Streptococcus Pneumoniae (Cases) Or Escherichia Coli (Controls)

ORIGINAL INVESTIGATION Pneumococcal Peritonitis in Adult Patients Report of 64 Cases With Special Reference to Emergence of Antibiotic Resistance

Olga Capdevila, MD; Roman Pallares, MD; Imma Grau, MD; Fe Tubau, MD; Josefina Lin˜ares, MD; Javier Ariza, MD; Francisco Gudiol, MD

Background: Few data are available regarding pneu- tis was associated with upper or lower gastrointestinal mococcal peritonitis. We studied the clinical character- tract diseases; in most cases, the infection appeared af- istics of intra-abdominal infections caused by Strepto- ter surgery. A hematogenous spread of S pneumoniae from coccus pneumoniae and its prognosis in relation to a respiratory tract infection might be the most impor- antibiotic resistance. tant origin of peritonitis; also, S pneumoniae might directly reach the gastrointestinal tract favored by endo- Methods: We reviewed all cases of culture-proved pneu- scopic procedures or hypochlorhydria. There was an mococcal peritonitis. Patients with liver cirrhosis and pri- increased prevalence of penicillin and cephalosporin re- mary pneumococcal peritonitis were compared with pa- sistance up to 30.7% and 17.0%, respectively, although tients with Escherichia coli peritonitis. it was not associated with increased mortality rates.

Results: Between January 1, 1979, and December 31, Conclusions: Primary pneumococcal peritonitis in pa- 1998, we identified 45 cases of primary pneumococcal tients with cirrhosis more often spread hematogenously peritonitis in patients with cirrhosis and 19 cases of sec- from the respiratory tract and was associated with early ondary (or tertiary) pneumococcal peritonitis. Patients mortality. In secondary (and tertiary) pneumococcal peri- with cirrhosis and primary pneumococcal peritonitis vs tonitis, a transient gastrointestinal tract colonization and those with primary E coli peritonitis had more frequent inoculation during surgery might be the most impor- community-acquired infection, 73% vs 47%; pneumo- tant mechanisms. Current levels of resistance were not nia, 36% vs 2%; and bacteremia, 76% vs 33%; and higher associated with increased mortality rates. attributable mortality (early mortality), 27% vs 9% (PϽ.05 for all). Secondary (or tertiary) pneumococcal peritoni- Arch Intern Med. 2001;161:1742-1748

TREPTOCOCCUS PNEUMONIAE is a most likely route of peritoneal fluid infec- common pathogen that causes tion.6,7,22,23 In some patients, a respiratory high morbidity and mortality tract focus is not clinically apparent, and, around the world.1,2 It is the in these cases, the gastrointestinal tract has most common cause of com- been hypothesized to be a source of pneu- munity-acquiredS pneumonia and the sec- mococci.7,22,24 However, pneumococci are ond most common cause of purulent men- soluble in bile salts,5 and, therefore, it is un- ingitis,3-5 but intra-abdominal pneumococcal likely that S pneumoniae can grow in the nor- infections are rarely found.6-9 mal gastrointestinal tract. Primary (or spontaneous) bacterial On the other hand, secondary in- peritonitis occurs mainly in patients with tra-abdominal infection (secondary peri- liver cirrhosis and is usually caused by tonitis) is due to the spread of gastroin- gram-negative bacilli.10-12 It is thought that testinal or genitourinary microorganisms in most cases the enteric microorganism into the peritoneal space from loss of in- gains access to the peritoneal cavity with- tegrity of the mucosal barrier. These are out loss of integrity of the intestinal wall often polymicrobial infections and through a mechanism of bacterial trans- can take the form of generalized perito- location.12-20 In addition, gram-negative nitis or localized peritonitis (localized bacteria can occasionally reach the peri- abscesses).14,15,22 toneal cavity by a hematogenous route To date, only anecdotal cases of adult From the Infectious Disease from a distant primary focus (eg, a uri- patients with secondary pneumococcal peri- Service (Drs Capdevila, nary tract infection).21 tonitis have been reported,25-28 and some of Pallares, Grau, Ariza, and Primary pneumococcal peritonitis in them were associated with appendici- Gudiol) and Microbiology 29,30 Service (Drs Tubau and patients with cirrhosis is usually associ- tis. The mechanism of the pneumococ- Lin˜ares), Hospital de Bellvitge ated with a respiratory tract infection such cus that causes these infections is not clear and University of Barcelona, as pneumonia, and, in this case, the blood- because it is not found in the gastrointes- Barcelona, Spain. stream (hematogenous spreading) is the tinal tract.

