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National Guideline Centre (UK). Cirrhosis in Over 16s: Assessment and Management. London: National Institute for Health and Care Excellence (NICE); 2016 Jul. (NICE Guideline, No. 50.)
11.1. Introduction
People with cirrhosis and upper gastrointestinal bleeding are frequently found to have bacterial infections during or soon after the bleeding episode, although at present, it is uncertain whether infection or bleeding is the primary event. Approximately 20% of patients have an infection at admission and 50% develop infections during the first days of hospitalisation in the absence of antibiotic prophylaxis.222 The most common infections are spontaneous bacterial peritonitis (SBP) (25%), followed by urinary tract infection (20%), pneumonia (15%), bacteraemia and cellulitis. Infections are culture positive in 50–70% of cases and gram-positive cocci are implicated in 50% of bacterial infections.65 Those diagnosed with bacterial infection within 48 hours of admission have a higher risk of death and a higher risk of early rebleeding, defined as recurrence of bleeding within 7 days after admission.19
It is essential that the prophylactic antibiotic is active against both Enterobacteriaceae and non-enteral streptococci. However, recent studies show an increasing prevalence of infections caused by antibiotic-resistant bacteria, especially in nosocomial episodes.64 The NICE guideline for the management of acute upper gastrointestinal bleeding recommended that prophylactic antibiotic therapy should be offered to patients with suspected or confirmed variceal bleeding.140 The purpose of this review was to find the most clinically and cost-effective route of administration of prophylactic antibiotics, therefore placebo controlled trials were excluded from the review.
11.2. Review question: What is the most clinical and cost-effective prophylactic antibiotic for the primary prevention of bacterial infections in people with cirrhosis and upper gastrointestinal bleeding?
For full details see review protocol in Appendix C.
11.3. Clinical evidence
One Cochrane review36,37 including 3 studies67,182,209 and 1 additional study110 was included in the review; these are summarised in Table 80 below. Evidence from these studies is summarised in the clinical evidence summary tables below (Table 81, Table 82, Table 83 and Table 84). See also the study selection flow chart in Appendix E, study evidence tables in Appendix H, forest plots in Appendix K, GRADE tables in Appendix J and excluded studies list in Appendix L.
Table 80
Summary of studies included in the review.
Table 81
Clinical evidence summary: IV ceftriaxone 2 g versus oral ciprofloxacin 500 mg twice daily (both for 7 days).
Table 82
Clinical evidence summary: IV ceftriaxone 1 g versus oral norfloxacin 400 mg twice daily (both for 7 days).
Table 83
Clinical evidence summary: oral norfloxacin 800 mg versus oral ofloxacin 400 mg (both for 5 days).
Table 84
Clinical evidence summary: oral norfloxacin 800 mg + IV ceftriaxone (combination) versus oral norfloxacin 800 mg (monotherapy) (both for 7 days).
The Cochrane review had a wider remit review considering both placebo controlled and head-to-head trials. Only the results of head-to-head trials of antibiotics were extracted for this report. Additionally, while ‘number of days of hospitalisation’ was one of the secondary outcomes in the Cochrane review, the review only reported this for studies comparing antibiotics with placebo. From examining the primary papers, 1 paper182 was found to report this outcome and these data were extracted from that paper. Most of the patients in the included studies had more severely decompensated cirrhosis (Child-Pugh B or C) but 1 paper (which was published as an abstract) did not report on disease severity209.
Of the outcomes in the review protocol (Table 79 and Appendix C), only occurrence of bacterial infection and length of hospital stay were reported in the literature. Since the preferred time-to-event data on the outcome all-cause mortality were not reported in the studies, dichotomous data were extracted and presented. However, this outcome was considered indirect. No evidence was found on any of the other outcomes. As there was only 1 study identified comparing one pair of interventions, no meta-analyses were conducted.
Table 79
PICO characteristics of review question.
11.4. Economic evidence
11.4.1. Published literature
No relevant economic evaluations were identified.
See also the economic article selection flow chart in Appendix F.
11.4.2. Unit costs
See Table 94 in Appendix O.
11.5. Evidence statements
11.5.1. Clinical
- IV ceftriaxone (2 g) showed a clinical benefit over oral ciprofloxacin (500 mg twice daily) for the outcome of bacterial infections (1 study, n=129, Moderate quality).
- IV ceftriaxone (1 g) showed a clinical benefit over oral norfloxacin (400 mg twice daily) for the outcome of bacterial infections, but was considered to cause clinical harm for the outcome of all-cause mortality (1 study, n=111, Very Low quality for both outcomes).
- There was no clinically important difference between oral norfloxacin (800 mg) and oral ofloxacin (400 mg) for the outcome of bacterial infections (1 study, n=365, Very Low quality).
