Scand J Infect Dis 24: 209-213, 1992
Effect of Piperacillin/Tazobactam Therapy on Intestinal Microf lora C A R L ERIK NORD’.’, BO BRISMAR2, BRITTA KASHOLM-TENGVE4 and GORAN TUNEVALL~ From the Departments of ‘Microbiology and ?Surgery, Huddinge University Hospital, Huddinge. the Naiional Bacteriological Laboratory, Stockholm, the Departments of “Surgery, Regional Hospital, Orebro, and 5Surgery, Danderyd Hospital, Stockholm, Sweden
Scand J Infect Dis Downloaded from informahealthcare.com by QUT Queensland University of Tech on 10/31/14 For personal use only.
’
The effect of piperacillin/tazobactam treatment upon the intestinal microflora was studied in 20 patients with intraabdominal infections. The patients received piperacillin 4 g combined with tazobactam 500 mg q 8 h by intravenous injection for 4-8 days. Stool specimens were collected before, during and after therapy for cultivation of aerobic and anaerobic microorganisms. Six patients had measurable concentrations of piperacillin (1.2-276 mgikg/faeces) and 4 patients tazobactam concentrations (0.8-22.2 mg/kg/faeces) in the faecal specimens during therapy. The number of enterobacteria and enterococci slightly decreased while there were no changes in the number of staphylococci and bacilli. The anaerobic microflora was also slightly affected. There was a minor decrease in the number of bifidobacteria, eubacteria, lactobacilli, clostridia and veillonella but the numbers of anaerobic Gram-positive cocci and bacteroides were not influenced by the treatment. After therapy, the aerobic and anaerobic microflora returned to normal levels in all patients. None of the patients had Clostrtdium difticile or cytotoxin in the stools or developed diarrhoea. C. E . N o d , MD,PhD, Department of Microbiology, Karolinska Institute, Huddinge University Hospital, S-14186 Huddinge, Sweden
INTRODUCTION The administration of antimicrobial agents may have a number of potentially adverse effects in relation to the human intestinal microflora. O n e is the development of antimicrobial resistance and the induction of beta-lactamases among bacteria in the normal microflora. A second consequence is the reduction of colonization resistance, i.e. the resistance displayed by the host to implantation of new microorganisms in the normal microflora. A third effect is the overgrowth of already present microorganisms such as yeasts which may produce systemic infections in immunocompromised patients, and of Clostridium difficile which may lead to diarrhoea and/or colitis. The major cause of antibiotic associated diarrhoea/colitis is antimicrobial treatment. The impact of new antimicrobial agents on the intestinal microflora in humans should therefore be investigated before the agents are used in clinical medicine (1).
Tazobactam is a newly-developed beta-lactamase inhibitor of the penicillanic acid sulfone class. Its structure is similar to that of sulbactam, except that one of the latter’s methyl groups has been replaced by a triazolylmethyl group. It is more active than sulbactam against Enterobacteriaceae producing class I11 and V plasmid-mediated beta-lactamases and more active than clavulanic acid against those producing class I chromosomal beta-lactamases (2). Piperacillin is an extended-spectrum penicillin which has been widely used in the treatment of serious infections ( 3 ) . Recently, however, the spread of beta-lactamase-producing microorganisms has raised concerns about the future utility of piperacillin and suggested its use in combination with a beta-lactamase inhibitor such as tazobactam. In vitro studies have I4 Scirnd J Infect Din
Scand J Infect Dis Downloaded from informahealthcare.com by QUT Queensland University of Tech on 10/31/14 For personal use only.
210 C.E. Nord et al.
BEFORE
DURING
Scand J Infect Dis 24
AFTER
TREATMENT Fig. I . Effect of piperacillinftazobactam on the aerobic intestinal microflora in 20 patients.
shown that piperacillin plus tazobactam is one of the most active penicillin/inhibitor combinations against a wide variety of resistant Gram-negative aerobic and anaerobic bacteria (4). The combination piperaciIlin/tazobactam may be suitable for treatment and prophylaxis of mixed aerobic-anaerobic infections. The aim of the present study was to investigate the effect of piperacillin/tazobactam treatment on the intestinal microflora.
Piperacillinltazobactam- ititestinal microflora 2 I1
Scmd J Infect Dis 24
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TREATMENT Fig. 2. Effect of piperacillidtazobactam on the anaerobic intestinal microflora in 20 patients.