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 PATIENTS AND METHODS culture (for S pneumoniae [case patients] or E coli [control patients]) were present, and without any clinical or radio- SETTING AND STUDY DESIGN logic data suggesting a surgically treatable intra- abdominal focus. The present study was carried out in Bellvitge Hospital, a Secondary (or tertiary) pneumococcal peritonitis was 1000-bed teaching hospital for adult patients in Barce- diagnosed in a patient with a localized or diffuse suppura- lona, Spain. It serves approximately 1 million people and tive intra-abdominal process together with a positive cul- admits more than 26000 patients per year. This hospital ture for S pneumoniae and in whom an intra-abdominal, sur- does not have pediatrics and obstetrics departments. gically treatable source was detected (or in whom the We reviewed the clinical and microbiological data of infection appeared after surgery). all patients who had a diagnosis of diffused or localized We considered a hospital-acquired peritoneal infec- peritonitis and a peritoneal sample that was positive for S tion (either primary or secondary peritonitis) when the epi- pneumoniae. These patients were admitted to Bellvitge sode occurred 48 hours after hospital admission (or ap- Hospital between January 1, 1979, and December 31, peared after surgery) and it was not in the incubated period. 1998, and most of them had been cared for and included Community-acquired infection was considered when it was in a protocol of invasive pneumococcal infections by one evident on hospital admission or within the first 48 hours. of us (R.P.). Pneumonia was considered (definitive diagnosis) in Patients with liver cirrhosis and primary pneumococ- a patient with signs or symptoms of a lower respiratory tract cal peritonitis (case patients) were compared with patients infection and a new pulmonary infiltrate on chest radiog- with cirrhosis and primary peritonitis due to E coli (control raphy, together with bacteremia or positive culture from a patients). For each case patient we selected a control patient lower respiratory tract sample (eg, pleural fluid). We also according to the nearest date of positive culture. If a case or considered pneumonia (presumptive diagnosis) in pa- control patient had more than 1 episode of primary perito- tients with clinical and radiographic findings compatible nitis, only the first episode was considered. with pneumonia, with a positive sputum sample or no respiratory tract samples available for culture (all of our pa- STUDY VARIABLES AND DEFINITIONS tients had concomitant positive ascitic fluid cultures for either S pneumoniae or E coli). The diagnosis of liver cirrhosis was established using In all patients, demographic characteristics, clinical find- clinical, laboratory, and exploratory findings and did ings, and laboratory and medication data were obtained from not require a liver biopsy with histologic confirmation. hospital records or from previous data recorded in the pro- The stage of cirrhosis was determined by the criteria of tocol of invasive pneumococcal infections. Pugh et al.34,35 Previous hospitalization was defined as admission to Primary peritonitis in a patient with cirrhosis was con- any hospital during the previous 6 months. sidered when clinical findings together with biochemical data of peritoneal inflammation and a positive ascitic fluid Continued on next page

There have been reported cases of primary and sec- abdominal pneumococcal isolates represented 4.3% of a to- ondary pneumococcal peritonitis in prepubertal girls and tal of 1476 S pneumoniae strains isolated from clinical speci- in postpubertal healthy women, mainly post partum, af- mens (all sterile fluid samples; sputum samples were not ter an abortion, after gynecologic procedures, or associ- included). Comparing 1979 to 1988 with 1989 to 1998, ated with intrauterine device use.25-28,31 It is well known the percentage of pneumococcal isolates from abdominal that S pneumoniae can colonize in the vagina and an as- samples vs the total number of sterile fluid samples was 3.6% cending infection can occur.32,33 In children, coloniza- (22/604) and 4.8% (42/872), respectively (P=.27). tion in the genitourinary tract with S pneumoniae occurs Of 64 patients with intra-abdominal pneumococ- because of inadequate hygiene or orogenital sexual cal infections, 45 with liver cirrhosis had primary pneu- abuse.24,29,30 In these patients, when no apparent puru- mococcal peritonitis and the remaining 19 had second- lent foci in the genitourinary tract is found, such cases ary (or tertiary) pneumococcal peritonitis. are usually called primary peritonitis.32 The main objectives of the present study were (1) to PRIMARY PNEUMOCOCCAL PERITONITIS describe different types of intra-abdominal infections caused by S pneumoniae; (2) to determine the clinical character- Prevalence istics, laboratory findings, and outcomes of patients with liver cirrhosis and primary peritonitis due to S pneumo- We analyzed all patients admitted to Bellvitge Hospital niae and to compare them with those infected by Escheri- between January 1, 1989, and December 31, 1998, with chia coli; and (3) to study antibiotic resistance in pneumo- a diagnosis of chronic liver disease (n=7535); approxi- coccal isolates and determine its clinical relevance. mately 90% of them had liver cirrhosis (an estimated 6871 patients). Primary bacterial peritonitis (of any etiology) RESULTS occurred in 513 patients (8% of all patients with liver cirrhosis). Primary pneumococcal peritonitis (30 cases At Bellvitge Hospital, during the 20-year study period, during 1989-1998) represented 5.8% of all primary bac- we identified 64 patients with intra-abdominal infections terial peritonitis and 0.4% of all hospital admissions for caused by S pneumoniae. During this period, the 64 intra- liver cirrhosis.

