Piperacillin–tazobactam versus ciprofloxacin plus amoxicillin in the treatment of infective episodes after liver transplantation

John Philpott-Howard1,*, Andrew Burroughs2, Neil Fisher3,§, Mark Hastings4,, Christopher Kibbler5, David Mutimer3, David Patch2, Nancy Rolando2, Jim Wade6, Julia Wendon7 and John O’Grady7

1 Department of Infectious Diseases, Guy’s, King’s & St Thomas’ School of Medicine, Bessemer Road, London SE5 9PJ; 2 Liver Transplantation and Hepatobiliary Medicine, Royal Free Hospital, Hampstead, London NW3 2QG; 3 Liver Unit and 4 Department of Microbiology, Queen Elizabeth Hospital, Birmingham B15 2TH; 5 Department of Medical Microbiology, Royal Free and University College Medical School, Pond Street, London NW3 2QG; 6 Health Protection Agency London, and 7 Institute of Liver Studies, King’s College Hospital, Denmark Hill, London SE5 9RS, UK

Received 23 July 2002; returned 11 September 2002; revised 17 July 2003; accepted 1 September 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
An optimum antimicrobial regimen for bacterial infection after orthotopic liver transplantation has not been identified. In this prospective 4 year study of patients undergoing liver transplantation, patients were randomized to receive either piperacillin–tazobactam (112 patient episodes) or ciprofloxacin plus amoxicillin (105 patient episodes) for empirical treatment of infective episodes in the first 3 months after transplant. Metronidazole was added to the ciprofloxacin–amoxicillin regimen where anaerobic infection was suspected. Patient groups were comparable with respect to clinical, biochemical and haematological parameters. At the 72 h primary efficacy end-point, the overall response rate for the intention-to-treat group was 74/112 (66.1%) for piperacillin–tazobactam and 63/105 (60.0%) for ciprofloxacin plus amoxicillin (P = 0.399); the corresponding figures for the per-protocol (PP) group were 73/82 (89.0%) (piperacillin–tazobactam) and 61/80 (76.3%) (ciprofloxacin plus amoxicillin) (P = 0.038). At the end-of-study assessment, 58.9% of episodes in the piperacillin–tazobactam group had a successful clinical outcome, compared with 50.5% in the ciprofloxacin plus amoxicillin group (P = 0.222); the corresponding figures for the PP group were 83.5% (piperacillin–tazobactam) and 68.8% (ciprofloxacin plus amoxicillin) (P = 0.038). Staphylococci and aerobic Gram-negative bacilli were the predominant pathogens in both groups. Bacteria resistant to the study drugs were encountered, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium and multiply-resistant Klebsiella spp. Empirical monotherapy with piperacillin–tazobactam is an effective treatment for infective episodes in liver transplant patients.

Keywords: liver transplant, antibiotic therapy, randomized controlled trial, infection


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Infection dominates the early post-operative period among patients undergoing orthotopic liver transplantation (OLT), and bacterial sepsis is a leading cause of death in several liver transplant series.14 Bacterial sepsis is a risk factor for fungal infection;57 cytomegalovirus, hepatitis C virus infection and transplantation for acute liver failure are associated with an increased risk of bacterial and fungal infections.810

The reported overall rate of bacterial infection following OLT lies between 5% and 60%1,3,1018 with an infection-related mortality that ranges between 4.6% and 81%.2,11 However, comparison between transplant centres is complicated by differences in follow-up times,1923 definitions of infection, inclusion of second or subsequent OLTs,10,19,22 immunosuppression regimens,9,2426 and the inclusion of adult and paediatric OLTs.14,23,27,28 In addition, some centres have adopted a regimen of selective decontamination of the digestive tract (SDD), to reduce infections caused by Gram-negative bacilli3,2931 and yeasts.