MATERIALS AND METHODS Parirrlrs The faecal flora was studied in 20 patients, 14 men and 6 women, with a mean age of 51 (range 25-80) years. Hospitalized patients with intraabdominal infections were included. There were 14 cases of appendicitis, 4 cases of peritonitis, and 2 cases of intraabdominal abscesses. All patients gave their informed consent to participate in the study, which had been approved by the Ethical Review Committee of Karolinska Institute, Stockholm. The patients received piperacillidtazobactam 4 g/500 mg q 8 h by intravenous injection over 30 min. The treatment period was 4-8 days. Faecal samples were taken 14'
212 C.E. Nord et al.
Scand J Infect Dis 24
Scand J Infect Dis Downloaded from informahealthcare.com by QUT Queensland University of Tech on 10/31/14 For personal use only.
from the patients before therapy, during therapy, and 1 week to 1 month after treatment had stopped. The samples were collected in sterile plastic containers and stored at -70°C until they were assayed.
Microbiological procedures The faecal samples were suspended and diluted in prereduced peptone yeast extract medium, inoculated on selective media, and manipulated as described by Heimdahl and Nord ( 5 ) . The aerobic and anaerobic microorganisms were identified using morphological and biochemical tests and gas-liquid chromatography. The antibiotic susceptibility for piperacillidtazobactam was determined for different new colonizing bacterial strains isolated from faeces before treatment, during treatment, and again 14 days after the withdrawal of piperacillidtazobactam. All faecal samples were assayed for the presence of Clostridium difficile and its cytotoxin. Assay of piperucillin and tazobactam in faeces The faecal concentrations of piperacillin and tazobactam were determined by the agar diffusion method. The test medium was Mueller Hinton I1 (BBL, USA). The indicator strains were Sarcina lutea ATCC 9341 for piperacillin and Escherichia coli 603 for tazobactam. The concentrations of piperacillin and tazobactam were determined in relation to diameters of inhibition zones caused by known concentration of piperacillinltazobactam from the standard series.
RESULTS
Effect of piperacillinltazobactarn on intestinal microflora The effect of piperacillin/tazobactam treatment on the aerobic intestinal microflora is shown in Fig. 1. The number of Escherichia coli and other enterobacteria decreased slightly during the treatment period. In 2 patients Enterobacter cloacae (MIC > 128 mgA) and in 1 patient E. agglomerans (MIC > 128 mg/l) appeared during treatment but disappeared after 14 days. The number of enterococci was slightly affected but no changes in the number of staphylococci and bacilli occurred. There was no overgrowth of yeasts. The aerobic microflora was normalized in all patients after the treatment was stopped. The anaerobic microflora was also slightly affected (Fig. 2). There was a decrease in the number of bifidobacteria, eubacteria, lactobacilli, clostridia and veilionella while the numbers of anaerobic Gram-positive cocci and bacteroides were not influenced by the piperacillin/tazobactam therapy. After treatment the anaerobic microflora was normalized in all patients. No new colonization with piperacillidtazobactam resistant bacteria was observed. No C. difficile or cytotoxin were detected in the faecal specimens. Faecal concentrations of piperacillinltazobactam Faecal concentrations of piperacillin were found in 6 patients and varied between 1.2 and 276 mg/kg/faeces during treatment. Four of these patients had measurable concentrations of tazobactam (0.8-22.2 mg/kg/faeces) at the same time. DISCUSSION Many antibiotics cause ecological changes in the intestinal microflora. The severity of these changes depends mainly on the agent’s spectrum and its concentration in the gut lumen. Parenteral broad-spectrum beta-lactam antibiotics such as ceftriaxone and cefoperazone secreted in the bile or from the intestinal mucosa may cause significant disturbances in the intestinal microflora (6). High bile concentrations of piperacillin (448-4 468 mg/l) have been reported (7) indicating that piperacillin is concentrated in patients with biliary tract diseases. In the present study
Scand J Infect Dis Downloaded from informahealthcare.com by QUT Queensland University of Tech on 10/31/14 For personal use only.
