Effects of the cefazolin shortage on the sales, cost, and appropriate use of other antimicrobials

The sustainable supply of medical drugs is important for providing quality-assured medicine; therefore, countermeasures for preventing shortages are required [1‐3]. According to a US Food and Drug Administration report, the United States has faced many drug shortages in various regions, and the shortages disturbed the use of quality-assured medicines [4]. A sustainable drug supply is also warranted for antimicrobials. Antimicrobial shortages can make first-line treatments unavailable, resulting in the use of less effective, more toxic, or more expensive alternatives [5]. In terms of treatment, narrow-spectrum antimicrobials can be compensated for by using broad-spectrum antimicrobials during shortages. However, such countermeasures increase the risk of the emergence of antimicrobial resistant organism [6]. The United States has repeatedly faced problems due to antimicrobial shortages, and their frequency has recently increased [7]. Piperacillin/tazobactam shortages increase the risk of nosocomial Clostridioides difficile infections [8], and it is estimated that one antimicrobial shortage results in excess costs of 2.4–3.5 million USD [9].

In January 2019, the largest pharmaceutical factory producing cefazolin in Japan experienced manufacturing difficulties. The background of the shortage was shown in Fig. 1 [10]. Cefazolin is the representative first-generation cephalosporin classified as an “Access” antimicrobial (i.e., countries should maintain availability at any time and in any situation) in the WHO Model Lists of Essential Medicines [11, 12]. It is often used for the treatment of methicillin-sensitive Staphylococcus aureus infections and many kinds of surgical prophylaxis [13‐15].

In Japan, cefazolin is the second most widely used parenteral antimicrobial followed by ceftriaxone, and the most used antimicrobial among inpatients [16]. The Ministry of Health, Labour and Welfare of Japan published a list of alternative antimicrobials to cefazolin [17]; however, this caused secondary shortages among the alternative drugs [18]. Collapse of antimicrobial stewardship due to the cefazolin shortage has already been reported by a single center, and demonstrated the rapid increase in the use of third-generation cephalosporins after the cefazolin supply became limited [19].

The aim of this study was to clarify the effect of cefazolin shortages on the supply of other antimicrobials by observing trends in antimicrobial sales at the national level, and to evaluate the effects on appropriate antimicrobial use and drug costs brought about by the shortage.

Our study highlighted that the cefazolin shortage led to a steep increase in total antimicrobial sales due to the rush to secure alternative antimicrobials to cephazolin. The shortage also led to an increase in the use of broad-spectrum antimicrobial agents, which in turn led to inappropriate use of antimicrobials. The cefazolin shortage highlighted various aspects of problems with the drug supply, including a deficiency in the management of distribution, inadequate supply of alternative antimicrobials, and regulations to prevent the overuse of non-recommended alternatives. Meanwhile, the basic drug production system and low drug prices have caused many of these issues.

First, the shortage drew attention to the inadequate management of drug distribution.

Temporal changes in DID values clearly showed that the shortage of essential antimicrobial brought confusion to the antimicrobial market. The cefazolin DID values decreased from April to May. Most Japanese hospitals buy drugs through wholesalers; therefore, wholesalers’ stockpiles might have resulted in this lag. Meanwhile, the total antimicrobial DID values increased from March to April, which was 1 month before the decline in the manufacture of cefazolin. This suggested that the increase in total antimicrobial sales was not brought by the cefazolin shortage itself, but by information provided on the coming shortage. The information resulted in hospitals stocking up on antimicrobials. From this perspective, action by the Ministry of Health, Labour and Welfare of Japan was later than when stocking up took place. This highlighted the importance of early recognition and the need for structures for an appropriate governmental response when a shortage occurs. We consider that the government should have moved more quickly and decisively to take control of the distribution. Accordingly, to move more quickly, the government, companies, and hospitals need to maintain a close connection, and exchange information with each other. Also, frameworks for avoiding reckless purchasing by hospitals and to secure the proper distribution of medical resources are needed.

