Clinical Infectious Diseases Advance Access published October 9, 2014 1 

HIGHER RISK OF NEUTROPENIA ASSOCIATED WITH PIPERACILLIN-

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TAZOBACTAM COMPARED TO TICARCILLIN-CLAVULANATE IN CHILDREN

Pierre Lemieux1,2,*, Jean-Pierre Grégoire1,3, Roseline Thibeault2,4, Luc Bergeron1,2

2

CHU de Québec – CHUL, Québec, Canada

3

Chair on adherence to treatments, CHU Research Center, Québec, Canada

4

Faculté de médecine, Université Laval, Québec, Canada

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Faculté de pharmacie, Université Laval, Québec, Canada

Contact information: Pierre Lemieux, B. Pharm., M. Sc. Hôtel-Dieu de Lévis, Pharmacy Department, 143, rue Wolfe, Lévis, QC, G6V 3Z1, Phone : 418 835-7121 # 3815, Fax : 418

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835-7178, Email : [email protected], Luc Bergeron, B. pharm., M.Sc, FCSHP, CHU de Québec – CHUL, pharmacy department, 2705 boul. Laurier, Québec, QC, G1V 4G2, Phone : 418 656-4141 # 71337, Fax : 418 654-2775, Email : [email protected] Actual affiliation : Hôtel-Dieu de Lévis, Lévis, Canada.

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*

Summary:

Our results suggest a four times increased risk of neutropenia associated with piperacillin-

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tazobactam compared to ticarcillin-clavulanic acid. Piperacillin-tazobactam should be used cautiously in children, especially in those less than 13 years old when a long course treatment is planned.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of  America. All rights reserved. For Permissions, please e‐mail: [email protected]

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ABSTRACT

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Background: A series of cases of piperacillin-tazobactam (P/T)-associated neutropenia has been observed recently in children in our center. Since neutropenia was seldom observed in children treated with ticarcillin-clavulanic acid (T/C), we conducted a study to determine if

there is an increased risk of neutropenia in children exposed to P/T in comparison with T/C.

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T/C between Jan 1, 2008 and June 30, 2011 were reviewed.

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Results: 299 episodes of treatment (65 P/T, 234 T/C) met inclusion criteria. Among those episodes, 213 had data allowing complete white blood cell (WBC) count analysis and were

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included in the final analysis. Thirteen cases of neutropenia were observed during the study period. The average time to onset was 17.6 days and all the cases were 13 years old or younger. Seven cases (10.8%) occurred in the P/T group and 6 (2.6%) in the T/C group

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(unadjusted odds ratio (OR) 4.59; 95% CI 1.48-4.17). While a statistically significant correlation was observed between age, treatment duration, total dose and the development of neutropenia (r = -0.121, P = 0.037, r = 0.267, P < 0.001, r = 0.260, P < 0.001), this was not the case for sex, indications, neutrophil count at initiation and concomitant drug treatments.

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Conclusion: Although our results need to be confirmed, they suggest that children receiving long courses of therapy (more than 2 weeks) with P/T may be at increased risk of

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neutropenia, compared with T/C.  

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Methods: Medical records of subjects < 18 years who received at least one dose of P/T or



Beta-lactam antibiotics are generally safe and effective against a wide range of bacterial

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infections in both children and adults. Serious adverse reactions to beta-lactams are

uncommon.(1) However, several successive cases of neutropenia, sometimes associated with skin rash and fever, have recently been observed in our centre during prolonged treatment

The association between the use of beta-lactam antibiotics and the development of

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neutropenia is well documented in the literature despite its low frequency. (2-4) There seems to be a relationship between the cumulative dose of penicillin, the duration of treatment and

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the onset of neutropenia. A systematic review of studies on the relationship between piperacillin use and neutropenia suggests that the occurrence of neutropenia varies between 0.04% and 34% among individuals exposed. (5) This variability between studies is due in

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part to differences in study designs and to variation in the way neutropenia is being defined. One cohort study (6) and several case reports describe piperacillin-induced neutropenia as occurring on average 19 days after initiation of piperacillin treatment. (2, 7-15) To our knowledge, no study has yet focused on piperacillin-associated neutropenia in the pediatric

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population.