To reduce post-operative infections in OLT, antibacterial prophylaxis is used. Typically, prophylaxis comprises a third generation cephalosporin or a broad-spectrum penicillin with an aminoglycoside, or other combinations for penicillin-allergic patients.1,2,12,20,22,24,30,32 A glycopeptide may be included if the patient is culture-positive for methicillin-resistant Staphylococcus aureus (MRSA). The value of prophylaxis in liver transplantation is uncertain although for such a major procedure it would appear to be reasonable. Apart from surgical prophylaxis, antimicrobials are used most frequently for post-operative infective episodes. However, although bacterial infection can be a life-threatening complication of OLT, there are few data to guide the selection of empirical antibacterial regimens in this setting.33

The aim of this study was, therefore, to compare the safety and efficacy of two antibiotic regimens for the treatment of febrile episodes in patients undergoing OLT. We evaluated piperacillin–tazobactam monotherapy with a combination of ciprofloxacin plus amoxicillin in the treatment of infective episodes within the first 3 months after OLT. Metronidazole administration was permitted in the ciprofloxacin and amoxicillin arm of the study when anaerobic sepsis was suspected or confirmed. These antimicrobials were selected because they were active against the bacteria that were known to cause infections in the participating centres, including S. aureus and resistant Enterobacteriaceae.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Three UK liver transplant centres participated in the study: King’s College Hospital and The Royal Free Hospital in London, and the Queen Elizabeth Hospital in Birmingham.

The study was a prospective, open, multicentre, parallel trial that compared the efficacy of two antimicrobial regimens used in the treatment of infectious episodes occurring in the first 3 months after liver transplantation. Eligible patients were those 18 years of age or more, who had undergone OLT, and had a microbiologically-proven or suspected infection. Suspected infection was defined as: changes in the chest radiograph and a clinical picture suggestive of infection; or a temperature greater than 38.0°C with a rise in the peripheral white blood cell count, but with no identifiable focus of infection (‘pyrexia of unknown origin’, PUO).

A computer-generated randomization list was created and allocations to either arm of the study were distributed in sequentially-numbered sealed envelopes. Patients who fulfilled the entry criteria and who gave written informed consent were allocated to receive either piperacillin–tazobactam, 4.5 g three times a day (P/T arm) or ciprofloxacin 400 mg two times a day plus amoxicillin 500 mg three times a day (C/A arm). Metronidazole was added to the C/A regimen where anaerobic infection was suspected. All drugs were given intravenously for a minimum of 5 days and a maximum of 10 days. This study was approved by the Research Ethics Committees of the three participating institutions.

All efficacy analyses were carried out on two groups; an ‘intention to treat’ (ITT) group that included all episodes and a ‘per-protocol’ (PP) group.

The response of each infective episode to treatment at 72 h was categorized as one of the following: complete resolution; partial resolution; clinical failure; or indeterminate response. An indeterminate response was defined as ‘no evaluation possible for any reason including treatment with study antibiotics for less than 72 h’. Infectious episodes with an indeterminate response or with data missing were excluded from the PP efficacy analysis. For the primary efficacy analysis, clinical response rates for each treatment group at 72 h were calculated as follows:

Clinical response rate = (complete resolution + partial resolution)/(complete resolution + partial resolution + indeterminate response + clinical failures + deaths)

At the end of the study (defined as 7 days after the completion of the study drugs), the overall success, defined as the proportion of clinical cures, was calculated for each of the treatments:

Overall success rate = (clinical cures)/(clinical cures + failures)

Episodes categorized as indeterminate or with data missing were excluded from the PP analysis, and included as default failures for the ITT analysis. Patient episodes in which the antimicrobial regimen was changed because of lack of clinical response to the study drugs were classified as clinical failures.

An overall microbiological assessment was carried out for each infection at the end of the study and episodes were categorized as: eradication (documented + presumptive); persistence (documented + presumptive); superinfection; new infection; or unassessable.

Pathogens isolated from clinical specimens and deemed to have caused infection were identified according to standard laboratory techniques, and their susceptibilities to the study drugs and other antimicrobials were determined by disc susceptibility testing (Stokes’ method). All adverse events that occurred during the study were recorded. Adverse events were defined as follows: Mild: the patient was aware of symptoms but they were easily tolerated; Moderate: discomfort was sufficient to interfere with the patient’s normal activities; Severe: the adverse event completely prevented normal activities. Serious or unexpected adverse events were notified to the trial coordinator. Abnormalities of laboratory values were also recorded.