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 We specifically investigated the performance of en- Antibiotic susceptibility to penicillin was initially deter- doscopic procedures, peritoneovenous shunt implemen- mined with a 1-µg oxacillin sodium disk using the tation, or surgery within 1 month of hospital admission. Kirby-Bauer disk diffusion method, and strains that Previous antibiotics were considered when the pa- showed a zone of inhibition of less than 20 mm were tient received any antibiotic for prophylaxis or treatment considered nonsusceptible to penicillin. Minimal inhibi- for more than 48 hours during the previous 30 days of peri- tory concentrations (the lowest concentration that inhib- tonitis. its pneumococcal growth) of isolated strains from 1979 Previous episodes of primary bacterial peritonitis to 1992 were determined using the agar dilution method were considered when they occurred within 1 year of in Mueller-Hinton agar supplemented with 5% sheep the current hospital admission and by a different micro- blood and containing antimicrobials, as described previ- organism. ously.36 Minimal inhibitory concentrations of isolated Septic shock was considered in a patient with a sys- strains from 1993 to 1998 were determined using the tolic blood pressure below 90 mm Hg and peripheral hy- microdilution method in Mueller-Hinton broth supple- poperfusion together with clinical or bacteriological evi- mented with 5% lysed horse blood, as recommended in dence of uncontrolled infection. the 1992 criteria of the National Committee for Clinical Antibiotic therapy was prescribed according to the at- Laboratory Standards.37 The following 7 antimicrobial tending physician’s criteria and varied during the study pe- agents were tested: penicillin G, ceftriaxone/cefotaxime, riod. The most common empirical antibiotic regimens were erythromycin, clindamycin, sulfamethoxazole and tri- penicillin or ampicillin sodium plus aminoglycosides or az- methoprim, tetracycline, and chloramphenicol. The treonam during the first years of the 1980s, and since 1986 results of susceptibility tests were evaluated according to almost all patients received a cephalosporin such as cefo- the 1998 criteria of the National Committee for Clinical taxime sodium or ceftriaxone sodium. Laboratory Standards. Mortality was considered when the patient died within 30 days of diagnosis of peritonitis. Attributable mortality STATISTICAL ANALYSIS (mortality probably related to infection) was considered when the patient died within 7 days of diagnosis and with- Statistical analysis was carried out using a statistical soft- out another evident cause of death. ware package (SPSS for Windows, version 9.0; SPSS Inc, Chicago, Ill). Data are given as mean±SD. Continuous vari- MICROBIOLOGICAL METHODS ables were compared using the unpaired t test, and cat- egorical variables were compared using ␹2 or Fisher exact Biological samples (eg, blood and peritoneal fluid) were tests when appropriate. Statistical significance was estab- studied at the Microbiology Laboratory. Strains of S lished at PϽ.05 (2-tailed). When many variables were ana- pneumoniae were identified using standard methods. lyzed, and to adjust for multiple comparisons, the Bonfer- Ascitic fluid cultures were performed by the method of roni adjustment was used (calculated by dividing ␣=.05 bedside inoculation of blood culture bottles with ascites. by ␬ variables).38

