n f l a m m a t o r y disease.
The authors wish to express their gratitude to Ms. Carol Worek for her assistance in this study.
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REFERENCES 1. Theodoridis A, Tsamboas D, Sivenas C, et al.: P a r e n t e r a l cephradine in the treatment of gonorrhea. Curr Ther Res 19: 20-23, 1976 2. Rudolph A, Price E; Penicillin reactions among patients in venereal disease clinics. J A M A 223:499-501, 1973. 3. Sanders A, Pelczar M, Hoefling A: Interactions of Staphylococcus and Neisseria gonorrhoeae in " p e n i c i l l i n r e s i s t a n t " gonorrhea. Antibiot Chemother 12: 10-16, 1962. 4. Physicians" Desk Reference. Oradell, New Jersey, Medical Economics, 1976. 5. Phillips I: B e t a - l a c t a m a s e producing penicillin-resistant gonococcus. Lancet 2 (7987): 656-657, 1976. 6. Ashford W, Golash R, H e m m i n g V: Penicillinase-producing Neisseria gonorrhoeae. Lancet 2 (7987): 65%658, 1976. 7. Rodriguez W, Saz A: Possible mechanism of decreased susceptibility of Neisseria g o n o r r h o e a e to p e n i c i l l i n . A n -
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timicrob A g e n t s Chemother 7: 788-792, 1975. 8. Kaplan A, Acosta A: M a n a g e m e n t of pelvic inflammatory disease with a new cephalosporin. Curr Ther Res 18: 793-799, 1975. 9. Nolan G, Osborne N: Gonococcal infections in the female. Obstet Gynecol 42: 156-164, 1973. 10. Schwarz R: Acute pelvic inflammatory disease, in Monif G (ed): Infectious Diseases in Obstetrics and Gynecology. New York, Harper & Row, 1974. 11. Thayer J, M a r t i n J: A selective medium for the cultivation ofN. gonorrhoeae and N. meningitidis. Public Health Rep 79: 49-57, 1964. 12. Thayer J, Martin J: Improved medium selective for cultivation ofN. gonorrhoeae and N. meningitidis. Public Health Rep 81: 559-562, 1966. 13. M a r t i n J, Lester A: Transgrow, a medium for transport and growth of Neisseria gonorrhoeae and Neisseria meningitidis. H S M H A Health Reports 86" 96-99, 1971.
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14. Eschenbach D, B u c h a n a n T, Pollack H, et al: Polymicrobial etiology of acute pelvic i n f l a m m a t o r y disease. N E n g l J Med 293: 166-171, 1975. 15. Chow A, Malkasian K, Marshall J, et al.: The bacteriology of acute pelvic inflammatory disease. A m J Obstet Gynecol 122: 876-879, 1975. 16. Monif G, Welkos S, Baer H, et al.: Cul-de-sac isolates from p a t i e n t s w i t h endometritis-s alphingit is-peritonitis and gonococcal c e r v i c i t i s . A m J Obstet Gynecol 126: 158-161, 1976. 17. H e n d e r s o n R: Recommended t r e a t m e n t schedules for g o n o r r h e a - - 1974. Arch Intern Med 135: 615-618, 1975. 18. Karney W, Pedersen A, Nelson M, et al.: Spectinomycin versus tetracycline for t h e t r e a t m e n t of gonorrhea. N E n g l J Med 296: 889-894, 1977. 19. Phillips I, King A, Warren C, et al.: The activity of eight cephalosporins and penicillin on Neisseria gonorrhoeae. J Antimicrob Chernother 2: 31-39, 1976.