- Combination therapy with oral norfloxacin (800 mg) and IV ceftriaxone (2 g) showed a clinical benefit over monotherapy with norfloxacin only (800 mg) for the outcomes of bacterial infections and all-cause mortality; however, there was no clinically important difference between combination therapy and monotherapy for the outcome of length of hospital stay (1 study, n=46, Very Low quality for all outcomes).
11.5.2. Economic
- No relevant economic evaluations were identified.
11.6. Recommendations and link to evidence
| Recommendation |
|
|---|---|
| Relative values of different outcomes | The NICE clinical guideline 141 ‘Acute upper gastrointestinal bleeding: Management’140 recommends that all patients with suspected or confirmed variceal upper gastrointestinal bleeding should be offered antibiotic prophylaxis. However, the GDG noted there is considerable variation in practice regarding the type of antibiotic and the route of delivery and hence they were particularly interested in the clinical and cost-effectiveness of different prophylactic antibiotics for the prevention of bacterial infections in people with cirrhosis and upper gastrointestinal bleeding. The occurrence of bacterial infections, health-related quality of life and all-cause mortality were identified by the GDG as the critical outcomes. Renal failure, length of hospital stay, hospital readmission rate and antibiotic-related complications (for example, antibiotic resistance or Clostridium difficile diarrhoea) were agreed to be important outcomes. |
| Trade-off between clinical benefits and harms | The GDG noted that for the critical outcome of occurrence of bacterial infection there was a clinical benefit favouring the use of intravenous antibiotics over oral preparations. There were insufficient data to identify a particular antibiotic class as being more beneficial. No data were available for any of the comparisons for the critical outcome of quality of life and evidence for the outcome of all-cause mortality was only available for 2 of the 4 comparisons. The GDG agreed that IV administration was more appropriate predominantly because of a reduction in bacterial infections, but also due to the difficulties of oral administration in people with haematemesis and critical illness, many of whom require intubation and ventilation in an intensive care environment. In such cases, placement of a nasogastric tube is relatively contra-indicated in the 48-hour period following treatment of bleeding varices necessitating IV antibiotic administration. The GDG considered the duration of antibiotic treatment but were unable to make a recommendation based on the evidence available. The included studies assess IV treatment for 5 days or 7 days. However, current clinical practice for prophylaxis of bacterial infections is to use IV antibiotics for around 48 hours before stopping or switching to oral administration if there is evidence of bacterial infection. The GDG agreed that a short course of intravenous antibiotics should be considered, with the duration being guided by the clinical status of the patient. The GDG noted the existing NICE guidance on reviewing intravenous antibiotics within a 48–72 hour period within NG15 Antimicrobial stewardship and agreed it would be helpful to make a cross reference to this. |
| Trade-off between net clinical effects and costs | No relevant economic evaluations were identified. The GDG examined the cost differences between intravenous ceftriaxone (£47.90 and 95.90 for 1 g and 2 g respectively) and oral antibiotics (between £1.05 and £8.57 depending on the antibiotic used) for a 5-day course. Considering these costs compared with the clinical benefits of treatment, the GDG felt that the costs for the intravenous delivery of antibiotics for a 48-hour period (current practice) would be outweighed by their clinical benefits; making intravenous antibiotics a cost-effective option compared to oral antibiotics at a cost-effectiveness threshold of £20,000 per QALY gained. |
| Quality of evidence | There was significant heterogeneity in the design of the 4 included studies as they all used different comparators. Given this, the GDG considered each study individually. The GDG noted that most studies included patients with cirrhosis and active upper gastrointestinal haemorrhage. All of the evidence examined was of Very Low quality with the exception of the outcome of bacterial infections for the comparison IV ceftriaxone versus oral ciprofloxacin, which showed a clinical benefit of IV ceftriaxone (Moderate quality evidence). |
| Other considerations | The GDG discussed the clinical issues related to this question. In particular they discussed concerns related to inappropriate antibiotic use in the development of resistance and of Clostridium difficile infection. It was felt that the choice of antibiotics should be determined by local microbiological practices. Clinicians should consider the prevalence of organisms in the local population, resistance profiles and the fact that the ‘at risk’ population consists of immune compromised people with decompensated cirrhosis with likely bacterial translocation of predominantly gram-negative organisms. Whilst the GDG noted that it would be possible for patients to receive both oral and IV antibiotics at home, patients with an upper gastrointestinal bleed are likely to be hospitalised for a minimum of 5 days. The GDG considered making a research recommendation with regards to the class of antibiotic and the duration of therapy, however ethical considerations would most likely preclude research in this area. |
- Primary prevention of bacterial infections in cirrhosis and upper gastrointestin...Primary prevention of bacterial infections in cirrhosis and upper gastrointestinal bleeding - Cirrhosis in Over 16s
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