Case-Control Study During the study, we found a significant decrease in the mortality rate in both groups. Thus, from 1979- Forty-five case patients with primary pneumococcal peri- 1988 to 1989-1998, mortality decreased in patients with tonitis were compared with 45 control patients with pri- pneumococcal peritonitis from 73% (11 of 15 patients) mary peritonitis due to E coli (Table 1). to 33% (10 of 30 patients) (P=.01) and in patients with The statistically significant differences between the E coli primary peritonitis from 64% (9 of 14 patients) to 2 groups were that patients with pneumococcal perito- 32% (10 of 31 patients) (P=.04). nitis were more frequently smokers, had associated pneumonia, more often had bacteremia, less frequently had a SECONDARY (OR TERTIARY) nosocomial-acquired infection, and had lower ascitic fluid PNEUMOCOCCAL PERITONITIS white blood cell counts (Table 1). Although not statistically significant, patients with We studied 19 patients (age, 59.7±18.6 years; 14 [74%] pneumococcal peritonitis had more associated comor- were men) with diffuse or focal pneumococcal peritoni- bidities, were more frequently alcohol abusers, received tis in whom an apparent source of the infection was de- previous antacid treatment, and had a previous endos- tected; they were divided into upper and lower abdomi- copy. The etiology and stage of liver cirrhosis were nal infections. similar in both groups; most patients had an advanced stage of the disease according to Child-Pugh scores Upper Abdominal Infection (Table 1). Mortality in patients with primary pneumococcal The 12 patients with upper abdominal pneumococcal in- peritonitis and E coli peritonitis at 30 days was 47% (21 fections had associated gastroduodenal or pancreatico- patients) and 36% (16 patients), respectively (P=.28) biliary tract disease. (Table 1). Patients with primary pneumococcal perito- Of 7 patients with gastroduodenal ulcer (per- nitis had higher attributable mortality than patients with forated or bleeding), in 1 case S pneumoniae was iso- E coli peritonitis: 27% (12 of 45 cases) vs 9% (4 of 45 lated in pure culture at the time of initial surgery and controls) (P=.05). in the remaining 6 cases the microorganism was iso-

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 1. Clinical Characteristics and Laboratory Findings in Patients With Liver Cirrhosis and Primary Peritonitis Due to Streptococcus pneumoniae (Cases) or Escherichia coli (Controls)

Cases Controls (n = 45) (n = 45) P * Demographic data Age, mean ± SD, y 55 ± 14 60 ± 13 . . . Men, No. (%) 37 (82) 33 (73) . . . Underlying conditions and cirrhosis status Associated comorbidities, No. (%)† 28 (62) 22 (49) . . . Diabetes 7 7 . . . Chronic obstructive pulmonary disease 10 6 . . . Human immunodeficiency virus 9 3 . . . Chronic renal failure 2 0 . . . Others‡ 4 7 . . . Origin of cirrhosis Alcoholic 21 (47) 25 (56) . . . Virus (B, C, or both)§ 16 (36) 16 (36) . . . Others 8 (18) 4 (9) . . . Child-Pugh (A/B/C)࿣ 0/13/28 0/9/36 . . . Associated hepatocarcinoma 6 5 . . . Predisposing factors (previous conditions/instrumentations), No. (%) Alcohol abuse 36 (80) 30 (67) . . . Smoking 28 (62) 18 (40) .03 Injecting drug user 7 (16) 3 (7) . . . Antacid treatment 7 (16) 3 (7) . . . Antimicrobial drug treatment¶ 9 (20) 10 (22) . . . Hospital stay 25 (56) 23 (51) . . . Endoscopy 9 (20) 6 (13) . . . Spontaneous bacterial peritonitis 6 (13) 8 (18) . . . LeVeen shunt 3 (7) 1 (2) . . . Clinical findings, No. (%) Fever 39 (87) 36 (80) . . . Abdominal pain 33 (73) 33 (73) . . . Encephalopathy 13 (29) 16 (36) . . . Shock 11 (24) 6 (13) . . . Associated pneumonia# 16 (36) 1 (2) Ͻ.001 Positive blood culture 34 (76) 15 (33) Ͻ.001 Nosocomial acquisition 12 (27) 24 (53) .01 Laboratory data, mean ± SD** Blood analysis Hematocrit (43, 45) 0.32 ± 0.60 0.32 ± 0.50 . . . Leukocyte count, ×109/L (42, 44) 11.510 ± 6.692 9.922 ± 6.554 . . . Prothrombin time, s (41, 44) 22.1 ± 5.4 21.8 ± 6.1 . . . Albumin, g/L (39, 44) 24 ± 6 24 ± 4 . . . Creatinine, µmol/L (mg/dL) (41, 45) 119 ± 70 (1.3 ± 0.8) 142 ± 96 (1.6 ± 1.1) . . . Bilirubin, µmol/L (mg/dL) (39, 43) 76 ± 69 (4.4 ± 4.0) 106 ± 106 (6.2 ± 6.2) . . . Alanine aminotransferase, U/L (40, 37) 24 ± 35 34 ± 57 . . . Ascitic fluid analysis Leukocyte count, cells/µL (30, 39) 3000 ± 3917 8152 ± 9975 .005 Protein, g/L (34, 40) 10 ± 7 9 ± 5 . . . Glucose, mmol/L (mg/dL) (34, 40) 6 ± 2 (0.3 ± 0.1) 7 ± 2 (0.4 ± 0.1) . . . Outcome, No. (%) Death (30 d) 21 (47) 16 (36) . . .

