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Clinical Infection & Immunity

Case Report

Volume 7, Number 1, March 2022, pages 22-26

Unintended Consequence of Antimicrobial Stewardship: Use of Piperacillin and Tazobactam in Preference to Gentamicin for Urine Infection Was Associated With Clostridium difficile Infection in a High-Risk Spinal Cord Injury Patient, a Case Report

The term “antimicrobial stewardship” is defined as “an organizational or healthcare-system-wide approach to promoting and monitoring judicious use of antimicrobials to preserve their future effectiveness” [1]. Restricting relevant antimicrobial agents can reduce colonization or infection with gram-positive or gram-negative resistant bacteria. A reduction of fluoroquinolone use was associated with decreased methicillin-resistant Staphylococcus aureus and fluoroquinolone-resistant Pseudomonas aeruginosa isolation rates [2].

Unintended consequences of antimicrobial prescribing policy have been documented. In 2009, the Scottish government issued a target to reduce Clostridium difficile (C. difficile) infection by 30% in 2 years. Consequently, Scottish hospitals changed from cephalosporins to gentamicin for surgical antibiotic prophylaxis. The occurrence of postoperative acute kidney injury (AKI) before and after this policy change was examined in 12,482 adults undergoing surgery (orthopedic, urology, vascular, gastrointestinal, and gynecology) with antibiotic prophylaxis between October 1, 2006, and September 30, 2010 in the Tayside region of Scotland. In orthopedic patients, change in policy from cefuroxime to flucloxacillin (two doses of 1 g) and single-dose gentamicin (4 mg/kg) was associated with a 94% increase in AKI (P = 0.04; 95% confidence interval (CI): 93.8-94.3%). Most patients who developed AKI after prophylactic gentamicin had stage 1 AKI, but some patients developed persistent stage 2 or stage 3 AKI [3].

In North West Regional Spinal Injuries Centre, Southport, England, an outbreak of gentamicin-resistant Klebsiella pneumoniae in patients, who were undergoing rehabilitation, occurred in 2019. In order to overcome this outbreak of gentamicin-resistant Klebsiella pneumoniae, amongst other measures, the prescribing habit was changed. Use of gentamicin was restricted; instead, piperacillin and tazobactam were prescribed for treatment of urinary tract infection in patients of the spinal unit. Some patients received a single dose of amikacin followed by piperacillin and tazobactam for varying length of time depending upon the site of infection (e.g., 14 days for orchitis; 5 days for urine infection).

We report the occurrence of C. difficile infection in a patient with paraplegia, who was already at risk for developing C. difficile infection. This patient was prescribed piperacillin and tazobactam for treatment of urinary tract infection due to Escherichia coli (E. coli), although the organism was sensitive to gentamicin.

A male Caucasian born in 1959 presented with back pain, febrile illness, and confusion. Computed tomography (CT) of chest, abdomen and pelvis revealed epidural collection at T4-7 and T-12. Past medical history included epilepsy - grand mal seizure in 1985, hemochromatosis in 2013, and infective hepatitis in 1969. In the tertiary hospital, magnetic resonance imaging (MRI) showed right subpleural empyema, paraspinal abscesses, anterior epidural abscess between T-7 and L-1 producing cord compression, and recent T-7 and T-11 compression fractures. Blood culture yielded Streptococcus anginosus. He was prescribed meropenem and clindamycin. Bilateral Seldinger chest drains were inserted. Percutaneous tracheostomy was done. This patient developed AKI and hepatic encephalopathy. Repeat chest X-ray showed worsening of right-sided empyema. Piperacillin and tazobactam were prescribed in view of worsening chest X-ray findings, rising white cell count and pyrexia.

Repeat MRI showed worsening of epidural abscess. Posterior spinal decompression T-9 to T-11 was done. This patient developed worsening of vertebral collapse at T-12. Therefore, spinal fixation and posterior thoraco-lumbar stabilization T-7 to T-12 were done 3 weeks later for pathological fractures and discitis.

This patient received antibiotics as detailed in Table 1 in the tertiary center before he was transferred to spinal unit.

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Table 1. List of Antibiotics, Dose and Duration of Therapya

This patient was transferred to North West Regional Spinal Injuries Centre for rehabilitation. On clinical examination, light touch and pin prick sensations were absent below T-6 bilaterally. Altered sensation was felt by the patient over S-3 and S-4 dermatomes. Bulbocavernosus reflex was absent. Voluntary anal contraction was absent. Deep anal pressure was absent. There was total paralysis of all groups of muscles in both lower limbs. International standards for neurological classification of spinal cord injury American Spinal Injury Association Impairment Scale was B (level of injury: T-6).