Scand J Infect Dis 24
Piperacillinltazobactam
- intestinal microflora 213
there were no patients with biliary tract diseases which explains the low concentrations of piperacillin found in the faecal specimens. The effect of piperacillin on the intestinal microflora in patients undergoing elective colorectal surgery has been studied by Kager et al. (8). The faecal concentrations of piperacillin ranged from undetectable values to 101.2 mgkg. Enterococci, streptococci and enterobacteria decreased in 25% of the patients during the administration period, while anaerobic Gram-positive cocci and rods, fusobacteria and bacteroides decreased in twothirds of the patients at the same period. The more pronounced effect of piperacillin on the intestinal microflora observed in the investigation of Kager et al. (8) compared to the present one may be explained by the fact that patients undergoing colorectal surgery were enrolled in the former study, since the surgical procedure may induce alterations in the microflora. In the present investigation, no significant changes were observed in the intestinal microflora during or after treatment. This is explained by the low concentrations of piperacillin and tazobactam detected in the intestine. No superinfections or diarrhoea developed during therapy. The present findings indicate that the combination piperacillidtazobactam has a minor ecological impact on the intestinal microflora. REFERENCES 1. Nord CE. Studies on the ecological impacts of antibiotics. Eur J Clin Microbiol Infect Dis 9: 517-518, 1990. 2. Jacobs MR, Aronoff SC, Johenning S , Shlaes DM, Yamabe S. Comparative activities of the beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with ampicillin and broad-spectrum penicillins against defined beta-lactamase-producing aerobic gram-negative bacilli. Antimicrob Agents Chemother 29: 980-985, 1986. 3. Fortner CL, Finley RS, Schimpff SC. Piperacillin sodium: antibacterial spectrum, pharmacokinetics, clinical efficacy, and adverse reactions. Pharmacotherapy 2: 287-299, 1982. 4. Gutmann L, Kitzis M-0, Yamabe S, Acar JF. Comparative evaluation of a new beta-lactamase inhibitor, YTR 830, combined with different beta-lactam antibiotics against bacteria harboring known beta-lactamases. Antimicrob Agents Chemother 29: 955-957, 1986. 5. Heimdahl A, Nord CE. Effect of phenoxymethylpenicillin and clindamycin on the oral, throat and faecal microflora of man. Scand J Infect Dis 11: 23S242, 1979. 6. Nord CE, Heimdahl A, Kager L. Antimicrobial induced alterations in the human oropharyngeal and intestinal microflora. Scand J Infect Dis, Suppl 49: 64-72, 1986. 7. Russo J , Thompson M, Russo ME, Saxon BA, Matsen JM, Moody FG, Rikkers LF. Piperacillin distribution into bile, gall-bladder wall, abdominal skeletal muscle and adipose tissue in surgical patients. Antimicrob Agents Chemother 22: 488-492, 1982. 8. Kager L, Malmborg AS, Nord CE, Sjostedt S . The effect of piperacillin prophylaxis on the colonic microflora in patients undergoing colorectal surgery. Infection 11: 251-254, 1983.
Effect of Piperacillin/Tazobactam Therapy on Intestinal Microf lora C A R L ERIK NORD’.’, BO BRISMAR2, BRITTA KASHOLM-TENGVE4 and GORAN TUNEVALL~ From the Departments of ‘Microbiology and ?Surgery, Huddinge University Hospital, Huddinge. the Naiional Bacteriological Laboratory, Stockholm, the Departments of “Surgery, Regional Hospital, Orebro, and 5Surgery, Danderyd Hospital, Stockholm, Sweden
Scand J Infect Dis Downloaded from informahealthcare.com by QUT Queensland University of Tech on 10/31/14 For personal use only.
’
The effect of piperacillin/tazobactam treatment upon the intestinal microflora was studied in 20 patients with intraabdominal infections. The patients received piperacillin 4 g combined with tazobactam 500 mg q 8 h by intravenous injection for 4-8 days. Stool specimens were collected before, during and after therapy for cultivation of aerobic and anaerobic microorganisms. Six patients had measurable concentrations of piperacillin (1.2-276 mgikg/faeces) and 4 patients tazobactam concentrations (0.8-22.2 mg/kg/faeces) in the faecal specimens during therapy. The number of enterobacteria and enterococci slightly decreased while there were no changes in the number of staphylococci and bacilli. The anaerobic microflora was also slightly affected. There was a minor decrease in the number of bifidobacteria, eubacteria, lactobacilli, clostridia and veillonella but the numbers of anaerobic Gram-positive cocci and bacteroides were not influenced by the treatment. After therapy, the aerobic and anaerobic microflora returned to normal levels in all patients. None of the patients had Clostrtdium difticile or cytotoxin in the stools or developed diarrhoea. C. E . N o d , MD,PhD, Department of Microbiology, Karolinska Institute, Huddinge University Hospital, S-14186 Huddinge, Sweden
INTRODUCTION The administration of antimicrobial agents may have a number of potentially adverse effects in relation to the human intestinal microflora. O n e is the development of antimicrobial resistance and the induction of beta-lactamases among bacteria in the normal microflora. A second consequence is the reduction of colonization resistance, i.e. the resistance displayed by the host to implantation of new microorganisms in the normal microflora. A third effect is the overgrowth of already present microorganisms such as yeasts which may produce systemic infections in immunocompromised patients, and of Clostridium difficile which may lead to diarrhoea and/or colitis. The major cause of antibiotic associated diarrhoea/colitis is antimicrobial treatment. The impact of new antimicrobial agents on the intestinal microflora in humans should therefore be investigated before the agents are used in clinical medicine (1).
