Ertapenem failure as therapy for nosocomial spontaneous bacterial peritonitis

Nosocomial spontaneous bacterial peritonitis (SBP) accounts for one third of all SBP episodes and is caused by microorganisms resistant to third generation cephalosporins (3rdGC) up to 40% of cases, mainly due to extended-spectrum β-lactamases (ESBL) Escherichia coli and Klebsiella pneumoniae producing strains, other Enterobacteriaceae spp. and some gram positive bacteria.¹ In this setting, 3rdGC must not be used as empirical antibiotic therapy in nosocomial SBP. Carbapenems have been recommended based in bacteriological data reported in these cases.^2,3 Ertapenem, a parenteral broad-spectrum 1-beta-methyl carbapenem was approved by FDA in US and in Europe for complicated intra-abdominal infections. We are treating nosocomial SBP with ertapenem provided that 93% of isolated bacteria in nosocomial SBP of our center were sensible in vitro to this carbapenem. We report three cases of nosocomial SBP caused by ertapenem-susceptible, ESBL-producing E. coli and K. pneumoniae with a microbiological and clinical failure to recommended standard doses of 1 g/24 h.

Case 1

A 62-year-old male cirrhotic patient was admitted because of refractory ascites and hepato-renal syndrome (HRS). He presented with anasarca and a MELD score of 24. After HRS recovery, he developed hepatic encephalopathy and fever with a creatinine of 66 μmol/L, albumin of 22 g/L and bilirubin of 121 μkat/L. He was receiving prophylaxis with norfloxacin. Ertapenem 1 g every 24 h was initiated. An ESBL-producing K. pneumoniae was isolated in ascitic fluid culture with a MIC < 0.5 mg/L for ertapenem, however after 48 h ascitic fluid (AF) PMN count was higher and culture was still positive. After changing therapy to meropenem 500 mg/8 h, the AF culture become negative and PMN count normalized.

Case 2

A 41-year-old female patient was admitted for fever and ascites 9 months after orthotopic liver transplantation. Creatinine was 110 μmol/L, albumin 36 g/L and bilirubin 12 μkat/L. She was immunosuppressed with tacrolimus. Ertapenem 1 g/24 h was begun. AF culture yielded an ESBL-producing K. pneumonia with a MIC <0.5 mg/L. During the following days, PMN count decreased but ascitic fluid culture remained positive. After 6 days, although the patient improved clinically, we changed antibiotic therapy to imipenem 500 mg/6 h and AF culture became negative after 24 h of therapy.

Case 3

A 65-year-old male was admitted due to acute variceal bleeding. Patient was treated following our standard protocol. He developed a hepato-renal syndrome and was treated with terlypressin and albumin. Creatinine was 152 μmol/L, albumin 29 g/L and bilirubin 121 μkat/L. AF analysis was diagnostic of SBP and ascitic and blood culture grew ESBL-E. coli with a MIC < 0.5 mg/L for ertapenem. In the following days, patient improved and the PMN count in ascitic fluid decreased; however AF culture remained positive until day 6 of therapy. We stopped antibiotic therapy at day 13 with normal PMN count and ascitic fluid culture finally negative. A summary of all AF analysis and cultures are shown in Table 1.

Table 1.

Asctic fluid, blood culture and polymorphonuclear count and antibiotic therapy in the three cases.

Case 1	Day 0	Day 2	Day 3	Day 7
AF^* PMN^&	200/μL	600/μL		200/μL
AF^* culture	Klebsiella pneumoniae-ESBL	Klebsiella pneumoniae-ESBL		Negative
Blood culture	Negative	Not done		Not done
Antibiotic therapy	Ertapenem 1 g/24 h		Stop ertapenem. Meropenem 500 mg/8 h	Meropenem 500 mg/8 h

Case 2	Day 0	Day 2	Day 6	Day 7
AF^* PMN^&	5478/μL	1496/μL	525/μL	200/μL
AF culture	Klebsiella pneumoniae-ESBL	Klebsiella pneumoniae-ESBL	Klebsiella pneumoniae-ESBL	Negative
Blood culture	Negative	Not done	Not done	Not done
Antibiotic therapy	Ertapenem 1 g/24 h		Stop ertapenem. Imipenem 500 mg/6 h	Imipenem 500 mg/6 h

Case 3	Day 0	Day 2	Day 4	Day 6	Day 9	Day 13
AF^* PMN^&	7221/μL	4590/μL	2960/μL	560/μL	330/μL	<100/μL
AF^* culture	Escherichia coli-ESBL	Escherichia coli-ESBL	Escherichia coli-ESBL	Escherichia coli-ESBL	Negative	Negative
Blood culture	Escherichia coli-ESBL	Not done	Not done	Not done	Not done	Not done
Antibiotic therapy	Ertapenem 1 g/24 h					Stop ertapenem

*

Ascitic fluid.

&

Polymorphonuclear count.

Carbapenems are considered the drugs of choice for serious infections due to ESBL-producing bacteria.⁴ Ertapenem is a good option when coverage against Pseudomonas aeruginosa or Acinetobacter baumannii is not needed,⁵ and it is recommended for the treatment of complicated intra-abdominal infections.⁶ It is noteworthy that despite a good sensibility in vitro measured by a MIC of <0.5 mg/L, treatment failed to resolve infection in patient 1 and 2 and delayed SBP resolution in case 3. Verdier et al.⁷ studied ertapenem concentration in plasma and peritoneal fluid from patients with severe intra-abdominal infections. The study showed that ertapenem at 1 gr/day achieved highly variable plasma and peritoneal antibiotic concentrations. Ertapenem had a good peritoneal diffusion, but concentrations were frequently below the susceptibility breakpoint for ESLB-Enterobacteriaceae. Data in cirrhotic patients with ascites are not available. Host factors as hypoalbuminaemia may have a profound effect on ertapenem pharmacokinetics producing a decreased concentration in plasma and tissues.⁸ This may be relevant in cirrhotic patients. As others β-lactams, time above MIC is a key point to achieve good clinical and microbiological results and prevent resistance.

Resistance to ertapenem in ESBL-producing isolates during therapy may occur due to concurrent loss of porins and has been described in both K. penumoniae⁹ and E. coli.¹⁰ Nevertheless, in our three cases, MIC for ertapenem did not change during therapy in AF isolated bacteria.

Appropriate antibiotic empirical therapy in nosocomial SBP is unknown. Other carbapenem, imipenem and meropenem, and piperacillin–tazobactam alone or associated with glycopeptides have been suggested although randomized clinical trials are scanty.¹¹ Knowing prevalence and susceptibility of bacteria involved in nosocomial SBP in each center is mandatory to choose the best option. Pharmacokinetic studies of new therapies are needed. In critically-ill cirrhotic patients, ertapenem at 1 g/day may be insufficient due to hypoalbuminaemia and a low AF antibiotic concentration and 1 gr twice day may be more suitable for nosocomial SBP treatment.