Second, the inadequate supply of alternative antimicrobials and the lack regulations to prevent the overuse of non-recommended alternative are also problems that were revealed by the shortage. The cefazolin shortage also affected DID values of other antimicrobials. The actual DID values of the government-recommended alternatives ceftriaxone, flomoxef, clindamycin, and cefotiam were higher than their predicted DID values. It was suggested that drug makers increased the production of these drugs to alleviate damage caused by the cefazolin shortage; however, the production increases were insufficient to compensate for the cefazolin shortage, which led to secondary shortages among these drugs [19]. According to a questionnaire-based study, the cefazolin shortage caused considerable damage in the maintenance of quality-assured medicines in various hospitals [23]. Furthermore, antimicrobial surveillance in Japan in 2017 showed that 5 drugs—ceftriaxone, cefazolin, ampicillin/sulbactam, piperacillin/tazobactam, and meropenem—accounted for 59.2% of total parenteral antimicrobial sales [16]. Increases in DID values among government-not-recommended alternatives, such as piperacillin/tazobactam and meropenem, may be explained by the extra production capacity that was brought about by their superiority in the market. However, unlike meropenem and piperacillin/tazobactam, ampicillin/sulbactam was not increased. The reason for this might be due to a lack of extra production capacity (ampicillin/sulbactam have been subject to supply issues several times in the past). Vancomycin was not also increased, but the reason for this is considered to be that physicians in Japan do not routinely use vancomycin for treatment or prevention of infectious diseases. Comparison by AWaRe group between actual and predicted DID values showed a decrease in “Access” antimicrobials and an increase in “Watch” antimicrobials. This means more broad-spectrum antimicrobials were used than narrow-spectrum ones because of the cefazolin shortage, meaning that the shortage appeared to harm appropriate antimicrobial use.

Since materials of domestically used antimicrobials depend on imports from China or India, it is difficult to improve the vulnerability of the supply chain by domestic measures alone [18, 24]. Currently, problems in antimicrobial factories in China or India have caused critical damage to the supply chain in developed countries; these are similar issues irrespective of the country. Likewise, this cefazolin shortage was caused by a Chinese government requirement pertaining to environmental protection and a temporary order to stop factories. From a short-range view, it is important to secure multiple antimicrobial resources for risk management to maintain a sustainable antimicrobial supply. From a long-range view, developed countries may need to develop domestic production of antimicrobial resources, but this requires support at the national or international level.

Finally, systems in drug pricing and production are the problems. Despite the cefazolin shortage, the cost of antimicrobials per sales barely changed. This is thought to be because most antimicrobials used in Japan are generic drugs, and thus the cost differences between cefazolin and alternative drugs were small. Moreover, another important reason is that a cefazolin price increase did not occur because the reimbursement price of drugs is fixed by the government. Price setting is an important tool for securing the economy of medicine. However, reimbursement prices of drugs are gradually reduced year by year, which reduces the profit margins of pharmaceutical companies, especially for older drugs. This trend was accelerated by a recent increase in production cost s[4, 25, 26]; cefazolin is also in the same situation. Low profits disrupt the production of affordable drugs and may lead to quality deterioration due to loss of investment. To maintain the stable production of essential medicines, the government should determine the appropriate drug price to sufficiently maintain companies’ investments. In the development of new antimicrobials, delinking profits and sales, for example, through government purchasing of drugs or/and the adoption of a subscription model, is desirable from a long-term perspective.

Our study has several limitations. First, because sales data can only clarify product circulation, the actual usage of antimicrobials was not assessed in this study. Different approaches such as the use of claims data or/and hospital data are needed to evaluate the prognosis of patients and changes in bacterial resistance patterns. Second, we created models based on past antimicrobial sales using a SARIMA model, and the models did not include unspecific events. The most important unspecific events are the emergence of endemic contagious diseases; nevertheless, no specific contagious diseases, including SARS-CoV-2 became endemic during the study period [27].

We clarified the effects of the cefazolin shortage on other antimicrobials in terms of sales, costs, and appropriateness of usage. Our study revealed the confusion brought to the antimicrobial market and the worsening of appropriate antimicrobial use due to the cefazolin shortage. Although patients’ prognoses and bacterial resistance patterns should be assessed, our study highlights the need for a framework for risk management against antimicrobial shortages, and for national and international measures for securing the sustainable supply of antimicrobials.