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On the other hand, neutropenia or agranulocytosis following the use of ticarcillin-clavulanate seems less frequent. In fact, only four cases of neutropenia attributed to the use of this antibiotic have been reported. (16-19) Two of these cases occurred in children aged 14 months and 2.5 years, respectively. As in the case of piperacillin-induced neutropenia, neutropenia observed with ticarcillin appears on average after 21 days of treatment.

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with piperacillin-tazobactam.



The primary objective of this study was to evaluate the risk of developing neutropenia in children and teenagers under 18 years exposed to piperacillin-tazobactam versus those

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exposed to ticarcillin-clavulanic acid.

METHODS

We conducted a retrospective cohort study in a pediatric population. We chose ticarcillin-

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combination and has similar antibacterial spectrum of activity, clinical indications, and

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dosing as piperacillin-tazobactam.

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Subjects were included in the study if they were aged less than 18 years and had received at least one dose of piperacillin-tazobactam or ticarcillin-clavulanate during their hospital stay between January 1, 2008 and June 30, 2011. Patients with active neoplasia or receiving

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chemotherapy were excluded from the study. In addition, children already neutropenic at the start of antibiotic treatment, patients treated with immunosuppressive agents introduced at least 30 days before the start of antibiotic treatment, those with known congenital anomalies associated with the development of neutropenia, and those with human immunodeficiency

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virus infection were also excluded.

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Neutropenia was defined as an absolute neutrophil count (ANC) less than 1.0 x 109 /l

occurring during the period between the administration of the first dose up to four weeks after the end of antibiotic treatment. In addition, subjects who received two separate treatments with the same antibiotic within a seven-day interval were considered to have received a single continuous treatment if there was no resolution of neutropenia during the

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clavulanate as a comparator since this antibiotic is also a penicillin/ß—lactamase inhibitor



antibiotic-free period. In the reverse situation, where there was a return of the neutrophil count greater than 1.5 x 109 /l between treatment periods, they were then treated

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independently. We deliberately chose a cut-off ANC value of 1.0 x 109 /l, because it

corresponds to the threshold many clinicians use in practice to consider withdrawing a

possible neutropenia-inducing drug before the ANC value attains 0.5 x 109 /l. Finally, in cases where the value of neutrophil count in the antibiotic-free period was unknown,

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was started within less than seven days after the end of the first. Otherwise, the treatments

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were considered independent from each other.

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The relative risk of developing neutropenia in the group exposed to piperacillin-tazobactam compared to those in the ticarcillin-clavulanate group was assessed through odds ratio (OR) estimated using binomial linear regression. The following potential confounding variables

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were considered in the analysis: age, duration of treatment, and neutrophil count prior to initiation. Concomitant drugs considered were those for which an association with neutropenia has been shown. (20-22) Two-tailed tests were used to determine statistical significance with a P value of less than 0.05 considered significant. Variables found to be

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significant in univariate testing were incorporated in the multivariate regression model with a stepwise approach. Survival distribution function was estimated using the Kaplan-Meier

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product–limit method and log-rank test was used to compare survival functions in different groups. All statistical analyses were performed with the SPSS statistics software, version 17.0.

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treatment episodes were considered as a single treatment provided that the second treatment



This study was approved by the clinical research ethics review board of the Centre

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Hospitalier Universitaire de Québec.

RESULTS

Two hundred eighty-two subjects who received 438 treatment episodes were identified. Eighty-four subjects received more than one treatment with piperacillin-tazobactam or

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65 (22%) with piperacillin-tazobactam and 234 (78%) with ticarcillin-clavulanate. The main

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reason for exclusion was the presence of chemotherapy (n = 78), while 45 records were excluded because they were not available at the time of data collection. Three patients (2.3 %) were excluded because they were immunosuppressed and 7 (5.3%) because they were

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neutropenic at the start of the antibiotic treatment.

