CASE REPORT cat bite; erythromycin; Pasteurella multocida
Erythromycin Failure With Subsequent Pasteurella Multocida Meningitis and Septic Arthritis in a Cat-Bite Victim We report the case of a 75-year-old woman who developed Pasteurella multocida meningitis and septic arthritis while being treated for a cat-bite wound infection with erythromycin. Review of the literature revealed that erythromycin has poor in vitro activity against this bacterium and has been associated with serious clinical failures. We r e c o m m e n d that erythromycin not be prescribed for empiric therapy of established animalbite infections. Suggestions for optimal empiric therapy of animal-bite infections and the differential diagnosis of severe cat-bite-associated sepsis are discussed. [Levin JM, Talan DA: Erythromycin failure with subsequent Pasteurella multocida meningitis and septic arthritis in a cat-Mte victim. Ann Emerg Med December 1990;19:1458-1461.] INTRODUCTION The management of animal-bite wound infections is particularly challenging because they may be caused by unusual and potentially virulent z o o n o t i c p a t h o g e n s . We p r e s e n t the case of a w o m a n w i t h an erythromycin-treated cat-bite wound infection who subsequently developed Pasteurella multocida meningitis and septic arthritis. Serious P multocida infections and the differential diagnosis of cat-biteassociated sepsis are discussed. The literature is reviewed with regard to erythromycin failure, and recommendations for empiric therapy of animalbite wound infections are given.
James M Levin, MD* David A Talan, MD*t Sylmar, California From the Departments of Internal Medicine* and Emergency Medicine,t Olive View/UCLA Medical Center, Sylmar, California. Received for publication June 21, 1990. Accepted for publication July 5, 1990. Address for reprints: David A Talan, MD, Department of Emergency Medicine, Olive View/UCLA Medical Center, Room 2A-208, 14445 Olive View Drive, Sylmar, California 91342.
CASE REPORT Paramedics were called to the home of a 75-year-old woman who was noticed to have not picked up her newspapers for two days. Ten days earlier, the patient sustained a cat bite on her left leg, and the wound had become infected. Her physician prescribed erythromycin 500 mg four times a day, with which she was compliant. The wound had not been cultured. The patient was well until one day before admission, when she developed vomiting, diarrhea, and lethargy. Her medical history was unremarkable. The patient had no history of drug use other than erythromycin and no allergies. On arrival at the patient's home, the paramedics found her lying on the floor confused, hot, tachypneic, and tachycardic. An empty pill bottle of her erythromycin prescription was found. In the emergency department, physical examination revealed an ill-appearing, lethargic, elderly woman. Her blood pressure was 140/62 m m Hg; pulse, 106; respirations, 32; and temperature, 39.0 C rectally. Pupils were equal and reactive to light. There was no papilledema. Neck examination was remarkable for meningismus with Kernig's and Brudzinski's signs. The cardiopulmonary examination was remarkable only for II/VI late peaking systolic murmur at the apex without radiation. On the left leg was a 1.0 x 0.5-cm crusted avulsion wound surrounded by 1.0 cm of erythema with a small amount of purulent drainage. Although lethargic, the patient could be aroused but was orientated to name only. There were no lateralizing neurologic signs. An IV line was established, and thiamine, dextrose, and rialoxone were administered without response. A lumbar puncture was performed, and cefotaxime 2 g IV was administered before transport to the ICU.
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Annals of Emergency Medicine
CAT BITE Levin & Talan
Cerebrospinal fluid (CSF) analysis demonstrated 338 WBCs/mm 3 with 89% p o l y m o r p h o n u c l e a r g r a n u locytes; glucose, 51 mg/dL; and protein, 236 mg/dL. CSF Gram stain showed Gram-negative pleomorphic cocc0bacilli. Computed tomography scans of the head and sinuses were negative. The patient's mental status improved in the ICU; the next morning, she complained of right knee pain. Examination of the joint revealed warmth and effusion. Arthrocentesis p r o d u c e d c l o u d y j o i n t fluid w i t h 30,200 WBCs/mm 3 with 99% polymorphonuclear granulocytes. Gram stain revealed Gram-negative pleomorphic coccobacilli. Cultures of blood, left leg wound, synovial fluid, and CSF grew P multocida. All isolates were susceptible to the following antibiotics at the indicated minimal inhibitory concentrations (MICs) (Fox ® fastidious microdilut i o n MIC m e t h o d ; S m i t h Kline, Beckman, La Brea, California): penicillin, 0.06 ~g/mL; ampicillin, 0.25 ~g/mL; cefazolin, 1 ~g/mL; ceftizoxime, < 0.5 ~g/mL; cefuroxime, < 0.5 ixg/mL; cefotaxime, < 0.5 p~g/mL; tetracycline, ~< 0.5 Ixg/mL; and chloramphenicol, < 0.25 ~g/mL. Isolates had intermediate susceptibility to erythromycin (MIC, 2 ~g/mL) and resistance to vancomycin (MIC, > 32 ~g/mL) and clindamycin (MIC, > 8 ~xg/mL). Cultures of the cat's paws and m o u t h also grew P multocida. The echocardiogram was normal. T h e p a t i e n t was s u b s e q u e n t l y treated with aqueous penicillin G 3 million units IV every four hours for 21 days and had a full recovery.