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Parenteral Cephalothin Therapy for Pelvic Gonococcal Infections Michael C. Tomlanovich, MD Richard M. Nowak, MD Tom Madhavan, MD Keith H. Burch, MD Evelyn J. Fisher, MD Eugene Mezger, MD Edward L. Quinn, MD Wadid Berzi, MD Detroit, Michigan
The efficacy of intravenous cephalothin was studied prospectively in 20 patients with acute pelvic inflammatory disease, all of whom presented with lower abdominal pain, cervical and adnexal tenderness, fever, and leukocytosis. Blood, cervical, and cul-de-sac cultures were obtained on admission. The latter was transported anaerobically and inoculated in routine and prereduced medium. Transgrow medium with trimethoprim was used for endocervical cultures. Neisseria gonorrhoeae was isolated from the endocervix in 15 patients and from the culde-sac and cervix in three. Anaerobic organisms were also isolated from the culde-sac in four patients. All received intravenous cephalothin, 2 gm every four hours for seven days. Clinical improvement was observed in 48 to 78 hours. The cervical cultures were negative for N. gonorrhoeae after 48 hours, at the completion of treatment, and two weeks post-treatment. The drug was well tolerated. It was concluded that cephalothin intravenously is an acceptable alternative antibiotic for the treatment of gonococcal pelvic infection. Tomlanovich MC, Nowak RM, Madhavan T, Burch KH, Fisher EJ, Mezger E, Quinn EL, Berzi W: Parenteral cephalothin therapy for pelvic gonococcal infections. JACEP 7:88-92, March, 1978.
adnexitis, cepha/othins, gonorrhea; gonorrhea, drug therapy.
INTRODUCTION Locally d i s s e m i n a t e d gonococcal infections in women, including endometritis, salpingitis, t u b o - o v a r i a n abscess, oophoritis, and pelvic peritonitis, have been successfully t e a t e d with aqueous penicillin or ampicillin p a r e n t e r a l l y for several years. 1 However, a s s e s s m e n t of a l t e r n a t e antibiotic r e g i m e n s is e s s e n t i a l for the following reasons: 1) p e n i c i l l i n a l l e r g y , 2 2) m i x e d infections w i t h penicillinase-producing organisms, 3 3) r e l a t i v e contraindications to e s t a b l i s h e d a l t e r n a t e r e g i m e n s 4 (eg, use of tetracycline in pregnancy), and 4) the r e c e n t l y recognized problem of p e n i c i l l i n - r e s i s t a n t gonococcal s t r a i n s causing localized and d i s s e m i n a t e d infections. ~-7 Some c e p h a l o s p o r i n s have been used in the From the Divisions of Emergency Medicine and Infectious Disease, and Department of Pathology, Henry Ford Hospital, Detroit, Michigan. Presented at the fifth annual ACEP/EDNA Scientific Assembly in San Francisco, California, November, 1977. The study was supported by a grant from the Eli Lilly Research Laboratories, Indianapolis,Indiana. Address for reprints: Michael C. Tomlanovich, MD, Division of Emergency Medicine, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan 48202. 7:3 (Mar) 1978
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t r e a t m e n t of gonococcal i n f e c t i o n s with acceptable cure r a t e s 2 , s The present study was u n d e r t a k e n to det e r m i n e the efficacy of c e p h a l o t h i n i n t r a v e n o u s l y in the t r e a t m e n t of gonococcal pelvic infections. Also, a n a t t e m p t was made to identify other possible bacterial agents in the etiology of the disease.
MATERIALS AND METHODS Study Population P a t i e n t s w i t h suspected pelvic infections were identified from the patient population p r e s e n t i n g to the Division of Emergency Medicine. The d i a g n o s i s of p e l v i c i n f e c t i o n was based on lower abdominal p a i n (less t h a n one week duration), lower abd o m i n a l t e n d e r n e s s , u t e r i n e and/or adnexal tenderness, fever over 38 C (104 F) a n d / o r l e u k o c y t o s i s over 12,000/cu mm. P a t i e n t s with severe u n d e r l y i n g diseases, concomitant infections r e q u i r i n g o t h e r a n t i b i o t i c t r e a t m e n t , previous antibiotic treatm e n t of a n y kind w i t h i n three days, and p r e g n a n t patients were excluded. All the p a t i e n t s were hospitalized because of severity of symptoms.