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Among subjects who met all inclusion criteria, two children had a normal ANC on the morning of the start of their antibiotic treatment. However, a second complete blood count (CBC) was done later that day for both of them and shown an ANC less than 1.0 x 109/l. It is therefore highly unlikely that these two subjects have developed piperacillin-tazobactam-

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associated neutropenia. They were therefore excluded from the final analysis.

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Study patients characteristics are presented in table 1. The patients in both groups were comparable with respect to age, weight and duration of antibiotic treatment. A statistically significant difference between study groups was however observed for the proportion of males and concomitant treatments. The indications for antibiotic treatment were similar in the two groups (table 1), the only difference being the greater proportion of children treated

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ticarcillin-clavulanate. A total of 299 treatment episodes were included in the final analysis:



with piperacillin-tazobactam for intra-abdominal infections, while a greater proportion of children with cystic fibrosis-associated pulmonary infections were treated with ticarcillin-

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clavulanate.

A CBC was available for 213 (70.9%) of the 299 treatment episodes included in the study. The proportion of subjects without any CBC performed during the course of antibiotic

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piperacillin-tazobactam group and 71 (30,3%) in the ticarcillin-clavulanate group (P =

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0.252).

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During the study period, seven cases of neutropenia (10.8%) were observed in patients treated with piperacillin-tazobactam while six cases (2,6%) were observed in those receiving ticarcillin-clavulanate (table 2). All cases of neutropenia occurred in patients less than 13

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years old, with a mean age of 3.5 ± 4.1 and 4.6 ± 4.2 years in the piperacillin-tazobactam and ticarcillin-clavulanate groups, respectively. No between-group difference was observed in relation to age, time to onset, total dosage, initial neutrophil count and neutrophil nadir.

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There was a statistically significant increased risk of developing neutropenia in the group piperacillin-tazobactam versus ticarcillin-clavulanate (unadjusted OR = 4.59, 95%CI: 1.48 -

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14.17). A statistically significant correlation was observed between age, duration of treatment, total dose and the development of neutropenia (respective Pearson’s correlation coefficient: r = -0.121, P = 0.037, r = 0.267, P < 0.001, r = 0.260, P < 0.001). This was not the case with regards to sex (r = 0.020, P = 0.731), indications (r = 0.001, P = 0.992), neutrophil count at initiation (r = -0.079, P = 0.185) and concomitant drug treatments (r

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treatment was not statistically different between the two groups: 15 (23.1%) in the



ranging from -0.057 to 0.044 and P ranging from 0.325 to 0.599). Since the number of events per adjustment variable to be considered in the logistic regression analysis was below

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10 (total number = 13), there would be a risk of over-fitting if conducting the multivariate logistic regression analysis. (23) Therefore we do not report the adjusted OR.

Kaplan-Meier curves show a faster decrease in the probability of survival without

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Consequently, the risk of developing neutropenia during antibiotic treatment increases more

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quickly with piperacillin-tazobactam. An examination of the curves suggests that this difference appears around the 10th day of treatment.

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DISCUSSION

Our findings suggest a four-fold increase in the risk of developing neutropenia in subjects

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exposed to piperacillin-tazobactam as opposed to those exposed to ticarcillin-clavulanate,. All the episodes of antibiotic-associated neutropenia were observed in children younger than 13 years old.

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This increase in the risk of developing neutropenia is difficult to explain. Both study groups were comparable albeit there was a significantly higher proportion of male patients and also

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of patients receiving concomitant drugs known to cause neutropenia in the piperacillintazobactam group. By contrast to what has been reported in case reports and review articles (21, 22, 24) we did not observe any association between the use of concomitant drugs and the development of neutropenia. The high proportion of concomitant beta-lactam use is

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neutropenia with piperacillin-tazobactam versus ticarcillin-clavulanate (figure 1).



mostly explained by the step-down from piperacillin-tazobactam or ticarcillin-clavulanate to

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oral therapy for the majority of the treatment episodes.

