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A Historical Overview of Spontaneous Bacterial Peritonitis: From Rare to Resistant

2021; Lippincott Williams & Wilkins; Volume: 18; Issue: S1 Linguagem: Inglês

10.1002/cld.1122

2046-2484

Lamia Haque, Guadalupe García–Tsao,

Burkholderia infections and melioidosis

Content available: Audio Recording Lamia Y. Haque Guadalupe Garcia-Tsao If one were to identify an "Achilles heel" in compensated cirrhosis, infection would be a strong contender. Spontaneous bacterial peritonitis (SBP) is an infection of ascites that is unique to patients with cirrhosis and is associated with a high mortality. In the English literature, the first descriptions of ascites infection in cirrhosis occurred in the mid-1960s,1-3 but this statement should not be taken to imply that anglophones had the sole proprietorship of this syndrome—far from it. Starting with an 1893 French publication,4 the two related and oftentimes concomitant phenomena of bacterial infection of ascites and bacteremia in patients with cirrhosis had been reported in German, French, and English a number of times5-12 before the 1964 seminal publication by Harold Osler Conn (1925-2011)3 (Fig. 1), a distinguished professor at Yale School of Medicine for half a century. Conn reported five cases of infected ascitic fluid that he treated at the West Haven Connecticut Veterans Affairs (VA) Hospital, where he was an iconic institution in his own right. Parenthetically, it is gratifying to note that the excitement and enthusiasm for hepatology research that was engendered at the West Haven VA by Harold O. Conn and Roberto J. Groszmann (Fig. 2) for more than 30 years, in an environment conducive for trainees, continues at that institution that of late has been glorified as The West Haven Campus of the US Department of VA Connecticut Healthcare System (Fig. 3). Hal, as he was known familiarly worldwide, was the first to designate the patients in his report as cases of "spontaneous peritonitis," for which he therefore coined the term SBP. Accordingly, Conn proceeded to publicize the previously barely and often belatedly recognized condition—for which the key word in the designation was spontaneous—including the publication of a dedicated monograph (Fig. 4) in collaboration with another two distinguished SBP aficionados of the day.13 After he retired from clinical medicine in 1992, Conn himself was diagnosed as having normal pressure hydrocephalus (NPH), from the Greek hydōr kephalē (ὕδωρ κεφαλή), meaning "water in the head" (Fig. 5)—ironically after a 10-year delay and a sustained misdiagnosis of Parkinson disease. But, after he received a ventriculoperitoneal shunt that had been devised by the highly creative Colombian neurosurgeon/engineer Salomon Hakim14* (1922-2011), Conn was miraculously restored to normality.15 He, therefore, abandoned hepatology and announced, publicly and without reticence, that he would dedicate his new life to becoming an expert on NPH and to making physicians and laypeople aware of this obscure illness,15, 16 including the unusual step of initial self-publication of his own case—an accomplishment shared by only a handful of other physicians—in which he even disclosed his own name in the Journal of the Royal College Physicians of London.17, 18 In fact, for his many contributions to the world of NPH, Dr. Conn became the first Posthumous Distinguished Award recipient given by the Hydrocephalus Association in 2012. The legacy stemming from the early 1960s observations of Kerr et al.2 and Conn3 is displayed graphically in Fig. 6 as a timeline of unwavering investigation of the pathogenesis, diagnosis, and treatment of SBP and its corollary bacterial infections in cirrhosis. In the cases of SBP that he reported in the Annals of Internal Medicine in 1964,3 Conn identified the constellation of fever, chills, hypotension, abdominal discomfort, and altered mental status in patients with cirrhosis as indicative of the presence of ascitic fluid infection.3 Diagnostic paracentesis revealed "turbid neutrocytic fluid" that grew Escherichia coli, Aeromonas liquefaciens, or Streptococcus faecalis. Antibiotic therapy was effective in eradicating the infection in most cases. However, Conn noted that hepatic function deteriorated, and all patients in this small series succumbed to complications of decompensated cirrhosis within 3 months.3 The presentation of the cases in this small series is a recapitulation of the terminal illness and dramatic death of Ludwig van Beethoven (Fig. 7), at 5:45 pm on March 26, 1827, during a violent thunderstorm as retold by his physicians and other