Laboratory Studies Blood s a m p l e s , e n d o c e r v i c a l swabs, and cul-de-sac aspirates were o b t a i n e d for c u l t u r e . Pelvic specim e n s were collected u n d e r sterile t e c h n i q u e with a n t i s e p t i c p r e p a r a tion of the vulva a n d v a g i n a l vault. E n d o c e r v i c a l swabs were i m m e d i ately inoculated on Transgrow med i u m with t r i m e t h o p r i m . T h e culde-sac aspiration was performed with a sterile spinal needle. If no m a t e r i a l was o b t a i n e d , s t e r i l e n o n b a c t e r i o • static s a l i n e was injected into the cul-de-sac a n d s u b s e q u e n t l y aspirated. Portions of the aspirate were placed in anaerobic prereduced med i u m a n d modified S t u a r t ' s bacterial transport medium. T h e s e s p e c i m e n s were i m m e d i a t e l y t r a n s p o r t e d to the laboratory for culture. The anaerobic culde-sac aspirate was inoculated on roll t u b e s of b r a i n - h e a r t i n f u s i o n a g a r with v i t a m i n K, hemin, and resazurin, a n d also into a chopped m e a t carbohydrate broth. These c u l t u r e s were m a i n t a i n e d a n a e r o b i c a l l y and incubated at 35 C (95 F). The aerobic cul-de-sac a s p i r a t e was i n o c u l a t e d onto chocolate agar, Colombia agar w i t h 10% sheep blood, M c C o n k e y agar, and Transgrow medium. These cultures were incubated at 35 C in a 5% to 10% CO2 atmosphere. Neisseria gonorrhoeae colonies
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were p r e s u m p t i v e l y i d e n t i f i e d by gram stain morphology and positive oxidase r e a c t i o n . Oxidase positive gram negative diplococci were subcultured on chocolate agar. Growth from the pure subcultures u n d e r w e n t c a r b o h y d r a t e u t i l i z a t i o n t e s t i n g on cysteine trypticase agar c o n t a i n i n g 1% glucose, lactose, maltose, or sucrose. The identity of isolates as N. gonorrhoeae was confirmed by the ability to ferment glucose but not the other sugars. The colonies were add i t i o n a l l y confirmed by fluorescent antibody testing (FA N. gonorrhoeae antiserum, Difco Laboratories).
Treatment and Follow-up Patients were admitted with w r i t t e n informed consent to the Infectious Diseases Service and treated for s e v e n d a y s w i t h i n t r a v e n o u s cephalothin (2 gm over a 20-minute period every four hours). Clinical exa m i n a t i o n s were performed daily to evaluate the clinical response and to observe for a n y drug intolerance or adverse reactions. Hematologic, hepatic, and r e n a l function studies were performed before, during, and after the c o m p l e t i o n of t r e a t m e n t . Follow-up cervical cultures were obtained after 48 hours, at the completion of t r e a t m e n t , and two weeks following discharge. A b n o r m a l laboratory studies were repeated and followed.
several nongonococca] aerobes were found in the peritoneal specimens inc l u d i n g Lactobacillus sp, Staphylococcus aureus, b e t a Streptococcus ( n o n - g r o u p A), a n d a l p h a Streptococcus (non-Group D). Aerobes were the exclusive peritoneal isolate in four p a t i e n t s and all were associated w i t h gonococcal e n d o c e r v i c a l infection.