There is large variation in the reported incidence rates for piperacillin-associated

neutropenia. In their review of 178 clinical trials, Scheetz et al reported a prevalence of

piperacillin-induced neutropenia of 0.04 % (5/13 816). (5) However, the vast majority of the

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treatment of intra-abdominal infections (16%) and pharmacokinetic/pharmacodynamics

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properties, whereas piperacillin-tazobactam and ticarcillin-clavulanate were used in our patients for complicated or mixed infections, such as intra-abdominal abscess, parapneumonic empyema or P. aeruginosa infections (table 1). Furthermore, the authors

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used a definition value for neutropenia of 0.5 x 109/l. In comparison, a retrospective cohort study in patients treated for osteomyelitis showed that 34% (14/41) of the patients treated

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with piperacillin for more than 10 days developed a neutropenia. (6) In this latter study the proportion of patients with piperacillin-associated neutropenia was probably overestimated because the authors used a less stringent definition criterion for neutropenia (ANC < 2.0 x 109/l). (8) The incidence of neutropenia measured in our study thus lies in-between the

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values reported in these studies. For example, if we had used an ANC cut-off value of 0.5 instead of 1.0, the percentage of neutropenia would then have been 9.2% (6/65) and 0.4%

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(1/234) in the piperacillin-tazobactam and ticarcillin-clavulanate groups, respectively (OR: 23.69 (95% CI 2.80 – 200.64). There is no data published on the possible role of the betalactamase inhibitor tazobactam in the development of neutropenia. Moreover, to our knowledge, no other study on the relationship between ticarcillin use and neutropenia has been published, both for adults and children, apart from four case reports. (17-20)

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studies included in their review were evaluating piperacillin for surgical prophylaxis (24%),

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In comparison with results reported in the literature, the higher incidence of neutropenia we

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have observed might be explained by the longer mean treatment duration observed in our study patients.

The mean time to onset of neutropenia was 17.6 days, which is similar to the 19 days

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were observed after a mean of 19 days of treatment while the time to onset for piperacillin-

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tazobactam was somewhat shorter (16.2 days). There was no statistically significant

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difference in time to onset in the two study groups.

This study has some limitations. The treatments were not randomized and therefore we may not have taken into account all variables that could have a protective or negative effect on the

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development of neutropenia. As mentioned above, it was not possible to conduct the multivariate logistic regression we had planned, as the number of events was too low. Therefore, we were not able to adjust for the presence of some potential confounders. Moreover, missing data, particularly follow-up complete blood counts, may have introduced

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information bias.

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CONCLUSION

To our knowledge, this is the first study evaluating the risk of neutropenia associated with the use of piperacillin-tazobactam, and the first one describing this adverse drug reaction in children. The findings of this study suggest the risk of neutropenia is higher when children

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reported in the literature. (2, 6-15) Ticarcillin-clavulanate-associated neutropenia episodes

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are treated with piperacillin-tazobactam than with ticarcillin-clavulanate. Piperacillintazobactam should therefore be used with caution in children, particularly in younger (less

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than 13 years-old) children when a longer duration of treatment is expected. Despite this finding, piperacillin-tazobactam can still be useful in clinical practice. A comprehensive benefit/risk assessment should be however be performed whenever one considers using

Notes

Funding: None

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Potential Conflicts of Interest: All authors: No reported conflicts

Figure Legend: Probability of survivial without neutropenia after the initiation of a

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treatment with piperacillin-tazobactam (P/T) and ticarcillin-clavulanate (T/C)

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piperacillin-tazobactam or any other antibiotic alternatives that also carry their own risks.