Determination of sample size

There were no previous studies of piperacillin–tazobactam available in this clinical setting or for this therapeutic indication. However, based on studies in similar groups of patients it was assumed that the clinical response rate at the end of the study clinical assessment would be 85% for the best treatment and 70% for the worst. Allowing for a type I error of 5% (two-sided) with a power of 80%, approximately 125 episodes per arm would be needed to detect a 15% difference in efficacy of the treatments.

Statistical analysis

Differences between treatment groups were analysed using {chi}2 and Fisher’s exact test. As well as individual response rates for each treatment group, the difference in response rates was calculated and presented with a corresponding 95% confidence interval, using Wilcoxon rank sum coefficient. Laboratory test profiles of the two treatment groups were compared using Fisher’s exact test.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Over a 4 year period (June 1994 to February 1998), 219 patient episodes were enrolled for the study: 159 at King’s, 44 at The Royal Free and 16 at Birmingham. Of the 217 in the intention-to-treat group (see below), there were 127 males and 90 females, of mean age 48.5 years (range 17–71 years); the majority (87.1%) were Caucasian. One-hundred and eighty-six patients were enrolled once, 13 twice, one patient three times and one patient four times. Patient groups were comparable in relation to age, sex, baseline biochemical and haematological parameters, and aetiology of the underlying disease. Ten patients in the P/T arm and seven in the C/A arm were mechanically ventilated at the time of inclusion in the trial. Antimicrobial prophylaxis regimens for transplantation most frequently included gentamicin or netilmicin plus a ß-lactam such as flucloxacillin or co-amoxiclav or a cephalosporin. A glycopeptide (vancomycin or teicoplanin) was added in eight and six regimens in the P/T and C/A arms, respectively. These regimens differed between centres but overall there was no significant difference in the range of prophylactic regimens used for patients in the two arms of the study.

Primary efficacy end-point

The results of the primary efficacy end-point analysis at 72 h and details of response by infection type are given in Table 1. Two patients were withdrawn: for one no written consent was obtained and the other was randomized but did not receive antimicrobials. Therefore the ITT group comprised 217 of the 219 episodes (112 randomized to P/T and 105 to C/A). Overall, at 72 h the response rate was 66.1% (74/112) in the P/T group compared with 60.0% in the C/A (63/105) group (difference: –6.1%; 95% CI: –19.8%, 7.7%; P = 0.399). A sub-analysis carried out on episodes of chest infection at 72 h showed a response rate of 82.9% (29/35) in the P/T group and 64.0% (16/25) in the C/A group (difference: –18.9%; 95% CI: –44.9%, 7.2%; P = 0.133).


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Table 1. Primary efficacy analyses and end of study clinical assessments for intention-to-treat and per-protocol groups 
 
The PP population consisted of 162 episodes: 82 in the P/T group and 80 in the C/A group (Figure 1). This group excluded 55 episodes: eight in which the inclusion criteria were not met [3 P/T, 5 C/A; these included one underage (17 years) patient] and 50 which lacked assessment at the primary end-point [28 P/T, 22 C/A; Figure 1: note that three patient episodes (1 P/T and 2 C/A) failed the inclusion criteria and also lacked assessment at the primary end-point, i.e. 55 episodes overall]. The reasons for the categorization as ‘no assessment’ were recorded in only 15 of these patient episodes (9 P/T and 6 C/A): deterioration in condition and withdrawal of therapy before 72 h in 7 (5 P/T and 2 C/A); non-compliance with medication and withdrawn before 72 h (2 P/T and 1 C/A); a clinically-significant pathogen resistant to the study drugs (1 P/T and 2 C/A); prohibited antibiotics and withdrawn (1 P/T); missing data, not withdrawn (1 C/A). Further information regarding the 35 remaining episodes categorized as ‘no assessment’ is not available, as the details were not recorded in the case report form.