*Values disclosed are those with a significance level of Ͻ.05. We applied the Bonferroni adjustment of 0.005 to determine which variables are significantly different. †Some patients had more than 1 comorbidity. ‡Gastric ulcer (n = 1), cardiac failure (n = 1), gastric neoplasm (n = 1), and polycythemia vera (n = 1) in cases and gastric ulcer (n = 3), cardiac failure (n = 2), oral cavity neoplasm (n = 1), and stroke (n = 1) in controls. §We identified patients infected with B virus, C virus, and both B and C virus; in cases there were 7, 4, and 5, respectively; in controls there were 4, 10, and 2, respectively. ࿣We do not know the Child-Pugh score in some patients because not all data were available for calculation. ¶Of 45 cases, 9 had received antibiotics: 6 for prophylaxis (4 took sulfamethoxazole and trimethoprim and 2 took norfloxacin) and 3 for treatment (2 took ampicillin plus cefotaxime and 1 took cefotaxime) (5 had missing data). Of 45 controls, 10 had received antibiotics: 3 for prophylaxis (2 took sulfamethoxazole and trimethoprim and 1 took norfloxacin) and 7 for treatment (2 took cefotaxime, 1 took ciprofloxacin, 1 took amoxicillin and clavulanate, 2 took ampicillin plus aztreonam, and 1 took amoxicillin). #Of 16 case patients with pneumococcal peritonitis, 13 had a definitive diagnosis of pneumococcal pneumonia (12 had bacteremia and 1 had pleural fluid positive for pneumococcus) and 3 had a presumptive diagnosis of pneumonia (1 had a positive sputum culture and 2 had no respiratory tract samples available for culture). The 1 control patient with E coli peritonitis had associated pneumonia with a definitive diagnosis (positive pleural fluid culture for E coli). **Number of case patients tested, number of control patients tested is shown in parentheses.

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 lated 4 to 31 days after surgery (4 had polymicrobial infection). Table 2. Mortality Rates in Patients With Primary and Of the other 5 patients, 3 were admitted to the hos- Secondary Peritonitis Due to Streptococcus pneumoniae According to MICs of Penicillin and Cefotaxime/Ceftriaxone* pital because of an exacerbation of chronic pancreatitis, and during hospitalization a pancreatic pseudocyst or ab- Mortality, No. (%) scess was diagnosed; S pneumoniae was isolated from a sample obtained from scanning guided puncture 12 to Primary Secondary 46 days after hospitalization (none of these patients un- Peritonitis Peritonitis Total Drug and MIC (n = 45) (n = 19) (N = 64) derwent previous surgery). The other 2 patients were admitted to the hospital because of biliary tract neoplasm Penicillin, µg/mL Ͻ0.06 (Susceptible) 17/32 (53) 1/11 (9) 18/43 (42) (n=1) or pancreatic neoplasm (n=1). The patient with 0.12-1.0 (Intermediate) 1/9 (11) 1/5 (20) 2/14 (14) a diagnosis of pancreatic neoplasm underwent surgery Ն2.0 (Resistant) 3/4 (75) 0/3 3/7 (43) on hospital admission, and S pneumoniae grew in pure Cefotaxime/ceftriaxone, µg/mL culture from an exudate obtained from a perineoplasm Յ0.5 (Susceptible) 21/45 (47) 1/15 (7) 22/60 (37) abscess. The patient with biliary tract neoplasm was ad- 1.0 (Intermediate) 0 1/2 (50) 1/2 (50) mitted to the hospital for elective surgery; 11 days later, Ն2 (Resistant) 0 0/2 0/2 an intra-abdominal abscess was detected in which S pneumoniae grew in pure culture. *MIC indicates minimal inhibitory concentration.