attendants.19 Was Beethoven's terminal illness SBP, as described by his personal physician, Dr. Andreas Ignaz Wawruch,20 or was it caused by repeated crude large-volume paracenteses that were performed under far from sterile conditions, when the great man's bed and the floor were awash with his ascites? Irrespective, Beethoven's plight appears to have been an early quasi-operatic description of both large-volume paracentesis and bacterial infection of ascites. Because blood cultures often grew the same organisms as ascitic fluid, Conn and other investigators astutely concluded that SBP occurred as a result of translocation of bacteria from the intestinal tract.3 They were not wrong. However, Kerr, Pearson, and Read,2 from Newcastle-upon-Tyne and Bristol in England, reporting a few months earlier in 1963 on 11 instances of ascitic infection in patients with advanced liver disease, considered that the source of the infection was the lumen of the injured gastrointestinal tract, which they mostly, but not invariably, attributed to paracentesis, even though they acknowledged that in some instances paracentesis had been performed several asymptomatic weeks previously or not at all. Their preoccupation with bowel trauma caused by paracentesis as the proximate cause of ascitic infection led Kerr et al.2 to recommend the use of a properly designed narrow-bore, blunt-ended trochar and cannula with a wide flange for fixation to the skin (Fig. 8),2 reminiscent of the bronze or lead tube with a flanged collar described by Aulus Celsus in Rome early in the first millennium CE.21† It is now known that, in cirrhosis, bacteria translocate to mesenteric lymph nodes and from there to the lymphatic system and the systemic circulation.22, 23 In the presence of ascites, circulating bacteria can seed the fluid and cause SBP or seed fluid in the pleural space leading to "spontaneous bacterial empyema" (SBE).24 Clinically, patients may have positive blood cultures in the presence of SBP or only bacteremia without SBP or SBE, an entity known as spontaneous bacteremia (SB).25 These three entities, SBP, SBE, and SB, constitute the three "spontaneous" infections in cirrhosis and should be managed equally. Importantly, bacterial translocation does not occur in prehepatic portal hypertension where liver function is normal and immune dysregulation is absent; it occurs only in cirrhosis where impairment in the hepatic reticuloendothelial system leads to inability to clear translocated bacteria.26 Vulnerable ascitic fluid is one that has a total protein ≤1 g/dL.27, 28 Bruce Runyon,29 who performed many of the initial studies regarding all aspects of SBP, showed that ascites total protein correlated with ascites complement levels and, therefore, with its opsonic activity,30, 31 that is, the capacity to phagocytose bacteria. Of great value, from the clinical perspective, was Runyon's popularization of the measurement of the serum ascites-albumin gradient32 that had been described initially by Paré et al.33 and that reliably distinguished portal hypertension from other causes as the etiology of ascites (Fig. 9), even if the ascites is infected. With time, it became obvious that not all patients with SBP presented with the constellation of symptoms and signs described by Conn. Because a delay in antibiotic therapy is associated with higher mortality,34 a diagnostic paracentesis is recommended for all patients with cirrhosis and new-onset ascites, in those with ascites who are hospitalized, and/or in patients who experience acute kidney injury (AKI) or encephalopathy, independent of symptoms.35, 36 SBP is defined by the presence of an ascitic fluid polymorphonuclear leukocyte (PMN) count ≥250 mm−3 in the absence of a secondary intra-abdominal source of infection or inflammation.35, 36 Although a PMN count >500 mm−3 is very specific for SBP, a lower cutoff of 250 mm−3 was recommended to decrease the false-negative rate.37 Isolating a microorganism is very important to inform decisions regarding antibiotic therapy. Bedside inoculation of ascites into blood culture bottles is the preferred method,38, 39‡ despite which up to 50% of cultures are negative.40 Because SBP is associated with bacteremia, blood cultures should be obtained at the same time.35, 36 Therapy for SBP includes appropriate systemic antibiotics and intravenous (IV) albumin infusion. These should be started even before a causative organism is identified. Up until the early 1990s, reports describing the use of amoxicillin/clavulanic acid and cefotaxime demonstrated ~90% response rates.41-43 However, over time, the response to initial antibiotic therapy