Results of Treatment All p a t i e n t s were hospitalized a n d received i n t r a v e n o u s cephalothin, 12 gm a day for seven days. The clinical response was excellent with freedom from fever, abdominal pain, and other systemic symptoms. Transient elevation of liver enzymes was n o t e d i n five p a t i e n t s (25%) and t h r o m b o p h l e b i t i s was o b s e r v e d in two p a t i e n t s (10%). Two p a t i e n t s reported mild pelvic discomfort after the c o m p l e t i o n of t r e a t m e n t . Two weeks after discharge from the h o s p i t a l , p e l v i c e x a m i n a t i o n revealed a n o n t e n d e r cervix a n d adn e x a a n d absence of m i l d nonspecific discharge in 17 p a t i e n t s who r e t u r n e d for follow-up. Microbiological studies done at 48 hours, at the completion of treatm e n t , a n d two weeks post-therapy were all negative for N. gonorrhoeae. However, a repeat cul-de-sac aspiration was not performed.
DISCUSSION RESULTS (Table 1) Demonstration of N. gonorrhoeae N. gonorrhoeae was recovered from the endocervix from 15 of 20 patients (75%). G r a m negative intracellular diplococci were seen on smear in two-thirds of these patients who had positive endocervical cultures for N. gonorrhoeae. Three of these pat i e n t s were also f o u n d to have N. gonorrhoeae in the cul-de-sac aspirate. In two patients, N. gonorrhoeae was the exclusive peritoneal isolate.
Demonstration of Anaerobes and Aerobes Of the 20 peritoneal specimens obtained, anaerobic organisms were found in four (20%) and exclusively in one (5%). These were demonstrable both by g r a m s t a i n and culture. The organisms included Peptostrep-
tococcus sp, Fusobacteriurn sp, Peptococcus asaccharolyticus, a n d Peptostreptococcus anaerobius. Two of these p a t i e n t s had a n e g a t i v e endocervical culture for N. gonorrhoeae a n d t h e r e m a i n i n g two h a d a gonococcal cervical infection. Also,
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The presence of acute pelvic infection is w e l l documented with abd o m i n a l p a i n (the m o s t c o m m o n symptom), lower a b d o m i n a l tenderness, fever, leukocytosis, a n d exquisite t e n d e r n e s s on m a n i p u l a t i o n of the cervix on pelvic e x a m i n a t i o n 2 Prompt t r e a t m e n t is i m p o r t a n t for both the cure and the control of gonorrhea. A presumptive diagnosis of infection by e x a m i n a t i o n of gram stained smears at the time of initial e v a l u a t i o n m u s t be confirmed by culture if the m a x i m u m gonococcal isolations are to b e obtained. 1° Hence, the speed a n d efficiency of culture diagnosis t a k e s o n c a r d i n a l importance.
Culture Techniques A selective m e d i u m for the cult i v a t i o n of gonococci a n d m e n i n gococci was reported by Thayer and M a r t i n in 1964.11 This m e d i u m was improved by the same investigators in 1966.12 The T h a y e r - M a r t i n selective m e d i u m is r e c o m m e n d e d for p r i m a r y isolation of the gonococcus from the sites where these organisms
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Table 1 RESULTS
Endocervical Culture for Case No. IV. gonorrhoeae
Aerobes
Anaerobes
neg beta Streptococcus (non Group A) neg
neg neg
3 5
neg neg
neg
Staphylococcus aureus
Peptostreptococcus sp.
3 2
neg neg
neg neg
neg neg neg
neg neg neg neg neg neg neg
N. gonorrhoeae
Fusobacterium sp.