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Figure 1. Treatment tree of patient episodes showing enrolment, withdrawals and exclusions.

 
The response rates at 72 h were 89.0% (73/82) in the P/T group and 76.3% in the C/A (61/80) group (difference: –12.8%; 95% CI: –25.5%, 0%; P = 0.038).

End of study clinical assessment

The data for the end of study clinical assessments are given in Table 1. For the ITT group, the overall clinical assessment revealed success in 66/112 (58.9%) episodes in the P/T group and 53/105 (50.5%) in the C/A group (difference: –8.5%; 95% CI: –22.6%, 5.7%; P = 0.222); failure occurred in 17 (15.2%) episodes in the P/T group and 27 (25.7%) in the C/A group; and an indeterminate response was seen in 29 (25.9%) of the P/T group and 25 (23.8%) in the C/A group. A sub-analysis carried out on episodes of chest infection at the end of the study in the ITT group showed a response rate of 62.9% (22/35) in the P/T group and 56.0% (14/25) in the C/A group (difference: –6.9%; 95% CI: –35.5%, 21.8%; P = 0.606).

In the PP group, three episodes in each arm were excluded as the response classification was indeterminate. Of the remaining 156 episodes, 66/79 (83.5%) in the P/T group were judged to have a successful clinical outcome, compared with 53/77 (68.8%) in the C/A group (difference: –14.7%: 95% CI: –29.2%, –0.2%; P = 0.038).

There were 20 episodes in which metronidazole was added to the C/A regimen. Treatment was deemed a success in 45.0% of these episodes compared with 51.8% of those in which metronidazole was not given.

Interval between operative procedure and 72 h clinical evaluation

The data were analysed in order to determine whether one or other arm had a higher proportion of patients with a delayed onset of confirmed or suspected infection after transplantation. This would reveal a possible increased likelihood of acquisition of more resistant pathogens; conversely, patients with a later presentation may have a less complex clinical course following healing and resolution of the post-operative state. Overall, in the ITT group, there was no significant difference between the two arms in terms of number of days to success or failure of treatment. For patients with successful outcome at 72 h (74 patients), the mean time interval since operation was 14.9 ± 16.5 days (± S.D.) for the P/T arm, and 12.5 ± 12.9 days for the C/A arm. For patients with a failure outcome at 72 h (37 patients), the mean time interval since operation was 10.8 ± 13.8 days for the P/T arm, and 16.0 ± 22.4 days for the C/A arm.

Similar data were obtained for the two arms in the time interval from transplantation to the date of overall clinical evaluation.

End of study microbiological assessment

In the microbiological assessment, a clinically-significant pathogen was isolated in 25 of 217 ITT episodes (11.5%: 14 in the P/T group and 11 in the C/A group). Staphylococci and aerobic Gram-negative bacilli were the predominant pathogens (Table 2). In both groups, failure to eradicate microbiologically-confirmed infection was commonly associated with pathogens that were resistant to the study drugs, including MRSA, vancomycin-resistant Enterococcus faecium and multiply-resistant Klebsiella spp. Of the organisms available for antimicrobial susceptibility testing, resistance to P/T, ciprofloxacin or amoxicillin, or ciprofloxacin plus amoxicillin combined, was documented in 63.0%, 75.9% and 66.6%, respectively. A glycopeptide was added for suspected MRSA sepsis in two episodes in the P/T arm and one in the C/A arm.


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Table 2. Pathogens isolated before initiation of antimicrobial therapy and end of study microbiological assessment
 
Analysis of data excluding re-entered patients

In order to account for any effect on the results that may arise from the re-entry of 18 patients into the study, we analysed the data for clinical assessment outcomes at 72 h and the overall end of study, with the following results:

Clinical assessment at 72 h. In the ITT analysis, the response rates for the P/T group were 65.1% (69/106), compared with 59.1% (55/93) in the patients in the C/A group [difference: –6.0% (CI –8.6%, 20.5%), P = 0.464]. For the PP analysis, the figures were: P/T group 88.3% (68/77), compared with 76.8% (53/69) in the C/A group [difference: –11.5% (CI –2.1%, 25.1%), P = 0.080].