has been declining because of the emergence of multidrug-resistant organisms (MDROs), defined as bacteria with acquired nonsusceptibility to at least one agent in three or more antimicrobial categories.44 Worse still has been the emergence of extensively and even pan-drug-resistant organisms (XDROs and PDROs, respectively§).44 Seminal prospective studies by Fernández et al.45 and a recent multinational study by Piano et al.46 have shown MDRO rates ranging between 21% and 52%. A recent study assessing epidemiological changes in antimicrobial resistance across Europe, among patients with cirrhosis afflicted with bacterial infections, found that the prevalence of MDROs in this population increased from 29% in 2011 to 38% in 2018.40 Recognized risk factors for MDROs include long-term norfloxacin prophylaxis, nosocomial infection, recent history of MDRO infection, and recent history of beta-lactam exposure.46, 47 Previous work also demonstrated that exposure to systemic antibiotics within 30 days before SBP was associated with resistant infections.47 Current guidelines therefore recommend that the initial empirical antimicrobial therapy be based on the local prevalence and site of acquisition.35, 36 The recommended therapy for patients with community-acquired SBP without recent beta-lactam exposure is a third-generation cephalosporin.36 Patients who have had recent beta-lactam exposure or have nosocomial SBP should receive broader-spectrum antibiotics based on local antimicrobial resistance patterns.36 As evidence, a small trial comparing meropenem plus daptomycin versus cephalosporins as initial antibiotics in patients with NO SBP revealed a marked significant difference in SBP resolution (87% versus 25%).48 Patients with cirrhosis are prone to development of nephrotoxicity from aminoglycosides49; therefore, these antibiotics should be used only as a last resort. The duration of antibiotic therapy is usually 7 days; however, in a study comparing standard duration of antibiotic therapy based on clinical observation (mean duration, 9.6 days) with discontinuation once ascites PMN counts reached ≤250 mm−3 (mean duration, 4.8 days), there was no significant difference in SBP recurrence or mortality between the groups.50 Development of AKI is by far the most common and most reported independent predictor of mortality in SBP.51-53 Therefore, preventing AKI or limiting its progression is crucial in the management of SBP. In a landmark study, Sort et al.54 demonstrated that the addition of IV albumin (to antibiotic therapy with cefotaxime) at doses of 1.5 g/kg of body weight at the time of SBP diagnosis and 1 g/kg on day three of therapy significantly reduced the incidence of renal impairment and improved survival (Fig. 10). The dose of albumin was entirely empirical and because the main effect of albumin is in preventing progression of renal failure, doses and frequency of administration should be based on AKI resolution (or not). Results of a retrospective study suggested that the use of nonselective beta blockers (NSBBs) increased mortality in patients with SBP by leading to AKI55; however, patients taking NSBBs had lower blood pressure, and about a third were taking carvedilol, which has a greater risk for causing hypotension.56 Results of a subsequent and also retrospective study showed that NSBBs are associated with improved survival in patients with SBP, particularly in those with a mean arterial pressure (MAP) ≥65 mm Hg,57, 58 which roughly corresponds to a systolic blood pressure of ≥90 mm Hg. Therefore, rather than discontinuing NSBBs in all patients with SBP, NSBB should be held in patients with hypotension or AKI and reinitiated with recovery. It is recommended that a diagnostic paracentesis be performed 48 hours after initiating antibiotic therapy to assess response. Serial measurements of ascitic fluid PMN counts show a marked decrease within the first 48 hours of antibiotic therapy, with a higher mortality in patients in whom PMNs do not decrease by at least 25% from baseline.59 Lack of such a response can indicate the presence of secondary peritonitis (usually from an intra-abdominal catastrophe requiring surgery) rather than SBP60 but could also indicate infection by an MDRO and, therefore, in addition to imaging studies, should lead to broadening of the antibiotic spectrum. Repeat paracentesis/thoracentesis may be unnecessary if an organism is isolated, it is susceptible to the antibiotic used, and the patient is improving clinically. Because risk factors that lead to the first episode of SBP generally remain in patients who continue to have ascites, SBP recurrence is