Anti-infective shortages are a pervasive problem in the United States. The objective of this study was to identify any associations between changes in prescribing of antibiotics that have a high risk for CDI during a piperacillin/tazobactam (PIP/TAZO) shortage and hospital-onset Clostridium difficile infection (HO-CDI) risk in 88 US medical centers.
We analyzed electronically captured microbiology and antibiotic use data from a network of US hospitals from July 2014 through June 2016. The primary outcome was HO-CDI rate and the secondary outcome was changes in antibiotic usage. We fit a Poisson model to estimate the risk of HO-CDI associated with PIP/TAZO shortage that were associated with increased high-risk antibiotic use while controlling for hospital characteristics.
A total of 88 hospitals experienced PIP/TAZO shortage and 72 of them experienced a shift toward increased use of high-risk antibiotics during the shortage period. The adjusted relative risk (RR) of HO-CDI for hospitals experiencing a PIP/TAZO shortage was 1.03 (95% confidence interval [CI], .85–1.26; P = .73). The adjusted RR of HO-CDI for hospitals that both experienced a shortage and also showed a shift toward increased use of high-risk antibiotics was 1.30 (95% CI, 1.03–1.64; P < .05).
Hospitals that experienced a PIP/TAZO shortage and responded to that shortage by shifting antibiotic usage toward antibiotics traditionally known to place patients at greater risk for CDI experienced greater HO-CDI rates; this highlights an important adverse effect of the PIP/TAZO shortage and the importance of antibiotic stewardship when mitigating drug shortages.
Definition of the PIP/TAZO Shortage
The general shortage period was determined a priori to correspond to the national shortage period starting at the end of December 2014. We identified the shortage quarter that showed the higher percentage of drop in PIP/TAZO use among the first two quarters of 2015 as the “shortage period”, in comparison to the last two quarters of 2014 (pre-shortage period). A hospital was considered to experience a PIP/TAZO shortage if there was a statistically significant decrease in at least one of the first two quarters of 2015 compared to the last two quarters of 2014. The severity of PIP/TAZO shortage was classified for each hospital as either mild (≤33% decrease), moderate (34-66% decrease) or severe (>66% decrease).
Figure 1. Unadjusted pre-shortage versus shortage period HO-CDI Rates by severity of PIP/TAZO shortage
Figure 2. Unadjusted pre-shortage versus shortage period HO-CDI rates by degree of change in high-risk antibiotic usage
HO-CDI was not based on symptoms however most patients who have a C. difficile assay drawn will be symptomatic with diarrhea.
Another limitation is that we used pharmacy orders and not antimicrobial administration to evaluate change in antimicrobial usage. Since the same process was used to measure antimicrobial use we believe that this would not change the directionality of the changes in antimicrobial use. It is also possible that some hospitals may have changed testing procedures during the study which may have impacted HO-CDI rates.
The changes in HO-CDI between the pre-shortage and shortage periods may have been due in part to seasonality; to address this we selected a recovery period for subgroup analysis that included the same seasonal months as the shortage period. However, the number of hospitals that fully recovered after the shortage was too small to conclusively demonstrate a subsequent fall in HO-CDI rates although the point estimates were directionally correct.
Finally, our assessment of hospitals experiencing a PIP/TAZO shortage was based on drug use data and not on direct confirmation from the hospital that they had experienced a shortage; however, given 82% of hospitals in the database experienced decreased use of PIP/TAZO, it is more likely these changes were a result of the national shortage and not a local stewardship intervention aimed at decreasing PIP/TAZO use.