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References

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1. Lagace-Wiens P, Rubinstein E. Adverse reactions to beta-lactam antimicrobials. Expert Opin Drug Saf. 2012 May;11(3):381-99. 2. Neftel KA, Hauser SP, Muller MR. Inhibition of granulopoiesis in vivo and in vitro by beta-lactam antibiotics. J Infect Dis. 1985 Jul;152(1):90-8. 3. Olaison L, Alestig K. A prospective study of neutropenia induced by high doses of beta-lactam antibiotics. J Antimicrob Chemother. 1990 Mar;25(3):449-53. 4. Olaison L, Belin L, Hogevik H, Alestig K. Incidence of beta-lactam-induced delayed hypersensitivity and neutropenia during treatment of infective endocarditis. Arch Intern Med. 1999 Mar 22;159(6):607-15. 5. Scheetz MH, McKoy JM, Parada JP, Djulbegovic B, Raisch DW, Yarnold PR, et al. Systematic review of piperacillin-induced neutropenia. Drug Saf. 2007;30(4):295-306. 6. Peralta FG, Sanchez MB, Roiz MP, Pena MA, Tejero MA, Arjona R. Incidence of neutropenia during treatment of bone-related infections with piperacillin-tazobactam. Clin Infect Dis. 2003 Dec 1;37(11):1568-72. 7. Wilson C, Greenhood G, Remington JS, Vosti KL. Neutropenia after consecutive treatment courses with nafcillin and piperacillin. Lancet. 1979 May 26;1(8126):1150. 8. Bressler RB, Huston DP. Piperacillin-induced anemia and leukopenia. South Med J. 1986 Feb;79(2):255-6. 9. Lang R, Lishner M, Ravid M. Adverse reactions to prolonged treatment with high doses of carbenicillin and ureidopenicillins. Rev Infect Dis. 1991 Jan-Feb;13(1):68-72. 10. Rye PJ, Roberts G, Staugas RE, Martin AJ. Coagulopathy with piperacillin administration in cystic fibrosis: two case reports. J Paediatr Child Health. 1994 Jun;30(3):278-9. 11. Behbahani R, Kostman JR. Hypersensitivity reaction during prolonged use of piperacillin/tazobactam in treatment of osteomyelitis. Ann Pharmacother. 1995 Sep;29(9):936-7. 12. Gerber L, Wing EJ. Life-threatening neutropenia secondary to piperacillin/tazobactam therapy. Clin Infect Dis. 1995 Oct;21(4):1047-8. 13. Ruiz-Irastorza G, Barreiro G, Aguirre C. Reversible bone marrow depression by high-dose piperacillin/tazobactam. Br J Haematol. 1996 Dec;95(4):611-2. 14. Kumar A, Choudhuri G, Aggarwal R. Piperacillin induced bone marrow suppression: a case report. BMC Clin Pharmacol. 2003 Jun 5;3:2. 15. Khan F. Severe neutropenia secondary to piperacillin/tazobactam therapy. Indian J Pharmacol. 2005;37(3):192-3. 16. Gastineau D, Spector R, Philips D. Severe neutropenia associated with ticarcillin therapy. Ann Intern Med. 1981 May;94(5):711-2. 17. Ohning BL, Reed MD, Doershuk CF, Blumer JL. Ticarcillin-associated granulocytopenia. Am J Dis Child. 1982 Jul;136(7):645-6. 18. Dubs MM. Beta-lactam-induced neutropenia. Pediatr Infect Dis. 1985 NovDec;4(6):705-6. 19. Mandl DL, Garrison MW, Palpant SD. Agranulocytosis induced by vancomycin or ticarcillin/clavulanate. Ann Pharmacother. 1997 Nov;31(11):1321-4.

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20. Kaufman DW, Kelly JP, Jurgelon JM, Anderson T, Issaragrisil S, Wiholm BE, et al. Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol Suppl. 1996;60:23-30. 21. Ibanez L, Vidal X, Ballarin E, Laporte JR. Population-based drug-induced agranulocytosis. Arch Intern Med. 2005 Apr 25;165(8):869-74. 22. van der Klauw MM, Goudsmit R, Halie MR, van't Veer MB, Herings RM, Wilson JH, et al. A population-based case-cohort study of drug-associated agranulocytosis. Arch Intern Med. 1999 Feb 22;159(4):369-74. 23. Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996 Dec;49(12):1373-9. 24. Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med. 2007 May 1;146(9):657-65.

