Alternative Antibiotic Selections During the 2022 Amoxicillin Shortage in the United States

Abstract

This study of 7 pediatric hospitals identified that the amoxicillin shortage in 2022 resulted in a decline in amoxicillin suspension prescribing by 30.8% with increases in use of amoxicillin nonsuspension (+7.9) and broad-spectrum antibiotics. Strategic planning and standardized guidelines are essential to address future shortages and ensure effective, guideline-based care.

INTRODUCTION

The years following the COVID-19 pandemic have seen volatility in respiratory conditions. A surge of respiratory viral infections among children in 2022–2023 placed substantial demands on acute care settings [1]. Compounding the systematic stress of this surge was a shortage of antibiotics, both in the United States and in Europe [2]. On October 28, 2022, the U.S. Food and Drug Administration (FDA) declared a shortage of amoxicillin powder for liquid suspension [3]. One single-center study reported that amoxicillin for children with acute otitis media (AOM) declined following this declaration [4]. The impact of this shortage has implications for future surges in respiratory infections in children. We evaluated changes in antibiotic utilization during the amoxicillin shortage among a sample of children’s hospitals.

METHODS

We performed a multicenter, retrospective, interrupted time series analysis of children (<18 years) who presented to the emergency department (ED) at 1 of 7 tertiary care hospitals in the United States participating in the PEDSnet data collaborative between July 24, 2022 and April 1, 2023 and were ordered or prescribed one of the following: amoxicillin, amoxicillin/clavulanic acid, azithromycin, clindamycin, cefdinir, or cephalexin [5]. We considered amoxicillin as narrow-spectrum and amoxicillin/clavulanic acid, cephalexin, azithromycin, clindamycin, and cefdinir as broad-spectrum [6]. This study was approved by our Institutional Review Board.

We extracted the following variables: demographics, week of encounter (36 7-day intervals between July 24, 2022, and April 1, 2023), diagnoses, and antibiotic(s) prescribed. We are unable to confirm pharmacy prescription fills in the PEDSnet data model. We used diagnosis codes to identify patients with pharyngitis, AOM, or community-acquired pneumonia (CAP; Supplementary Table 1).

Our outcome was antibiotic-prescribed; each encoded as a dichotomized variable. We stratified amoxicillin into suspension and nonsuspension formulations. We performed an interrupted time series analyses using linear regression to compare trends in antibiotic ordering or prescribing before and after the FDA declaration (October 28, 2022, week 43 of the calendar year 2022, or week 14 of the study period). We expressed results using the parameters of slope prior to the FDA declaration, step change during the FDA declaration, and change in slope following the intervention, as coefficient estimates with 95% confidence intervals (CIs). We analyzed the subset of encounters with pharyngitis, AOM, or CAP, evaluated use of amoxicillin by contributing ED, and compared return visit rates 7 days after discharge between children in the 30 days before and after the declared shortage. As an exploratory analysis, we evaluated changes in antibiotic prescribing during the year before (July 25, 2021, to April 2, 2022) and after (July 23, 2023, to March 30, 2024) the FDA declaration to detect changes related to antibiotic on the same day (October 28). We repeated our analysis in a sample of children having either pharyngitis, AOM, or CAP (irrespective of use of any antibiotic) and evaluated for changes in any antibiotic use following the FDA declaration.

RESULTS

Of 730 400 pediatric ED encounters, one of the study antibiotics was prescribed in 141 380. Of these, 19 045 (13%), 53 633 (38%), and 6418 (5%) had diagnoses of pharyngitis, AOM, and CAP, respectively (with 1.3% having >1 of these diagnoses). The median patient age was 4 years (IQR 2–7 years; Table 1). Among children prescribed amoxicillin suspension, the median age was 3.8 years (IQR 1.7–6.2). Among children prescribed amoxicillin nonsuspension, the median age was 9.2 years (IQR 5.3–13.3).

Table 1.

Demographics of the Study Sample Among All Children Prescribed at Least 1 Antibiotic

	Overall N = 141 380
Age; years median [IQR]	4 [2–7]
Female sex; n (%)	69 217 (49.0)
Race; n (%)
American Indian, Alaska Native, Native Hawaiian or Other Pacific Islander	623 (0.4)
Asian	7983 (5.6)
Black	31 296 (22.1)
Multiple race	8010 (5.7)
Not known	22 697 (16.1)
White	70 771 (50.1)
Ethnicity n (%)
Hispanic or Latino	27 831 (19.7)
Not Hispanic or Latino	113 549 (80.3)
Payor status n (%)
Public	63 905 (45.2)
Private/commercial	55 811 (39.5)
Other/unknown, or self-pay	21 664 (15.3)
Diagnosis; n (%)
Pharyngitis	19 045 (13.4)
Acute otitis media	53 633 (37.9)
Community-acquired pneumonia	6418 (4.5)

Numbers in parentheses represent percentages and in brackets represent interquartile ranges (IQRs).

Among included encounters for which at least 1 antibiotic was provided, amoxicillin suspension prescribing significantly increased during the weeks leading up to the FDA declaration. Following this, there was an immediate decrease of 30.8% (95% CI −36.7, −24.9; P < .001) without a continued change in trend in subsequent weeks (Figure 1; Supplementary Table 2). The FDA declaration was associated with increased use of amoxicillin nonsuspension (+7.9%), as well as most other antibiotics evaluated: amoxicillin–clavulanic acid (+13.7%), cephalexin (+3.4%), azithromycin (+0.7%), and cefdinir (+6.4%). The extent of the decline in amoxicillin suspension use varied among the studied hospitals, though the declaration was associated with a significant step change within each (Supplementary Figure 1). There was no decrease in the use of amoxicillin before/after October 28, 2021, or before/after October 28, 2023 (Supplementary Table 3). Seven-day return visit rates were similar between the pre- (1.3%) and post-declaration periods (1.2%; Supplementary Table 4).