DISCUSSION This case illustrates an uncommon presentation of a zoonotic infection. The history of a cat bite in a septic patient should alert the physician to a unique differential diagnosis that may help direct subsequent antibiotic therapy. In our patient, P multocida meningitis and septic arthritis o c c u r r e d in a p a t i e n t r e c e i v i n g e r y t h r o m y c i n for a cat-bite wound infection, thus raising the issue of the optimal antibiotic treatment of these wound infections. A wide range of unusual infectious pathogens must be considered in the differential diagnosis of a cat-bite victim who presents with fever and altered mental status. Cat scratch 136/1459
disease, caused by an identified but yet unnamed organism, typically produces a chronic regional lymphadenopathy syndrome but is occasionally associated with encephalitis. 1 Tularemia can occur after a cat bite or scratch and can cause severe systemic illness but rarely meningitis. 2 R a t - b i t e fever, c a u s e d by S t r e p t o b a c i l l u s m o n i l i f o r m i s , has been transmitted by carnivores that prey on rats and m a y cause s y s t e m i c sepsis and central nervous system infection. 3 Rabies can also be transmitted by cat bites. In 1988, cats accounted for the first time for the largest percentage of domestic animals with rabies (35%). However, transmission of rabies from this animal is rare in the United States. 4 Several other serious infections may be associated with encephalopathy after cat exposure. However, these are usually the result of exposure to infected arthropods on the cat or to infected cat tissues or discharges. These infections include plague and m u r i n e t y p h u s 5 (flea bites), leptospirosis (contact with contaminated tissue or urine), Q fever (inhalation of aerosolized particles after e x p o s u r e to p a r t u r i e n t cats), 6 and toxoplasmosis (exposure to cat feces). Cat-bite wounds may be infected with certain virulent zoonotic bacteria that produce severe systemic infection. Among these, the Centers for Disease Control designated bacteria DF-2 and IIj as producing bacteremia that may be complicated by meningitis.7, s The organism isolated in our patient, P m u l t o c i d a , characteristically produces a rapidly developing cellulitis that m a y produce local complications such as osteomyelitis and bacteremic complications such as meningitis and septic arthritis. There have been numerous reports of bacteremia due to P m u l t o c i d a . Weber et al cited 47 cases of bacteremia that had been reported in the literature. 9 Review of these cases suggests that P multocida bacteremia is predisposed to by underlying illness, including cirrhosis of the liver, diabetes, rheumatoid arthritis, malignancy, and i m m u n o c o m p r o m i s i n g medications. Meningitis due to P m u l t o c i d a is uncommon; only 21 adult cases are reported in the English literature, lo Of three epidemiologic studies of Annals of Emergency Medicine
bacterial meningitis, P multocida accounted only for ten of 612 cases (1.6%). 9 Approximately 50% of patients with P m u l t o c i d a meningitis are less than 1 year old. Cases in infants are often due to direct traumatic intracranial inoculation but may result from bacteremic seeding of the meninges from noncranial wounds. Meningitis due to P m u l t o c i d a has been described in all age groups, with 30% of cases occurring in those more than 60 years old. In addition to bite wound infections, P multocida meningitis in adults has been associated with skull t r a u m a and neurosurgery, 11 sinus surgery, 12 chronic otitis media, 13 and orbital exenteration. 14 There have been several reported cases of septic arthritis due to P multocida. 