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Characteristics

P/T

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Table 1. Study patient characteristics

T/C

(n = 234)

Male sex; N (%)

42 (64.6)

110 (47.0) †

Mean age (years ± SD)

7.3 ± 6.0

7.4 ± 6.0

28.6 ± 25.6

24.1 ± 18.3

9.9 ± 7.0

9.3 ± 5.4

7.8 ± 6.4

7.6 ± 5.9

6.3

6.2

Cystic fibrosis

3 (4.6)

66 (28.2) †

Pulmonary infections*

17 (26.2)

46 (19.7)

Intra-abdominal infection

16 (24.6)

4 (1.7) †

Skin and skin structure infection

8 (12.3)

16 (6.8)

Osteomyelitis

2 (3.1)

2 (0.9)

Sepsis

1 (1.5)

9 (3.8)

18 (27.7)

91 (38.9)

0 (0)

1 (0.5)

Initial ANC (x 109 cells/l ± SD)

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Mean treatment duration (days ± SD)

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Mean weight (kg ± SD)

Median treatment duration (days)

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Indications; N (%)

Others

Concomitant treatment; N (%) Salicylates

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(n = 65)

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1 (0.5)

Phenytoin

3 (5.5)

7 (3.6)

Carbamazepine

1 (1.8)

5 (2.7)

Corticosteroids

14 (25.5)

83 (44.9) †

Co-trimoxazole

5 (9.1)

15 (8.1)

Erythomycin

0 (0)

1 (0.5)

Beta-lactams* *

52 (94.5)

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0 (0)

149 (80.5) †

P/T: piperacillin-tazobactam; T/C: ticarcillin-clavulanate

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ANC: Absolute Neutrophil Count

* Pulmonary infections include: parapneumonic empyema, aspiration pneumonia,

infections ** Other than P/T or T/C P < 0.05 vs P/T

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pneumonia in children colonized with P. aeruginosa and other complicated pulmonary

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Indomethacin

Table 2. Characteristics of the 13 episodes of neutropenia  Total Age Drug

Time to onset

Sex

1.0 0.4 0.4 0.5 0.2 0.4 0.3

6.3 (3.7)

0.5 (0.3)

9.9 5.0 12.3 4.8 11.6 7.4 8.5 (3.3)

1.0 0.6 1.0 0.7 0.5 1.0 0.8 (0.2)

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ANC: absolute neutrophil count

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M: male; F: female

SD: Standard deviation

Pip-tazobactam: piperacillin-tazobactam

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9.0 13.1 6.9 3.7 3.7 3.2 4.5

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11.2 32.4 1.6 8.6 0.5 7.2 2.1 26.5 8.1 22.1 4.0 19.0 4.6 (4.2) 19.2 (10)

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4.4 (1.3)

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Pip/Tazobactam Ticar-clavulanate Mean (SD)

3.5 (4.1) 16.2 (6.7) F F F M F M

3.1 6.2 3.9 5.5 3.2 5.7 3.6

(x109 L)

Ticar-clavulanate: ticarcillin-clavulanate

7.9 2.6 1.1 1.3 0.6 5.9 3.2 (3.0)

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Mean (SD)

4.2 20.4 17.1 21.1 13.3 24.4 13.0

ANC

(x109 L)

(g/kg) 0.2 2.0 4.8 12.2 2.6 0.9 1.8

Initial

Nadir of neutrophils

dose (years) (days)

M F F M M F M

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Higher risk of neutropenia associated with piperacillin-tazobactam compared with ticarcillin-clavulanate in children.

A series of cases of piperacillin-tazobactam (P/T)-associated neutropenia has been observed recently in children in our center. Because neutropenia wa...
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