Clinical assessment at end of study. In the ITT analysis, the response rates for the P/T group were 58.5% (62/106), compared with 49.5% (46/93) in the patients in the C/A group [difference: –9.0% (CI –5.8%, 23.9%), P = 0.254]. For the PP analysis, the figures were: P/T group 83.8% (62/74), compared with 68.7% (46/67) in the C/A group [difference: –15.1% (CI –0.2%, 30.5%), P = 0.046].

Adverse events

All randomized episodes were included in the safety analysis, including one of the withdrawn patients. One hundred and fifty adverse events of all types were reported during the study. Forty-two of 113 patients (37.2%) in the P/T arm had at least one reported adverse event, compared with 47/105 (44.8%) in the C/A arm. Some patients had more than one adverse event. Of the 64 adverse events in the P/T group, 32 (50.0%) were mild, 24 (37.5%) moderate and eight (12.5%) severe. Of the 86 adverse events in the C/A group, 26 (30.2%) were mild, 47 (54.7%) moderate and 13 (15.1%) severe. One episode of Clostridium difficile toxin-associated diarrhoea was reported, in the P/T arm. For patients receiving P/T, one adverse event (a skin rash) was considered definitely related to P/T; six others were possibly related, and 57 (89.1%) were classified as remotely or definitely not related. For patients receiving C/A, one adverse event was considered to be related to ciprofloxacin (a skin rash); nine others (10.5%) possibly related to ciprofloxacin; and 76 (88.4%) to be only remotely or definitely not related. Similarly, one adverse event was considered to be related to amoxicillin use (a skin rash), six (7%) possibly related and 79 (91.9%) remotely or definitely not related. For patients receiving metronidazole, one reaction was considered to be possibly related to the drug, and 11 remotely or definitely not. There was one patient death in the C/A arm (a cardiac arrest) which was definitely not drug related. All serious adverse events and the most frequent adverse events (irrespective of severity) are given in Table 3. As expected for patients with severe liver disease, there was a high proportion of abnormalities among the biochemical and haematological laboratory tests; a number of these abnormalities were reported as adverse events by the clinicians (Table 3). However, there were no significant differences between the laboratory test profiles of the two treatment groups either before, during or after antimicrobial therapy.


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Table 3. Summary of all reported severe and frequent adverse events
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients who undergo OLT are at great risk of bacterial and fungal infection. Although previous studies have assessed the incidence and type of infection, the optimum antimicrobial interventions have not yet been reported. This is the first study where two different antibiotic regimens have been assessed in the treatment of infectious complications in the OLT population. The antibiotics chosen reflected the likely infections encountered in this group of patients, particularly sepsis of the respiratory tract, biliary tree and abdomen.10 The prominence of respiratory tract infections was confirmed in this study; sepsis with no obvious originating focus was also common. The mortality rate of such infections can reach 30–40%,10 but it was notable that in this study, there were no infective deaths in either arm. This may be because the range of infections was broad (Table 1), but they were evenly distributed between the two treatment arms. Response rates to infections such as ‘PUO’ and ‘sepsis’ were also similar, and the response rates to more defined and potentially severe infections such as bacteraemia, cholangitis or chest infection were not significantly different from PUO and sepsis (data not shown). In addition, although we did not score the severity of infections, and inevitably a range of severities are included in the study as it reflects clinical practice, there was no evidence that either of the arms of the study contained fewer severely ill patients.

