An Investigation of Aspects Affecting Availability and the Health-economical Consequences of Shortages ofVancomycin and Piperacillin/Tazobactam

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An Investigation of Aspects Affecting Availability and the Health-economical Consequences of Shortages of

Vancomycin and Piperacillin/Tazobactam

Lina Molin, Ida Cederwall, Laura Faghihi, Lobna Ali Mohsen and Ramon Yekerusta

Project supervisors: Enrico Baraldi, Petter Bertilsson Forsberg, Simone Calligari Independent Project in Chemical Engineering

Department of Materials Science and Engineering Uppsala, Sweden 2020

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1 Abstract

This thesis investigates the supply chain of Vancomycin and Piperacillin/Tazobactam in order to understand why the two antibiotics have been exposed to back orders during recent years in Sweden. The health economical consequences due to these back orders of the two antibiotics was also examined. The used methods were literature search and elementary calculation methods.

The supply chains for the two antibiotics consists of multiple manufacturing actors, both primary and secondary. The manufacturing actors are mostly located in low and middle income countries, which increases risks for the supply chains. The Swedish market is unattractive due to its small size and ineffective purchasing system, which also increases risks of shortages. The unattractive market is a probable cause of the lower amount of market authorisation holders which sell the antibiotics in Sweden.

Furthermore, a financial model was created to assess the health economic impacts of shortages. The costs were calculated as the sum of the additional labor required to deal with shortages along with the costs of the alternative medicines. It was estimated that a shortage of Vancomycin can cost up to SEK 1 600 000 in fixed costs followed by up to SEK 202 997 per additional day of shortage and that a shortage of Pipetazo can cost up to SEK 1 600 000 in fixed costs followed by up to SEK 923 650 per day. There are also other negative aspects of these consequences, such as worsening of patient health and contributions to increased AMR.

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2 Nomenclature

Abbreviations

Table 1: Useful abbreviations Abbreviation Meaning

API Active Pharmaceutical Ingredient DDD Defined Daily Dosage

EEA European Economic Area

FASS Farmaceutiska Specialiteter i Sverige FDA The US Food and Drug Administration FDF Finished Dosage Form

IPC Infection prevention and control MAH Market Authorization Holder Pipetazo Piperacillin/Tazobactam

SMPA Swedish Medical Products Agency VRE Vancomycin resistant enterococci 3PL Third Party Logistics

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3 Introduction

3.1 Introduction

During the recent years Sweden has been increasingly afflicted by the shortage of antibiotics. Antibiotics are crucial drugs for mankind because they are used to treat numerous types of bacterial infections. The shortages of these crucial drugs lead to serious consequences. The inability for the Swedish Healthcare to properly treat their patients with the correct antibiotics not only affects the patient negatively, but the health care economy.

Additionally, when shortages occur doctors may resort to using less optimal antibiotic treatments or to postpone treatment altogether, which may cause disease progressions and patient suffering. Moreover, sub-optimal use of antibiotics is one of the leading causes for antimicrobial resistance (AMR) [1]. In the last week of December 2019 the Public Health Agency reported that 25 antibiotics were back ordered, and up to 100 antibiotics have been back ordered during the last two years.

It is problematic to entirely understand the reasons behind the shortages, not only because the supply chain is complex due to large number of actors, but also because some connect- ing steps in the supply chain are considered as confidential information. PLATINEA is a collaboration platform consisting of 15 actors varying from the universities, the industry, public organisation and healthcare. Their common object is to improve the usage and ensure the availability of antibiotics that are at risk of disappearing from the Swedish market [2]. In 2019, studies were made by PLATINEA to understand why the shortages of antibiotics occur and what the underlying risk factors might be. [3][4][5] However, there is more to understand about these supply chains in order to contribute with concrete solutions for the Swedish healthcare.

3.2 Aim

This thesis is done in collaboration with PLATINEA with the aim to further research the supply chain of the two antibiotics Vancomycin and Piperacillin/Tazobactam and also how limited availability of the antibiotics may affect the Swedish healthcare economy.

This will be done by answering the following research questions.

RQ1: What is the current structure for the pharmaceutical supply chain for Vancomycin and Pipetazo with regard to the Swedish market?

RQ2: Why have Vancomycin and Pipetazo been back ordered?

RQ3: What consequences does antibiotic shortages have on the Swedish healthcare economy? In particular the costs of substituted drugs and additional labor.

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4 Background

4.1 Vancomycin

Vancomycin is an antibiotic belonging the glycopeptide class of and works by inhibiting the cell wall synthesis of murein in microorganisms. It has a strong inhibition effect on gram-positive bacteria and it is known to have high treating effect on diseases de- rived from methicillin-resistant Staphylococcus aureus (MRSA) [6]. MRSA, as one can understand by its name, is a bacterial infection which is highly resistant against some antibiotics, mainly pencillins. [7]

Vancomycin is considered to be a drug of last resort, meaning that it is only used after all alternative and more commonly used antibiotics have failed. The lesser usage of this antibiotic also prevents resistance developing against Vancomycin [8]. It is important that the resistance against Vancomycin is as low as possible because of its importance to fight more persistent infections. Vancomycin is one out of 80 drugs which is on the World Health Organizations list of essential medicine from 2019 [9].