9 In a p p r o x i m a t e l y 70% of cases, only one joint was involved, and it was usually adjacent to the animal-bite wound. Patients with rheumatoid arthritis, severe degenerative joint disease, or prosthetic devices seem to be at particular risk. This case of meningitis and septic arthritis appears to have been caused by baeteremic spread of P multocida after inoculation of an extremity. It is noteworthy that systemic P multocida infection developed in a patient who had no underlying predisposing illness. Our patient developed severe systemic complications despite initial treatment of her local cat-bite wound infection w i t h e r y t h r o m y c i n . Although the patient's serum level of erythromycin was not documented, she claimed to be compliant and had completed her prescription. Susceptibility testing of the P m u l t o c i d a isolate revealed an MIC of 2 txg/mL. The usual achievable serum levels with oral administration of 500 mg four times a day of erythromycin are 1 to 2 ixg/mL. Because P multocida was c u l t u r e d f r o m the p a t i e n t ' s wound, this case appears to represent a serious clinical failure of erythromycin to treat a P multocida wound infection. In vitro resistance of P multocida to erythromycin has been reported. Shikuma and Overturf performed antibiotic susceptibility testing on 15 clinical isolates of P m u l t o c i d a by the m a c r o t u b e dilution technique and found MICs for erythromycin to range from 0.8 to 6.25 ~/mL (mean, 3.13 ~g/mL) with minimal bactericidal concentrations ranging from 0.4 19:12 December 1990
to 6.25 ~ g / m L . 15 W e b e r et al perf o r m e d agar d i l u t i o n s u s c e p t i b i l i t y t e s t i n g on 19 c l i n i c a l i s o l a t e s of P m u l t o c i d a a n d f o u n d o n l y 32% of isolates to be susceptible to erythromycin, w i t h an MIC9o of 8.0 p~g/mL. 9 G o l d s t e i n et al performed agar dilution s u s c e p t i b i l i t y t e s t i n g of the 22 clinical isolates of P m u l t o c i d a and f o u n d t h a t 14% w e r e r e s i s t a n t to e r y t h r o m y c i n (MIC range, ~< 0.06 to > 32 txg/mL; MICgo , 4 ~g/mL).16,17 To t h e b e s t of o u r k n o w l e d g e , there have been five reported cases of c l i n i c a l f a i l u r e of e r y t h r o m y c i n to treat P multocida wound infection.tO, 18-21 These cases were associated w i t h severe c o m p l i c a t i o n s , inc l u d i n g o s t e o m y e l i t i s , s e p t i c arthritis, b a c t e r e m i a , and m e n i n g i t i s . In two cases, in vitro s u s c e p t i b i l i t y data were reported, and P m u l to c i d a was found to be resistant to erythromycin.lO, 18 In our p a t i e n t , w e suspect that erythromycin may have treated s o m e of the w o u n d pathogens s u c h as G r a m - p o s i t i v e c o c c i a n d temporarily suppressed P multocida growth. S u b s e q u e n t l y , P m u l t o c i d a m a y have d e v e l o p e d a s e l e c t i v e advantage to proliferate and invade the bloodstream. T h e d e v e l o p m e n t of p o t e n t i a l l y fatal septic c o m p l i c a t i o n s after erythr o m y c i n t r e a t m e n t of a c a t - b i t e w o u n d i n f e c t i o n p r o m p t s the question of w h i c h a n t i b i o t i c s c o n s t i t u t e o p t i m a l e m p i r i c t h e r a p y for established a n i m a l - b i t e w o u n d infections, of w h i c h m o s t are c a u s e d b y dogs and cats. E m p i r i c t h e r a p y m u s t be based in part On the expected microbiology of infected dog- and cat-bite wounds, w h i c h has been investigated previously. G o l d s t e i n et al r e p o r t e d the aerobic a n d a n a e r o b i c bacteriology of e i g h t c o n s e c u t i v e i n f e c t e d d o g - b i t e w o u n d s . 32 T h e m o s t frequent i s o l a t e s were Staphylococcus aureus (four), E n t e r o b a c t e r cloacae (three), and P mu l t o ci d a (two), O n review of 20 hospitalized patients w i t h infected dog bites, Feder et al found P m u l t o c i d a to be i s o l a t e d i n n i n e cases; B a c t e r o i d e s sp (five), Streptococcus sp (four), A c i n e t o b a c t e r sp (three), a n d S aureus (three) w e r e o t h e r f r e q u e n t isolates. 23 O t h e r series have n o t found a high prevalence of P m u l t o c i d a in infected dog bites. O r d o g r e p o r t e d 52 p r o s p e c t i v e l y s t u d i e d p a t i e n t s w i t h i n f e c t e d dog bites in w h o m aerobic and anaerobic cultures were performed. 24 The m o s t 19:12 December 1990