Tazobactam is a newly-developed beta-lactamase inhibitor of the penicillanic acid sulfone class. Its structure is similar to that of sulbactam, except that one of the latter’s methyl groups has been replaced by a triazolylmethyl group. It is more active than sulbactam against Enterobacteriaceae producing class I11 and V plasmid-mediated beta-lactamases and more active than clavulanic acid against those producing class I chromosomal beta-lactamases (2). Piperacillin is an extended-spectrum penicillin which has been widely used in the treatment of serious infections ( 3 ) . Recently, however, the spread of beta-lactamase-producing microorganisms has raised concerns about the future utility of piperacillin and suggested its use in combination with a beta-lactamase inhibitor such as tazobactam. In vitro studies have I4 Scirnd J Infect Din
Scand J Infect Dis Downloaded from informahealthcare.com by QUT Queensland University of Tech on 10/31/14 For personal use only.
210 C.E. Nord et al.
BEFORE
DURING
Scand J Infect Dis 24
AFTER
TREATMENT Fig. I . Effect of piperacillinftazobactam on the aerobic intestinal microflora in 20 patients.
shown that piperacillin plus tazobactam is one of the most active penicillin/inhibitor combinations against a wide variety of resistant Gram-negative aerobic and anaerobic bacteria (4). The combination piperaciIlin/tazobactam may be suitable for treatment and prophylaxis of mixed aerobic-anaerobic infections. The aim of the present study was to investigate the effect of piperacillin/tazobactam treatment on the intestinal microflora.
Piperacillinltazobactam- ititestinal microflora 2 I1
Scmd J Infect Dis 24
I
9 c
ANAE~OBICCOCCI
I
I I I
Scand J Infect Dis Downloaded from informahealthcare.com by QUT Queensland University of Tech on 10/31/14 For personal use only.
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.
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E D
I1I *
-
AFTER
TREATMENT
m D
AFTER
TREATMENT Fig. 2. Effect of piperacillidtazobactam on the anaerobic intestinal microflora in 20 patients.
MATERIALS AND METHODS Parirrlrs The faecal flora was studied in 20 patients, 14 men and 6 women, with a mean age of 51 (range 25-80) years. Hospitalized patients with intraabdominal infections were included. There were 14 cases of appendicitis, 4 cases of peritonitis, and 2 cases of intraabdominal abscesses. All patients gave their informed consent to participate in the study, which had been approved by the Ethical Review Committee of Karolinska Institute, Stockholm. The patients received piperacillidtazobactam 4 g/500 mg q 8 h by intravenous injection over 30 min. The treatment period was 4-8 days. Faecal samples were taken 14'
212 C.E. Nord et al.
Scand J Infect Dis 24
Scand J Infect Dis Downloaded from informahealthcare.com by QUT Queensland University of Tech on 10/31/14 For personal use only.
from the patients before therapy, during therapy, and 1 week to 1 month after treatment had stopped. The samples were collected in sterile plastic containers and stored at -70°C until they were assayed.
Microbiological procedures The faecal samples were suspended and diluted in prereduced peptone yeast extract medium, inoculated on selective media, and manipulated as described by Heimdahl and Nord ( 5 ) . The aerobic and anaerobic microorganisms were identified using morphological and biochemical tests and gas-liquid chromatography. The antibiotic susceptibility for piperacillidtazobactam was determined for different new colonizing bacterial strains isolated from faeces before treatment, during treatment, and again 14 days after the withdrawal of piperacillidtazobactam. All faecal samples were assayed for the presence of Clostridium difficile and its cytotoxin. Assay of piperucillin and tazobactam in faeces The faecal concentrations of piperacillin and tazobactam were determined by the agar diffusion method. The test medium was Mueller Hinton I1 (BBL, USA). The indicator strains were Sarcina lutea ATCC 9341 for piperacillin and Escherichia coli 603 for tazobactam. The concentrations of piperacillin and tazobactam were determined in relation to diameters of inhibition zones caused by known concentration of piperacillinltazobactam from the standard series.