high. In a landmark multicenter randomized clinical trial assessing oral norfloxacin at a dose of 400 mg daily, the 1-year probability of development of recurrent SBP was significantly lower with norfloxacin (20%) compared with placebo (68%).61 In the absence of norfloxacin, a reasonable alternative is oral ciprofloxacin 500 mg daily, although this recommendation is empirical. Evidence is lacking to make recommendations on secondary prophylaxis for patients infected with gram-positive organisms or MDROs. Instituting antibiotic prophylaxis in patients with ascites without a history of SBP should be based on the identification of patients at the highest risk for development of SBP. In a randomized clinical trial, Fernández et al.62 were able to identify the combination of risk factors with the highest risk for development of SBP, which included ascitic total protein <1.5 g/dL with advanced liver disease (Child-Turcotte-Pugh score ≥ 9 points with serum bilirubin ≥ 3 mg/dL) or renal impairment (serum creatinine ≥ 1.2 mg/dL, urea nitrogen ≥ 25 mg/dL, or sodium ≤ 130 mmol/L). The 1-year probability of SBP at 61% was comparable with that of recurrent SBP and was significantly higher than the 7% 1-year probability observed in patients randomized to oral norfloxacin at a dose of 400 mg daily.62 Patients randomized to norfloxacin were also less likely to experience hepatorenal syndrome (HRS) and death (Fig. 11).62 However, it is disappointing that evidence against primary prophylaxis has arisen. Norfloxacin has been associated with development of infections by MDROs.45, 63 In a recent randomized clinical trial of norfloxacin versus placebo in patients with Child-Turcotte-Pugh class C (comparable with patients included in Fernández et al.'s 2012 prospective study45), the primary endpoint, death, was not significantly different between groups,64 perhaps reflecting a change in susceptibility of bacteria to norfloxacin over the years. Furthermore, data from the North American Consortium for the Study of End-Stage Liver Disease revealed that patients receiving primary prophylaxis for SBP were at greater risk for admission to the intensive care unit, AKI, and inpatient mortality compared with those receiving secondary prophylaxis.65 Therefore, primary prophylaxis cannot be widely recommended, and in practice, its use has decreased in large published studies. Although quinolone prophylaxis was reported in 32% of patients with cirrhosis admitted with infections between 2005 and 2007,45 only 2% of patients admitted with acute-on-chronic liver failure in a more recent series had received quinolone prophylaxis.40 We end as we began, alluding to Harold Conn with the pun on his name that appeared on his very last seasonal greeting card in 2011. It has been more than 50 years since SBP in cirrhosis was described in the English medical literature, and since then there has been tremendous relentless progress in our understanding of its epidemiology, pathogenesis, and treatment (Fig. 6). The effort that has been invested in SBP over these many years is a testimony to the importance of this complication of cirrhosis. Certainly, SBP is no longer a rarely diagnosed entity and is now considered a common and treatable complication of decompensated cirrhosis, unlike the wound in Achilles' heel‖ that resulted from a poisoned arrow shot by Paris (Fig. 12), to avenge his brother Hector's death and to thwart Achilles as he climbed the walls of Troy. There are new and ongoing challenges, particularly in the realm of MDROs and XDROs, making treatment and prevention of SBP more challenging than previously. Continued efforts must be made to develop novel preferably nonantibiotic measures to prevent this deadly complication of cirrhosis. In this latest title in the History of Hepatology series, the authors, Lamia Y. Haque (fellow) and Guadalupe Garcia-Tsao (professor), both of the Section of Digestive Diseases at Yale University and the West Haven Campus of the VA Connecticut Healthcare System, portray infection as the "Achilles heel" of decompensated cirrhosis. Strictly speaking, of course, the Achilles heel in decompensated cirrhosis is the increased susceptibility to invasive migration from the lumen of the gut by bacteria, associated with impairment of the body's defenses to remove them, which leads to infection. But why sully this superb essay with pedantic criticism? In point of fact, the susceptibility to infection is not the only Achilles heel in cirrhosis. Pathological circulatory changes that are characteristic of cirrhosis lead to proliferation of varicose portosystemic collateral vessels that bleed because