Figure 1.

Use of antibiotics among all patients before and after the FDA declaration for the amoxicillin shortage (noted by vertical dotted line) among encounters for children prescribed at least 1 study antibiotic. Numbers represent step changes, with 95% confidence intervals in parentheses. In each panel, the x-axis represents study week, with the FDA declaration occurring on week 14 of the study period. The y-axis represents proportion of children prescribed the antibiotic.

Among encounters for which at least one antibiotic was provided, the FDA declaration was associated with a decline in the use of amoxicillin for each of the studied diagnoses, with increases in the use of other antibiotics (Supplementary Table 5). For children with pharyngitis, there was an increase in the use of cephalexin. For children with AOM or CAP, there was an increase in the prescribing of amoxicillin/clavulanic acid and cefdinir.

In a revised sample limited to encounters having 1 or more of the specific infections, to evaluate overall changes in antibiotic prescribing, 84 805 encounters with or without antibiotics were included (20 291 with pharyngitis, 57 784 with AOM, and 8745 with CAP; 2006 having more than 1 diagnosis). We identified a −7.0% (95% CI −9.5, −4.5) change in the use of any of the six antibiotics (Supplementary Table 6).

DISCUSSION

We found a decline in amoxicillin suspension use, with a concurrent rise in the use of broader-spectrum antibiotics, following the FDA shortage declaration. There was an additional decline in antibiotic use for children with studied infections. Our findings support the hypothesis that clinicians adapted to the antibiotic shortage by prescribing second-line, often broader-spectrum, antibiotics for common infections.

Our findings align with a single-center study of amoxicillin use for AOM that reported a 91% decrease in odds of amoxicillin prescription, with a concurrent increase in alternative antibiotic use [4]. This corresponds with the viral respiratory surge reported during the fall and winter of 2022, increasing the potential for secondary bacterial infections [1]. We found an increase in prescribing of broad-spectrum antibiotics, including amoxicillin–clavulanic acid and cefdinir, deviating from established practice guidelines for AOM, CAP, and streptococcal pharyngitis, but which was likely done due to a lack of suitable alternatives [7–9]. Interestingly, some of the observed antibiotic increases (such as use of cephalexin for AOM) did not align with American Academy of Pediatrics (AAP) guidelines, which potentially will lead to an increased risk of treatment failure because of high rates of antibiotic resistance [10]. While adaptability is a crucial strategy for future drug shortages, it raises concerns about antibiotic resistance from inappropriate use of broad-spectrum antibiotics and treatment failure from resultant antibiotic selection, particularly if future shortages are longer or more frequent [11]. The lack of change in the use of clindamycin is due to its poor taste and a preference among clinicians to avoid this broad-spectrum antibiotic for most respiratory conditions, potentially guided by local antibiogram data.

We found a decline in the overall use of antibiotics during the study period. This finding may suggest that during this time, there may have been a greater reliance on non-antimicrobial treatment strategies, which are specifically incorporated into AOM and CAP practice guidelines [7, 8]. This suggests that in some situations, the antibiotic shortage may have improved alignment with these practice guidelines. We note site-specific differences in the use of antibiotics during the study period. The AAP advised the use of tablets, capsules, and chew tabs for amoxicillin (when able) during this period, none of which were impacted by the suspension shortage [10]. Potentially, some sites were better able to adapt to alternative formulations, such as through institutional guidance or because of differences in local availability of antibiotics. Further study into the strategies of individual institutions would have important implications for strategies during future shortages.

These shortages indicate the systemic need to develop capacity to manufacture generic drugs. The lack of profitability from the manufacture of generic drugs (including any formulation of amoxicillin) remains a threat that can drive further shortages [12]. While we focused on shortages in the United States, shortages of amoxicillin were also reported in Europe, highlighting the need for collaboration to secure a consistent supply for these drugs [2]. In addition to efforts to increase supply, organizations, including the AAP, must continue to provide centralized guidance for easily implemented alternatives, while minimizing the risk of treatment failure and the promotion of antimicrobial resistance. Other strategies include encouraging local manufacturing and supply chain diversification, developing stockpiling and communication plans, and improving decision support systems.

Our findings are subject to limitations, including in the use of secondary data, which may have errors in abstraction and coding. We were unable to evaluate the presence and extent of local shortages of amoxicillin suspension and nonsuspension formulations. We were limited to prescription status and did not have access to pharmacy claims. We could not evaluate the appropriateness of each antibiotic prescription choice.

We found a decrease in amoxicillin suspension use following the FDA declaration in 2022, with a concurrent rise in the use of nonsuspension amoxicillin and alternative, broader-spectrum antibiotics, though antibiotic prescribing for common infections decreased overall. These findings underscore the need for systemic strategies, such as improved manufacturing capacity, international collaboration, and centralized guidance, to manage future drug shortages while maintaining antimicrobial stewardship. Strategic planning and uniform prescribing protocols are crucial for mitigating the impact of such shortages on pediatric care.

Supplementary Material

Supplementary materials are available at the Journal of the Pediatric Infectious Diseases Society online (http://jpids.oxfordjournals.org).

Data Availability.

The data used for this study was provided by PEDSnet and can be shared only with approval from the PEDSnet consortium and an appropriate Data Use Agreement.