One concern for clinicians managing infection in high-dependency areas, such as liver transplantation units, is the high potential for overuse of antibiotics and emergence of multiply-resistant pathogens.34 In this study, the prevalence of multiply-resistant pathogens was carefully monitored throughout the 4 year period, and there was no evidence that patient care was compromised by continued use of the study drugs. We considered the ethics of administering these study drugs on clinical units where multiply-resistant organisms such as MRSA and multiply-resistant Enterobacteriaceae are prevalent. Although these organisms are of concern, most clinicians would recognize that empirical therapy cannot and need not cover all known pathogens. Furthermore, it is clearly important to have adequate empirical therapy for Gram-negative aerobes since these are more likely to cause serious sepsis in this patient group. We also consider that addition of vancomycin or teicoplanin should generally be reserved for confirmed sepsis as a result of ß-lactam-resistant Gram-positive bacteria, including MRSA, since overuse of these glycopeptide antibiotics can be associated with other problems such as superinfection with glycopeptide-resistant enterococci or even glycopeptide-insensitive S. aureus. In the setting of antimicrobial treatment of fever in patients with neutropenia, empirical use of glycopeptides for initial therapy has similarly been avoided.35

Even so, a high proportion of organisms recovered from clinical samples were resistant to the study drugs. This may be because of frequent inpatient episodes before transplantation or significant antibiotic use in cases of acute liver failure. This is likely as, at our centres, only a short course of peri-operative antibiotics, not exceeding 48 h duration, is used. However, despite the isolation of the resistant organisms, the clinical response rates in this study suggest that most infections (where no organism is isolated) are caused by organisms that are susceptible to the study drugs rather than multiply-resistant strains. Overall, the proportion of episodes from which pathogens were isolated was low (11.5%). The inclusion of ‘PUO, sepsis and sepsis syndrome’ as clinical diagnoses partly accounts for this since a relatively high number of patients came into this category.

Our patients were given neither prolonged antibacterial prophylaxis nor selective bowel decontamination (SDD) after liver transplantation.36 There is evidence that SDD in liver transplantation is not cost-effective.37,38

This study aimed to reflect the typical current practice in the UK where antimicrobial treatment is commenced in OLT patients mainly on the basis of clinical criteria. This was the case in 71 patient episodes, where antimicrobials were commenced on the basis of a temperature greater than 38°C, and in 60 instances because of clinical signs and symptoms together with chest radiograph appearances. This type of clinical practice is considered to be appropriate, since waiting for microbiological confirmation may put these patients at risk of severe and overwhelming sepsis. For the same reason, a placebo-controlled trial would be inappropriate in this setting. A second analysis (listed in the Results) that excluded second or subsequent episodes among re-entered patients, showed only minor changes in P values and response rates, but overall the outcomes were comparable.

The reasons for the improved outcome with piperacillin–tazobactam in the analysis of per-protocol patients compared with the intention-to-treat analysis are not clear. It may be that the latter group was more likely to have non-standard prophylaxis and other interventions that were confounding factors in the analysis. However, as noted in the results, a review of the prophylactic regimens did not indicate any dissimilarity between the two arms of the study.

Empirical monotherapy with piperacillin–tazobactam was, clinically, highly efficacious, and in comparison to ciprofloxacin plus amoxicillin differences between treatment groups favoured piperacillin–tazobactam. However the differences were only statistically significant in the per-protocol analyses. This may be because fewer patients were enrolled than was originally planned, and the differences in outcomes between the treatment groups were smaller than expected. Therapeutic failure with either regimen was uncommon. The drug regimens were well tolerated with relatively few side effects, and were found to be suitable for use in three units with problem antibiotic-resistant organisms. Each clinical unit must develop its policy for empirical antimicrobial therapy with due regard to the current antimicrobial resistance patterns, but our data show that patient care is not compromised by the selection of treatment regimens that are not active against all potential pathogens.


    Footnotes
 
* Corresponding author. Tel: +44-20-7346-3213; Fax: +44-20-7346-3404; E-mail: john.philpott-howard{at}kcl.ac.uk Back

§ Present address. Department of Gastroenterology, Dudley Group of Hospitals NHS Trust, Russells Hall Hospital, Dudley, West Midlands DY1 2HQ. Back

Present address. Department of Medical Microbiology, University Hospital of Wales, Cardiff CF14 4XW. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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