they do not resist the elevation of the causative pressure gradient, as described in this series by J. Bosch [Clin Liver Dis (Hoboken) 2020;15(suppl 1):S8-S12], and J.G. Abraldes and M. Niazi [Clin Liver Dis (Hoboken) 2020;16(suppl 1):S73-S82]. The aforementioned splanchnic and systemic circulatory dysfunction is also responsible for salt and water retention and renal impairment (which will be the focus of the forthcoming essay by Wong and Blendis). Deleterious secondary changes occur in the pulmonary circulation [see Krowka MJ. Clin Liver Dis (Hoboken) 2020;15(suppl 1):S13-S24], as does cardiac dysfunction of the so-called cirrhotic cardiomyopathy, which Sam Lee will soon chronicle as well. Impaired handling of ammonia produced in the gut and elsewhere leads to hepatic encephalopathy (as set out in the forthcoming essay by Tony Bass), while patients with cirrhosis are also susceptible to exacerbations of both liver dysfunction and harmful systemic inflammation in the acute-on-chronic liver failure syndrome [see Jalan R, et al. Clin Liver Dis (Hoboken) 2020;15(suppl 1) :S45-S51] and to unbridled liver proliferation, that is, various forms of liver cancer, which are detailed in imminent essays by Natarajan and El-Serag and also Rabiee and Mishra. If Achilles had just one more vulnerable heel, he would not have had a leg to stand on. Clinical research in hepatology was initiated originally by Harold Osler Conn at the West Haven VA Medical Center, where under his grandiloquent auspices, hepatology luminaries from around the world lectured at the weekly Thursday lunchtime "Pizza" Seminar series. Parenthetically it is worth observing that the conducive academic atmosphere at the West Haven VA Medical Center was not confined to the investigation of cirrhosis. It was there that Gerald Klatskin (1910-1986, David Paige Smith Professor Emeritus at the Yale School of Medicine) learned—in truth, taught himself—liver histopathology (see Reuben68). It is a great pity that his two-volume text and atlas, Histopathology of the Liver,69 which Hal Conn published after Klatskin's death, did not do justice to the photomicrographs derived from Klatskin's library of thousands of liver biopsy specimens that he photographed himself. Nobody who attended the famed Pizza Seminars could forget how Gerald Klatskin hinted to the visiting speaker that the time allotted for the talk had been exceeded, from the sound of pizza boxes being opened prematurely and the tinkling of ice in his soda. However, the abiding tradition of innovative scientific enquiry into the complications of cirrhosis—at the clinical level, using animal models, and with basic cellular and molecular methods—was firmly established in his West Haven VA Hepatic Hemodynamic Laboratory by the late Roberto J. Groszmann (who passed away in January 2021). For upward of 30 years, Roberto instilled the excitement and satisfaction of the rewards of investigation into the hearts of numerous trainees—not all of whom were Spanish speaking—from around the world. In this regard, there could be no worthier heir to Roberto's mantel of hepatology research and mentorship than Guadalupe "Lupe" Garcia-Tsao. Aside from her own original studies, Lupe is a consummate codifier of findings in all aspects of portal hypertension, because of her ability to correlate, summarize, and lucidly present expansive amounts of study/published data in her inimical lightning yet articulate style. It is tempting to call Lupe the Kamala Harris of American Hepatology, on account of her female gender and dual minority ethnicity (her mother, from Shanghai, and her father, from Veracruz, met as university students at a summer camp in Connecticut). Forsooth, it would be more logical to name Kamala Harris as the Garcia-Tsao VP, because Lupe has already achieved the status of full President—in her case of the American Association for the Study of Liver Diseases (2012-2013), a role she carried out with aplomb. It is safe to predict here that Lupe's mentee and junior coauthor of this essay, Lamia Y. Haque—a New York City native of Bangladeshi parents—also has a shining career ahead of her based on her academic productivity thus far and her laudable involvement in interracial, interreligious community service and care for the disadvantaged. In closing, in the current essay, the authors elegantly trace the evolution of our knowledge of the clinical presentation, pathogenesis, diagnosis, and treatment of SBP, from its definitive recognition in the early 1960s to the present day, as summarized so ably in a very useful timeline (Fig. 6). 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