frequent isolates were enterobact e r i a c e a e (15), P s e u d o m o n a s aeruginosa (11), and S aureus (eight); P m u l tocida was n o t r e c o v e r e d from a n y p a t i e n t ' s wound. Similarly, C a l l a h a m did n o t find P m u l t o c i d a among the 13 p a t i e n t s who developed infection in a placebo-controlled study of penicillin prophylaxis of d o g - b i t e wounds. 25 T h e m i c r o b i o l o g y of i n f e c t e d cat bites is less well studied than that of dog bites. However, P m u l t o c i d a is apparently isolated m o s t often from cat-inflicted wounds. In the study of Feder et al, P m u l t o c i d a was cultured from all six p a t i e n t s w i t h i n f e c t e d cat bites and was the sole isolate in five p a t i e n t s . 23 Kiser r e p o r t e d t h a t four of five retrospectively identified c a s e s of c a t - b i t e w o u n d i n f e c t i o n were caused by P multocida, z6 Series of m i x e d p o p u l a t i o n s of infected anim a l bites (dogs, cats, and other animals) have found P m u l t o ci d a in 9% to 44% of cases; other frequent isol a t e s i n c l u d e d S aureus and Streptococcus sp. 22,27,28
E r y t h r o m y c i n is a frequently used t r e a t m e n t for s k i n infections; a recent review discounted claims of its ineffectiveness for a n i m a l - b i t e infections, r e c o m m e n d i n g this a n t i b i o t i c as a "good" alternative for penicillinallergic patients. 29 However, considering the f r e q u e n c y and s e v e r i t y of p a s t e u r e l l a i n f e c t i o n s , t h e in vi t ro d a t a i n d i c a t i n g p o o r a c t i v i t y of e r y t h r o m y c i n , and reports of clinical f a i l u r e of e r y t h r o m y c i n a s s o c i a t e d w i t h severe P m u l t o c i d a sepsis (including our patient), we believe t h a t e r y t h r o m y c i n should n o t be used as e m p i r i c t h e r a p y for a n i m a l - b i t e inf e c t i o n s and that o t h e r a l t e r n a t i v e s should be considered. Because to the best of our k n o w l edge there have been no double-blind c o m p a r a t i v e clinical studies of antib i o t i c s for a n i m a l - b i t e w o u n d inf e c t i o n s , r e c o m m e n d a t i o n s for empiric t h e r a p y m u s t be guided by in vitro s u s c e p t i b i l i t y data and clinical o b s e r v a t i o n s . T h e a n t i b i o t i c s of choice to treat an established P m u l tocida infection include penicillin or ampicillin; alternative agents are second- a n d t h i r d - g e n e r a t i o n c e p h a l o sporins, t e t r a c y c l i n e , i m i p e n e m , trim e t h o p r i m / s u l f a m e t h o x a z o l e , or ciprofloxacin.9,15-17, 30 However, i n i t i a l therapy is empiric and m u s t also address the expected broad range of potential pathogens, in particular, S auAnnals of Emergency Medicine
reus, S t r e p t o c o c c u s sp, a n a e r o b e s ,
and perhaps some other aerobic G r a m - n e g a t i v e bacteria. Oral regimens that cover this bacterial s p e c t r u m inclUde a m o x a c i l l i n / c l a v u l a n i c acid, c e f u r o x i m e a x e t i l , a n d a m p i c i l l i n or p e n i c i l l i n w i t h d i c l o x a c i l l i n or cephalexin. C o m p a rable parenteral regimens include ampicillin/sulbactam, ticarcillin/ clavulanic acid, cefuroxime, and amp i c i l l i n or penicillin w i t h nafcillin or cefazolin. Trimethoprim/sutfam e t h o x i z o l e (oral or p a r e n t e r a l ) or ciprofloxacin (oral use in adults only) can be used in a p a t i e n t w i t h a history of serious penicillin allergy and can have good a c t i v i t y against m o s t i m p o r t a n t aerobic a n i m a l - b i t e pathogens. 3o
SUMMARY T h e o c c u r r e n c e of P m u l t o c i d a m e n i n g i t i s and septic a r t h r i t i s in a p a t i e n t treated w i t h e r y t h r o m y c i n for a cat-bite w o u n d infection illustrates the p o t e n t i a l l y serious septic complications that can result from an anim a l - b i t e infection. Based on this case a n d a r e v i e w of t h e p e r t i n e n t literature, we believe that erythrom y c i n s h o u l d n o t be p r e s c r i b e d for e m p i r i c t r e a t m e n t of established anim a l - b i t e infections. The authors thank Dr Glenn Mathisen and Dr Gary Overturf for their review of this manuscript, Dr Norman Clover for microbiological assistance, and Ms Sylvia Anguiano for expert manuscript preparation.
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