neg
neg neg
2 3 4 6 2 6 1 7 4 4 5
neg neg neg neg neg neg neg neg neg neg neg
2 3 3
neg neg neg
2 5
neg neg
1 2
neg pos
3 4
pos pos
5 6 7 8 9 10 11 12 13 14 15
pos neg pos pos pos neg pos pos pos po s neg
Lactobacillus sp. alp ha Streptococcus
16 17 18
pos pos neg
(non-Group D) neg neg neg
19 20
pos pos
neg neg
N. gonorrhoeae N. gonorrhoeae
are o u t n u m b e r e d by o t h e r m o r e r a p i d l y g r o w i n g b a c t e r i a l flora (eg cervix). O v e r g r o w t h by g r a m positive, o t h e r g r a m n e g a t i v e bacteria, and y e a s t is p r e v e n t e d in most cases by this m e d i u m because of added antibiotics (vancomycin, colistin, and nystatin). T r a n s g r o w m e d i u m (modifled T h a y e r - M a r t i n m e d i u m ) h a s been shown to be a valuable tool for transp o r t a t i o n of s u s p e c t e d g o n o c o c c a l specimens ~3 and was used with considerable success in our study. Microbiologic Studies As noted in our study, N. Gonorrhoeae was recovered from the endocervix in 75% of p a t i e n t s and from the cul-de-sac in 15%. Cul-de-sac cult u r e s w e r e p o s i t i v e in 42% w i t h 37.5% growing more t h a n one organism (Table 2). T h e s e b a c t e r i o l o g i c r e s u l t s fall into five categories: 1) patients with positive gonococcal endocervical culture and negative cul-de-sac c u l t u r e (8 of 15); 2) p a t i e n t s with positive gonococcal endocervical c u l t u r e s a n d gonococcal cul-de-sac cultures (3 of 15); 3) p a t i e n t s with pos7:3 (Mar) 1978
Response to Therapy Clinical (sx improved Bacteriologic in days) (repeat cultures)
Cul-de-sac Cultures
Peptococcus asacchrolyticus neg neg
Peptostreptococcus anaerobius neg neg
itive gonococal endocervical cultures and mixed (gonococci and other organisms) cul-de-sac cultures (1 of 15); 4)
p a t i e n t s with positive gonococcal culde-sac cultures (3 of 15), and 5) patients with negative endocervical cultures and
Table 2 PERITONEAL ISOLATES AND ASSOCIATED ENDOCERVICAL CULTURES Case No.
Endocervical Culture
7 8 12 2
N. gonorrhoeae N. gonorrhoeae N. gonorrhoeae N. gonorrhoeae
4
N. gonorrhoeae
14 15
N. gonorrhoeae
18
negative
negative
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Cul-de-sac Culture
N. gonorrhoeae N. gonorrhoeae N. gonorrhoeae Fusobacterium sp. beta Streptococcus (Non-Group A) Staphylococcus aureus Peptostreptococcus sp. Lactobacillus sp. alpha Streptococcus (NonGroup D) Peptococcus asacchrolyticus Peptostreptococcus anaerobius
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positive nongonococcal cul-de-sac cultures (2 of 5). Our findings suggest the followi n g s e q u e n c e of e v e n t s in t h e pathogenesis of pelvic i n f l a m m a t o r y disease. First, gonococcal cervicitis is associated w i t h gonococcal endometritis/salpingitis without bacterial i n v o l v e m e n t of the p e r i t o n e a l cavity. Second, further gonococcal s p r e a d to the pelvic p e r i t o n e u m occurs. Third, t h e r e is a d d i t i o n a l p e r i t o n e a l bact e r i a l c o n t a m i n a t i o n by s e c o n d a r y invaders from the vaginal flora. Fourth, there is progression of this superinfection with consequent peritoneal gonococcal supression. F i n a l l y , there is locally o v e r w h e l m i n g superinfection w i t h t o t a l e l i m i n a t i o n of