RESULTS
Effect of piperacillinltazobactarn on intestinal microflora The effect of piperacillin/tazobactam treatment on the aerobic intestinal microflora is shown in Fig. 1. The number of Escherichia coli and other enterobacteria decreased slightly during the treatment period. In 2 patients Enterobacter cloacae (MIC > 128 mgA) and in 1 patient E. agglomerans (MIC > 128 mg/l) appeared during treatment but disappeared after 14 days. The number of enterococci was slightly affected but no changes in the number of staphylococci and bacilli occurred. There was no overgrowth of yeasts. The aerobic microflora was normalized in all patients after the treatment was stopped. The anaerobic microflora was also slightly affected (Fig. 2). There was a decrease in the number of bifidobacteria, eubacteria, lactobacilli, clostridia and veilionella while the numbers of anaerobic Gram-positive cocci and bacteroides were not influenced by the piperacillin/tazobactam therapy. After treatment the anaerobic microflora was normalized in all patients. No new colonization with piperacillidtazobactam resistant bacteria was observed. No C. difficile or cytotoxin were detected in the faecal specimens. Faecal concentrations of piperacillinltazobactam Faecal concentrations of piperacillin were found in 6 patients and varied between 1.2 and 276 mg/kg/faeces during treatment. Four of these patients had measurable concentrations of tazobactam (0.8-22.2 mg/kg/faeces) at the same time. DISCUSSION Many antibiotics cause ecological changes in the intestinal microflora. The severity of these changes depends mainly on the agent’s spectrum and its concentration in the gut lumen. Parenteral broad-spectrum beta-lactam antibiotics such as ceftriaxone and cefoperazone secreted in the bile or from the intestinal mucosa may cause significant disturbances in the intestinal microflora (6). High bile concentrations of piperacillin (448-4 468 mg/l) have been reported (7) indicating that piperacillin is concentrated in patients with biliary tract diseases. In the present study
Scand J Infect Dis Downloaded from informahealthcare.com by QUT Queensland University of Tech on 10/31/14 For personal use only.
Scand J Infect Dis 24
Piperacillinltazobactam
- intestinal microflora 213
there were no patients with biliary tract diseases which explains the low concentrations of piperacillin found in the faecal specimens. The effect of piperacillin on the intestinal microflora in patients undergoing elective colorectal surgery has been studied by Kager et al. (8). The faecal concentrations of piperacillin ranged from undetectable values to 101.2 mgkg. Enterococci, streptococci and enterobacteria decreased in 25% of the patients during the administration period, while anaerobic Gram-positive cocci and rods, fusobacteria and bacteroides decreased in twothirds of the patients at the same period. The more pronounced effect of piperacillin on the intestinal microflora observed in the investigation of Kager et al. (8) compared to the present one may be explained by the fact that patients undergoing colorectal surgery were enrolled in the former study, since the surgical procedure may induce alterations in the microflora. In the present investigation, no significant changes were observed in the intestinal microflora during or after treatment. This is explained by the low concentrations of piperacillin and tazobactam detected in the intestine. No superinfections or diarrhoea developed during therapy. The present findings indicate that the combination piperacillidtazobactam has a minor ecological impact on the intestinal microflora. REFERENCES 1. Nord CE. Studies on the ecological impacts of antibiotics. Eur J Clin Microbiol Infect Dis 9: 517-518, 1990. 2. Jacobs MR, Aronoff SC, Johenning S , Shlaes DM, Yamabe S. Comparative activities of the beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with ampicillin and broad-spectrum penicillins against defined beta-lactamase-producing aerobic gram-negative bacilli. Antimicrob Agents Chemother 29: 980-985, 1986. 3. Fortner CL, Finley RS, Schimpff SC. Piperacillin sodium: antibacterial spectrum, pharmacokinetics, clinical efficacy, and adverse reactions. Pharmacotherapy 2: 287-299, 1982. 4. Gutmann L, Kitzis M-0, Yamabe S, Acar JF. Comparative evaluation of a new beta-lactamase inhibitor, YTR 830, combined with different beta-lactam antibiotics against bacteria harboring known beta-lactamases. Antimicrob Agents Chemother 29: 955-957, 1986. 5. Heimdahl A, Nord CE. Effect of phenoxymethylpenicillin and clindamycin on the oral, throat and faecal microflora of man. Scand J Infect Dis 11: 23S242, 1979. 6. Nord CE, Heimdahl A, Kager L. Antimicrobial induced alterations in the human oropharyngeal and intestinal microflora. Scand J Infect Dis, Suppl 49: 64-72, 1986. 7. Russo J , Thompson M, Russo ME, Saxon BA, Matsen JM, Moody FG, Rikkers LF. Piperacillin distribution into bile, gall-bladder wall, abdominal skeletal muscle and adipose tissue in surgical patients. Antimicrob Agents Chemother 22: 488-492, 1982. 8. Kager L, Malmborg AS, Nord CE, Sjostedt S . The effect of piperacillin prophylaxis on the colonic microflora in patients undergoing colorectal surgery. Infection 11: 251-254, 1983.