Lower Abdominal Infection bleeding secondary to duodenal ulcer who developed a polymicrobial infection after surgery in which grew S pneu- Of 7 patients with lower pneumococcal abdominal in- moniae and Morganella morganii; he died despite surgi- fections, 6 were admitted to the hospital for elective sur- cal drainage and antibiotic therapy (amoxicillin and cla- gery (5 with intestinal neoplasm and 1 with Gardner vulanate potassium plus tobramycin sulfate). syndrome). The intra-abdominal infection appeared 5 to 20 days after surgery (in 4 of the 6 cases, S pneumoniae ANTIBIOTIC RESISTANCE was isolated in pure culture). The last patient is a post- partum woman who was admitted to the hospital be- Overall, in the abdominal pneumococcal isolates (n=64) cause of abdominal pain and fever and was diagnosed as we found an increase in penicillin resistance during having an intra-abdominal abscess in which S pneumo- the study: 14% (2 of 14 strains) between 1979 and 1985, niae grew in pure culture. 33% (5 of 15 strains) between 1986 and 1991, and 40% (14 of 35 strains) between 1992 and 1998 (P=.05). The Predisposing Factors mortality rate did not differ significantly between patients infected with penicillin-resistant and penicillin- Most patients with secondary pneumococcal peritonitis had susceptible strains (Table 2). Only 4 patients had re- some predisposing factors for pneumococcal infection or sistance to cefotaxime/ceftriaxone, and one of them died. colonization. Of 19 patients, alcohol abuse was present in Table 3 shows our experience with antibiotic re- 14 (74%), liver cirrhosis in 2 (11%), chronic bronchitis sistance in 1095 pneumococcal blood isolates during 2 or chronic obstructive pulmonary disease in 7 (37%), and different periods. There was increased prevalence of peni- clinical and radiologic findings suggestive of a lower res- cillin, cephalosporin, and macrolide resistance and de- piratory tract infection coinciding with or preceding the creased tetracycline and chloramphenicol resistance. intra-abdominal pneumococcal infection in 5 (26%). Only 4 patients (21%) underwent previous endoscopy, and 8 COMMENT (42%) had previous antacid treatment. We suggest a comprehensive classification of pneumo- Treatment and Mortality coccal peritonitis (Table 4). Most patients with pneumococcal peritonitis can be included in 1 of 3 catego- All but one patient required drainage (surgically or by ries: (1) primary peritonitis associated with liver cirrhosis, scanning guide puncture); this was a patient with cir- nephrotic syndrome, or chronic renal failure and con- rhosis who died (see the following paragraph). All but 3 tinuous ambulatory peritoneal dialysis; (2) secondary (or patients received antibiotic therapy; these 3 patients re- tertiary) peritonitis associated with gastrointestinal dis- covered with only surgical drainage. ease (or after surgery); and (3) peritonitis in young women Two (11%) of 19 patients died, both within 3 days with or without an apparent genitourinary focus. of diagnoses of pneumococcal infection. One of them, a To date, most cases of pneumococcal peritonitis have 73-year-old man with liver cirrhosis in an advanced occurred in patients with liver cirrhosis.7,9 According to stage, had a polymicrobial infection after surgery for a different studies,10,11,39 of all cases of primary peritonitis perforated gastric ulcer; a culture from an abdominal fluid in patients with cirrhosis, 1% to 11% are caused by S pneu- puncture grew S pneumoniae and Pseudomonas aerugi- moniae. However, pneumococcus rarely causes second- nosa (resistant to initial therapy with ceftriaxone and clin- ary (or tertiary) peritonitis, and there have been only an- damycin); no surgical drainage could be performed. The ecdotal reports of well-documented secondary (or tertiary) second patient was a 78-year-old man with chronic ob- pneumococcal peritonitis associated with gastrointesti- structive pulmonary disease and gastrointestinal tract nal disease8,9,29,30 or in young women.5,22-28,33