N. gonorrhoeae. The b a c t e r i o l o g y of p e l v i c inf l a m m a t o r y disease has been somew h a t v a r i a b l e in d i f f e r e n t studies. E s c h e n b a c h et al TM s t u d i e d 204 w o m e n w i t h p e l v i c i n f e c t i o n to further d e l i n e a t e the causes of this disease. Gonococci were r e c o v e r e d from the endocerviX in 90 p a t i e n t s (44%). N. gonorrhoeae was found in the peritoneal e x u d a t e in 8 of 21 pat i e n t s with, and 0 of 33 without, cerv i c a l gonococcal infection. A m o n g p a t i e n t s w i t h severe disease, o t h e r bacteria were recovered from the p e r i t o n e u m in 5 of 16 w i t h and 19 of 20 w i t h o u t g o n o c o c c a l c e r v i c i t i s . Mixed anaerobic and aerobic bacter i a l p e r i t o n e a l infection was common in nongonococcal pelvic disease. The most frequent species recovered were Bacteroides fragilis, peptostreptococci, and peptococci. They described two different clinical and b a c t e r i a l etiologic forms of pelvic i n f l a m m a t o r y d i s e a s e : gonococcal t u b o p e r i t o n e a l i n f e c t i o n in p a t i e n t s w i t h c e r v i c a l gonococcal infection, and polymicrobial nongonococcal tuboperitoneal infection in p a t i e n t s w i t h o u t gonococcal cervicitis. However, ~the clinical diagnosis was l i m i t e d to p a t i e n t s who had pain in the lower abdomen of < three weeks' duration." Inclusion of p a t i e n t s w i t h such v a r i a b l e d u r a t i o n of s y m p t o m s will produce b a c t e r i o l o g i c r e s u l t s t h a t m a y be compatible with different pathogenic stages of the same disease r a t h e r t h a n the two different etiologic forms of diseases. Chow et al, 15 in a n a l y z i n g the value of cul-de-sac cultures and the i m p o r t a n c e of gonococci a n d o t h e r b a c t e r i a in pelvic i n f l a m m a t o r y disease, studied 20 p a t i e n t s with simultaneous cul-de-sac, cervical, and blood cultures w i t h aerobic and fast i d i o u s a n a e r o b i c t e c h n i q u e s . Cul-
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de-sac cultures were positive in 18 of 20 patients, while all eight n o r m a l control subjects yielded negative results. A n a e r o b i c b a c t e r i a (predomin a n t l y peptococci a n d p e p t o s t r e p tococci) were p r e s e n t in ten p a t i e n t s (59%) a n d were the exclusive isolates in three patients. N. gonorrhoeae was isolated only once from the cul-de-sac d e s p i t e its p r e s e n c e in 13 c e r v i c a l specimens (65%). However, selective m e d i u m for N. gonorrhoeae was not r o u t i n e l y used in cul-de-sac cultures. The authors concluded t h a t culdocentesis is a reliable technique for the bacteriologic diagnosis of acute pelvic i n f l a m m a t o r y disease. The gonococcus m a y be i m p o r t a n t in initiating a c u t e pelvic i n f e c t i o n a n d appears to pave the w a y for secondary i n v a d e r s from t h e v a g i n a l flora to g a i n a c c e s s to t h e u p p e r g e n i t a l tract. Successful t r e a t m e n t m a y be d e p e n d e n t on bacteriologic identific a t i o n of these s e c o n d a r y i n v a d e r s via culdocentesis and subsequent use of appropriate antibotics. Monif et al 1~ cultured N. gonorrhoeae from the cul-de-sac in 11 of 17 p a t i e n t s w i t h b a c t e r i o l o g i c a l docum e n t e d gonococcal cervicitis/endometritis. N. gonorrhoeae was t h e only p e r i t o n e a l i s o l a t e in five p a t i e n t s . The presence of o t h e r a e r o b e s and a n a e r o b e s as well as N. gonorrhoeae was documented in six patients. In t h e r e m a i n i n g six p a t i e n t s , o n l y nongonococcal aerobic and anaerobic o r g a n i s m s were isolated. After a review of o t h e r bacteriologic s t u d i e s and an a n a l y s i s of his results, Monif concluded t h a t anaerobic superinfections follow i n i t i a l infection w i t h N. gonorrhoeae l a t e r in the course of pelvic i n f l a m m a t o r y disease.