In the spinal unit, a rectal swab showed growth of vancomycin-resistant Enterococcus. A 29 mm size in circumference penile sheath was applied; this patient was allowed to pass urine by himself. Residual urine was not checked by ultrasound scan of urinary bladder until 9 days after admission. Ultrasound scan revealed 349 mL of urine; intermittent catheterization, performed at 13:30, yielded 500 mL of urine. Subsequently, this patient did not pass urine until 19:00. Later during the next day, only small volume of urine was drained. This patient developed temperature of 39.1 °C; heart rate was 138; National Early Warning Score was 7.

Blood test revealed C-reactive protein of 60 mg/L, lactate of 1.86 mmol/L, and white cell count of 16.7. Urine sample taken 9 days earlier showed growth of coliform species sensitive to nitrofurantoin, trimethoprim and gentamicin. Microbiologist advised single dose of amikacin followed by piperacillin and tazobactam 4.5 g every 8 h for 5 days, followed by trimethoprim.

Microbiology report of urine sample, which was taken on the day the patient developed pyrexia, showed growth of E. coli and coliform species; these organisms were sensitive to nitrofurantoin, trimethoprim, gentamicin and piperacillin-tazobactam, but resistant to amoxicillin. E. coli was not extended spectrum beta-lactamase (ESBL) producing organism. Rectal swab was also negative for ESBL; however, rectal swab showed growth of vancomycin-resistant Enterococcus faecium.

Ultrasound scan of urinary tract revealed no focal cortical thinning; no hydronephrosis, no calculus in the kidneys; normal bladder outline; no bladder calculus.

Six days after completing the course of tazobactam/piperacillin (November 11, 2019), this patient passed loose stools. Stool revealed toxin-producing C. difficile. This patient was clinically ill; white cell count was raised (12.1 × 10⁹/L; reference range: 3.7 - 9.5). C-reactive protein was high (39 mg/L; reference range: 0 - 4). On clinical grounds, a decision was made that C. difficile-directed treatment was really indicated.

He received fidaxomicin, 200 mg every 12 h for 12 days. Fidaxomicin was preferred to vancomycin in this patient as this patient harbored vancomycin-resistant Enterococcus faecium.

The Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): “2021 Focused Update Guidelines on Management of Clostridioides difficile infection in adults” recommends that for patients with an initial Clostridioides difficile infection episode, fidaxomicin be used rather than a standard course of vancomycin (conditional recommendation, moderate certainty of evidence). The panel suggested the use of fidaxomicin as the preferred therapy for an initial Clostridioides difficile infection episode, to improve sustained response after therapy, but recognized that vancomycin remains an acceptable alternative if fidaxomicin is not available [4].

This patient improved with fidaxomicin therapy. Patient recovered from C. difficile infection. He was discharged to a nursing home.

The factors, which increase the risk of C. difficile infection, include broad-spectrum antibiotics, advanced age, underlying morbidity, hospitalization, exposure to other people with the infection, long duration of antibiotic treatment, taking multiple antibiotics concurrently or taking multiple antibiotic courses, and inflammatory bowel disease. This patient had more than one risk factor (receiving ceftriaxone for 11 weeks, taking multiple antibiotic courses, hospitalization, underlying morbidity), for C. difficile infection.

This patient had received ceftriaxone for 11 weeks for epidural abscess. Subsequently, he was prescribed piperacillin and tazobactam for urine infection.

Following the establishment of the C. difficile ribotyping network service, the combination penicillins have become the antibiotics most frequently reported as being associated with C. difficile infections. Penicillin combination antibiotics, such as co-amoxiclav and piperacillin-tazobactam, were associated with a statistically significant 50% relative increase in the risk of C. difficile infection (six studies; odds ratio (OR): 1.54, 95% CI: 1.05 - 2.24) [5].

We learn from this case that we should take into account the benefits and harms for an individual patient associated with the particular antimicrobial, including the risk of healthcare-associated infections, for example, C. difficile. Antimicrobial stewardship programme includes reporting of patient safety incidents related to antimicrobial use, including infections with C. difficile [6].