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 Herein, we found that in patients with cirrhosis, the mechanism of spread and prognosis are the 2 most im- Table 3. Trends in Antibiotic Resistance in 1095 Blood portant differences between primary peritonitis due to Isolates of Streptococcus pneumoniae* S pneumoniae and primary peritonitis due to E coli. In patients with cirrhosis and primary peritonitis due Resistance, % to E coli, the most important mechanism is thought to 1979-1988 1989-1998 be translocation from the gastrointestinal tract, and, in Drug and MIC (n = 468) (n = 627) P † some cases, it can be due to a bacteremic spread from a Penicillin, µg/mL distant focus (eg, urinary tract infections). On the other 0.1-1 8 14 Ͻ.001 hand, the mechanism of primary pneumococcal perito- Ն2416 nitis in patients with cirrhosis is controversial because Cefotaxime/ceftriaxone, µg/mL 1 ... 13 ... S pneumoniae is not found in the gastrointestinal tract, Ն2 ... 4 ... probably because this microorganism is soluble in bile Erythromycin, Ն0.5 µg/mL 3 12 Ͻ.001 salts that avoid bacterial growth.5 However, we can specu- Clindamycin, Ն0.5 µg/mL 3 12 Ͻ.001 late that hematogenous spreading might be important. Tetracycline, Ն0.4 µg/mL 54 27 Ͻ.001 Thus, in our study, 16 patients (36%) had associated pneu- Chloramphenicol, Ն8 µg/mL 39 18 Ͻ.001 monia, and, in these cases, hematogenous spread from Sulfamethoxazole and 39 41 .53 trimethoprim, Ն1/19 µg/mL the respiratory tract could be suggested.7 In addition, other patients who develop pneumococcal peritonitis are those *MIC indicates minimal inhibitory concentration (the lowest concentration without an apparent respiratory tract infection but who that inhibits pneumococcal growth). are at higher risk of S pneumoniae oropharyngeal colo- †Values disclosed are those with a significance level of Ͻ.05. We applied the Bonferroni adjustment of 0.005 to determine which variables are nization (eg, smokers and alcoholics) and who were re- significantly different. Pneumococcal strains were not routinely tested for cently subjected to previous endoscopic procedures. Tran- cefotaxime/ceftriaxone susceptibility during 1979-1988. However, we might sient bacteremia can occur after endoscopy.40 assume that almost all cases were susceptible because the first cases with Recent studies41-46 have shown that short-term prog- increased MICs of cefotaxime/ceftriaxone appeared at the end of the 1980s. nosis in patients with cirrhosis and primary bacterial peritonitis (most cases caused by Enterobacteriaceae) has im- proved during the past decade, probably as a consequence Table 4. Classification of Peritonitis Caused by Streptococcus pneumoniae of early diagnosis and better therapeutic approaches. Thus, mortality from primary bacterial peritonitis (all cases) de- I. Primary peritonitis in patients with liver cirrhosis,* nephrotic creased from more than 75% in the 1970s to about 40% syndrome,† or chronic renal failure and continuous ambulatory 13,14,17,21,22,47 in the 1990s. We also found a decreased mor- peritoneal dialysis‡ tality rate during recent years in patients with either pneu- II. Secondary (and tertiary) peritonitis associated to gastrointestinal mococcal or E coli primary peritonitis. tract disease§ In our study, we found a higher 30-day mortality Upper Perforated gastric or duodenal ulcer rate in patients with pneumococcal peritonitis com- Complicated pancreatitis pared with those with E coli peritonitis, but this differ- Biliary tract disease ence did not reach statistical significance (Table 1). More- Lower over, patients with pneumococcal peritonitis had higher Perforated appendicitis attributable mortality (27%) than those with peritonitis Complicated colorectal disease due to E coli (9%). We can speculate that S pneumoniae III. Peritonitis in young women࿣ might be more virulent than E coli and that pneumococ- Primary peritonitis Complicated salpingitis or pyosalpinx cal peritonitis is often associated with pneumonia, which can be complicated with respiratory failure and septic *Approximately 40% of cases had associated pneumonia. shock. We did not find that patients with pneumococcal †Most cases occurred in children. peritonitis had a more advanced stage of cirrhosis. ‡Most of these patients had associated pneumonia or complication of an intrauterine device. Of note is the high number of nosocomial-acquired §Most cases occurred after surgery (tertiary peritonitis), and rarely pneumococcal and E coli peritonitis in our study. Despite S pneumoniae was isolated from an initial intraoperative culture. the fact that these microorganisms are usually components ࿣In women, an ascendant infection from the genitourinary tract of the patient’s own flora (acquired in the community), (secondary peritonitis) can occur, but in some cases no apparent local suppurative process could be found (primary peritonitis). in recent years patients with cirrohsis have a long life ex- pectancy and might develop peritonitis during hospitalization for other reasons. However, we cannot exclude that pneumococcal infections48 and might be because levels some of these microorganisms were transmitted from in- of ␤-lactams achieved in serum and ascitic fluid are much patients or hospital personnel. higher than minimal inhibitory concentrations. Table 3 shows trends in antibiotic resistance dur- In cases of secondary peritonitis, the infection might ing the past 2 decades. We observed significant in- occur as a result of loss of integrity of the gastrointestinal creases in cases with intermediate or resistant penicil- tract wall (eg, perforation of gastric ulcer or colonic lin, cephalosporin, and macrolide. We did not find a neoplasm).14 Secondary peritonitis caused by S pneumo- correlation between the minimal inhibitory concentra- niae has rarely been reported.9 We identified 19 cases of tions of penicillin and cephalosporin and mortality rates secondary (or tertiary) pneumococcal peritonitis associ- (Table 2). This is also found with other nonmeningeal ated with upper or lower gastrointestinal tract diseases.