Treatment Various r e g i m e n s are employed in the t r e a t m e n t of pelvic i n f l a m m a t o r y d i s e a s e . T h e 1974 r e c o m m e n d a t i o n s by t h e C e n t e r for Disease Control ~7 call for the administ r a t i o n of 1 g m of o r a l p r o b e n e c i d and 4.8 million units of i n t r a m u s c u lar procaine penicillin G or a single dose of 3.5 gm of oral a m p i c i l l i n with probenecid. Both are followed by 500 mg of oral ampicillin taken four times a day for t e n days. In p a t i e n t s who are allergic to penicillin, an alt e r n a t e r e g i m e n is 1.5 gm of oral tetracycline hydrochloride followed by 500 mg t a k e n four times a day for t e n days. H o s p i t a l i z e d p a t i e n t s are t r e a t e d with 20 million u n i t s of int r a v e n o u s aqueous c r y s t a l l i n e penic i l l i n G d a i l y u n t i l " c l e a r cut improvement," followed by 500 mg of
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o r a l a m p i c i l l i n t a k e n four t i m e s a day to complete ten days of therapy. Since it is impossible to distinguish gonococcal from nongonococcal pelvic infection p r i o r to b a c t e r i o l o g i c results, some p h y s i c i a n s also use an aminoglycoside in addition to penicillin as i n i t i a l therapy, s For s e v e r a l r e a s o n s , i n c l u d i n g the a p p e a r a n c e of penicillinase prod u c i n g gonococci a n d m i x e d infections not c o m p l e t e l y r e s p o n s i v e to penicillin (eg, N. gonorrhoeae and C. trachomatis), K a r n e y a n d Holmes~S felt t h a t a r e - e x a m i n a t i o n of current g o n o r r h e a t h e r a p y g u i d e l i n e s was necessary. They t r e a t e d a large patient population randomly with e i t h e r t e t r a c y c l i n e or spectinomycin and observed a m i n i m u m 94% cure r a t e for u n c o m p l i c a t e d a n o g e n i t a l g o n o r r h e a w i t h e i t h e r d r u g . However, t h e s e l e c t i n g out of e x i s t e n t strains ofN. gonorrhoeae r e s i s t a n t to m a x i m a l doses of t e t r a c y c l i n e would p r e c l u d e its w i d e s p r e a d use. Subsequently, they concluded t h a t future research concerning g o n o r r h e a therapy should e v a l u a t e the efficacy of other a n t i m i c r o b i a l a g e n t s including cephalosporins. Phillips et a119 s t u d i e d the in vitro activity of various cephalosporins a g a i n s t gonococci, a n d f o u n d t h a t cephalosporins were effective against both penicillin sensitive and penicillin r e s i s t a n t (ie, penicillinase produci n g ) gonococci. A g a i n s t p e n i c i l l i n s e n s i t i v e gonococci, c e f u r o x i m e , cefamandole, cefoxitin, cephalothin, cefazolin, c e p h r a d i n e , c e p h a l e x i n , and cephaloridine were found to be effective. A g a i n s t penicillin r e s i s t a n t gonococci, c e f u r o x i m e , c e f o x i t i n , cefazolin, cefamandole, cephalothin, cephaloridine, cephalexin, a n d cephr a d i n e w e r e e f f e c t i v e . T h e y concluded that clinical trials with cephalosporins m a y be worthwhile. Prior to our study, K a p l a n and Acosta s reported good clinical results (over 90% b a c t e r i a l : cures) in pelvic i n f l a m m a t o r y disease using 3 gm of i n t r a m u s c u l a r cephacetrile or cephaloridine daily for a n a v e r a g e of four days. The present study suggests t h a t cephalothin given p a r e n t e r a l l y in the dose of 12 gm/day for one week is an acceptable a l t e r n a t i v e regimen in h o s p i t a l i z e d p a t i e n t s w i t h acute pelvic i n f l a m m a t o r y disease.
The authors wish to express their gratitude to Ms. Carol Worek for her assistance in this study.
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