In contrast to the penicillin combination antibiotics such as co-amoxiclav, and piperacillin/tazobactam, gentamicin is considered to be a safe antibiotic in patients who are at high risk for developing C. difficile infection because gentamicin has low propensity to cause C. difficile infection. Gentamicin does not enter the colonic lumen when it is given intravenously. So it is a balance between the amount of the antibiotic that is in the lumen, the effect that it has on the colonic microflora, and the effect that it has on C. difficile. Staley and associates [7] recommend gut-sparing treatment of urinary tract infection in patients at high risk of C. difficile infection.

In this case, the use of gentamicin was restricted in the spinal unit to control the outbreak of gentamicin-resistant Klebsiella pneumoniae. Restriction of the use of certain antibiotics has been the cornerstone of antimicrobial stewardship. However, the restriction of gentamicin use may not always be associated with decreased incidence of resistant gram-negative bacterial infection. Antibiotic stewardship did not affect the incidence ratios of vancomycin-resistant enterococci and quinolone-resistant and aminoglycoside-resistant gram-negative bacteria [8]. Moreover, antimicrobial stewardship interventions showed that very large changes in prescribing were associated with much smaller changes in resistance [9]. The reductions in resistance took much longer than reductions in prescribing to become evident, and relative reductions were more modest. The overall pattern was of flattening rather than reversal of previously rising resistance rates. Therefore, Hernandez-Santiago and colleagues concluded that prevention of resistance through judicious use of new antimicrobials may be more effective than trying to reverse resistance that has become established [9].

This case illustrates that we should take into account the undesirable effects of antimicrobial stewardship programme, both expected and the unexpected effects after implementation [10]. In this patient, treatment of urinary tract infection with gut-sparing antibiotic might have reduced the risk of C. difficile infection, as this patient was already at risk for developing C. difficile infection.

C. difficile infection was not a consequence of the latest cycle of antibiotics (piperacillin/tazobactam) given to the patient for urinary tract infection, rather it was due to the very long and largely inappropriate treatment given in the weeks before. Blood cultures were positive for Streptococcus anginosus, which in most cases is penicillin and ampicillin sensitive. Thus, there was no need to use ceftriaxone, nor meropenem, piperacillin/tazobactam or teicoplanin. We should use narrow spectrum antibiotic whenever possible. This is the key point for learning.

We should tend to prefer aminoglycoside such as gentamicin if the organism is sensitive particularly in selected patients, who are at high risk for developing C. difficile infection, as this patient.

We should assess patients, who are spontaneously voiding, at more frequent intervals so that there is no delay in detecting the presence of large amount of residual urine. In this patient, there was a delay in recognizing that the patient was retaining 500 mL of urine. Prompt diagnosis and appropriate intervention (e.g., intermittent catheterization) is likely to reduce the risk of urine infection. If urine infection can be prevented, this will in turn, reduce the need for antibiotics to treat urine infection and consequently, decrease the risk of C. difficile. Education of health professionals on early recognition of the risk factors for urine infection (e.g., those patients, who are spontaneously voiding), and prompt intervention to achieve low-pressure, complete emptying of urinary bladder will reduce the risk of urine infection in persons with spinal cord injury. If urinary tract infections can be prevented, the need for antibiotics will be decreased and subsequently the risk of developing C. difficile infection will be reduced.

Many patients who are referred to spinal unit for rehabilitation would have received several courses of antibiotics for spinal infection (e.g., epidural abscess) or chest infection (e.g., hospital-acquired pneumonia). As these patients have been prescribed multiple courses of different antibiotics, they are at high risk for C. difficile infection. The United Kingdom Department of Health’s policy “Start smart - then focus” should begin from the first hospital visit for these patients.

Acknowledgments

The authors acknowledge the help rendered by other clinicians in the spinal unit and microbiology in providing care for this patient.

Financial Disclosure

Both authors declare that they did not receive any funding from any source.

Conflict of Interest

Both authors declare that they do not have any conflict of interest.

Informed Consent

Publication of this case report was discussed with the patient’s wife over the phone during the COVID pandemic; following this discussion, she gave consent for the publication of this case regarding her husband.

Author Contributions

SV wrote the draft; both authors reviewed the final manuscript.

Data Availability

Important clinical details of the patient, laboratory investigations and imaging studies used to support the findings of this study are included within the article. However, further details such as date of birth of the patient or the name of the patient are restricted in order to protect patient’s privacy and confidentiality.

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