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 Although S pneumoniae is not a component of gas- 13. Runyon BA. Spontaneous bacterial peritonitis. Hepatology. 1988;8:171-175. 14. Johnson C, Baldessarre J, Levison M. Peritonitis: update on pathophysiology, trointestinal tract flora, we can speculate that in some cir- clinical manifestations, and management. Clin Infect Dis. 1997;24:1035-1047. cumstances the microorganisms might become part of the 15. Guarner C, Soriano G. Spontaneous bacterial peritonitis. Semin Liver Dis. 1997; transient gastric flora. Despite not being well docu- 17:203-217. 16. Garcia-Tsao G, Albillos A, Barden GE, West B. Bacterial translocation in acute mented, upper abdominal transient colonization by S pneu- and chronic portal hypertension. Hepatology. 1993;17:1081-1085. moniae might occur in patients with low gastric acidity who 17. Llovet JM, Bartolı´ R, March F, et al. Translocated intestinal bacteria cause spon- had oropharyngeal colonization by S pneumoniae, and par- taneous bacterial peritonitis in cirrhotic rats. J Hepatol. 1998;28:307-313. 18. Llovet JM, Bartolı´ R, Planas R, et al. Selective intestinal decontamination with ticularly in patients subjected to endoscopic procedures. norfloxacin reduces bacterial translocation in ascitic cirrhotic rats exposed to hem- In lower abdominal infections, the pneumococcal colo- orrhagic shock. Hepatology. 1996;23:781-787. 19. Garcia-Tsao G. Identifying new risk factors for spontaneous bacterial peritoni- nization is more difficult to explain, and we found in the tis: how important is it? Gastroenterology. 1999;117:495-499. literature only a few cases of acute appendicitis caused by 20. Llovet JM, Bartoli R, Planas R, et al. Bacterial translocation in cirrhotic rats: its role S pneumoniae.9,29,30 In our study, we identified 6 patients in the development of spontaneous bacterial peritonitis. Gut. 1994;35:1648-1652. 21. Bhuva M, Ganger D, Jensen D. Spontaneous bacterial peritonitis: an update on with colonic diseases and pneumococcal peritonitis, and evaluation, management and prevention. Am J Med. 1994;97:169-175. in all cases the infection appeared after surgery. In cases 22. Abalde M, Molina F, Guerrero A, Llinares P. Streptococcus pneumoniae peritoni- of pneumococcal peritonitis that occur after surgery (ter- tis secondary to a tubo-ovarian abscess. Eur J Clin Microbiol. 1998;17:671-673. 23. Al-Wali W, Baillod R, Hamilton-Miller JMT, Brumfitt W. Peritonitis by Strepto- tiary peritonitis), one can speculate that the microorgan- coccus pneumoniae secondary to pneumococcal chest infection in a patient on ism might also be inoculated during the surgical proce- continuous ambulatory peritoneal dialysis [letter]. Nephron. 1991;59:173. dure from the oropharyngeal flora of the surgical personnel. 24. Sirotnak AP, Eppes SC, Klein JD. 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