The active ingredient in the drug is Vancomycin hydrochloride. The antibiotic can be administrated either oraly in the form of a pre prepared capsule or intravenously as an infusion solution [10]. The prefatory dose of Vancomycin is individually based on the patient’s total body weight, from 15 mg/kg to 20 mg/kg injected generally three times daily for ten days [11]. The dosage treatment duration varies depending on renal func- tion, which indication that is being treated and the severity of the infection. However, the DDD of vancomycin should not exceed 2 g [12].

Vancomycin is produced commercially through the fermentation of the bacterium Amyco- latopsis orientalis. High-vancomycin-producing Amycolatopsis Orientalis mutant strains have been identified and isolated, but this process unfortunately still reports low yields on an industrial scale and results in a high cost in production of Vancomycin. [6]

4.1.1 Vancomycin resistant enterococci

Enterococci is a group of intestinal bacteria which usually occur in wounds like urinary catheters and other surgical scars and damages [13]. These bacteria often cause complications with infections of different bio material or foreign material inside the body during surgery, such as prostheses, implants, and heart valves.

Vancomycin is the antibiotic used to treat enterococcal infections. Bacterial resistance is extremely concerning for all antibiotics, and especially for Vancomycin since it is a drug of last resort [14] [15]. VRE (Vancomycin resistant enterococci) are enterococci bacteria resistant to Vancomycin. There are several occasions where VRE can spread, such as travels to high risk countries or at hospitals.This of course results in higher costs and extended care times at the hospital and other facilities [14].The mandatory reports of antibiotic resistance show that the proportion of clinical infection is approximately 5%

for VRE in 2018 [12]. This data can be interpreted as the amount of percentage that can

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or will have the risk of patients with septicemia and higher mortality [12].

Data from 2018 Swedres-swarm summary report shows multiple VRE outbreaks stated around the hospital in Sweden. A total of 444 cases were reported in 2018, which is an increase from the year before with approximately 82%. Unfortunately, this increase not uncommon as it is a growing problem globally. During a VRE-outbreak the education of the medical personnel led by IPC doctors is one of the measures introduced which also contributes to the extra workload for the health care workers [12]which adds to the financial burdens to the healthcare by placing a higher demand on cleaning and hygiene routines to diminish the spread of infection.

4.2 Piperacillin/Tazobactam

Pipetazo is a semisynthetic penicillin in which the two active substances Piperacillin and Tazobactam are combined. Both active substances are produced through fermentation.

Piperacillin is a broad spectrum beta-lactamase antibiotic that acts bactericidal by inhibiting the synthesis of cell walls. The active substance has a high efficiency against gram-positive and gram-negative anaerobe and aerobic bacteria. Piperacillin’s antibac- terial spectrum increases in combination with Tazobactam, which is a beta-lactamase inhibitor. This now broader spectrum also includes beta-lactamase producing bacteria which exhibits resistance against Piperacillin. In other words, Tazobactam allows Piperacillin to act more effective since it will not be inactivated by beta-lactamase en- zymes. [16][17][3]

Because of it´s broad spectrum, Pipetazo is a common first choice penicillin when treating patients with different types of intra abdominal infections [16]. Other typical indications for Pipetazo usage is hard pneumonia, complicated urinary tract infections and complicated skin infections [17].

The most common route of administration for the drug is intravenous infusions and the drug is sold as a powder for infusion liquid in Sweden [17]. The general dose of Piperacillin/Tazobactam is injection of 4g three to four times each day, for 10 days [11].

The DDD of Piperacillin/Tazobactam is recommended as 14g and the dosage does not vary remarkably when treating patients with or without hepatic impairment [12].

4.3 Antimicrobial resistance and shortages

Microbes are microscopic organisms such as parasites, fungi and bacteria. There exist an immeasurable amount of microbes on our planet. Some microbes are harmless, and others can cause infections. Antibiotics is the most commonly known antimicrobial drug which kill or stop the growth of bacteria. But bacteria use resistance mechanisms to defend themselves against antibiotics. The mechanisms change the DNA of the bacteria, creating genes that are resistant against antibiotics [18]. When an antibiotic shortage occurs, patients may be prescribed with a sub-optimal antibiotics which is less effective, giving

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4.4 Supply Chain

4.4.1 Primary Manufacturing

The first step of the supply chain of a pharmaceutical drug is to produce the biologically active component, the active pharmaceutical ingredient (API). The API is made from raw material, which is either supplied by the API manufacturer or outsourced. [20] The raw material for a fermentation process include bacteria and an appropriate growth medium [6].

4.4.2 Secondary manufacturing

The contract manufacturing organisation (CMO) is the next step in the supply chain.

The CMO is the manufacturer of the finished dossage form (FDF) of the pharmaceutical.

This intermediary is not always necessary if the API manufacturer also produces the FDF. [4]

4.4.3 Marketing authorisation holder

All pharmaceutical products have a marketing authorisation holder (MAH) which is the company that has the authority to market the product in one or several countries [21].

When it comes to patient safety, it is the MAH that is responsible for monitoring safety once the pharmaceutical product is on the market and used by patients [22].

4.4.4 Parallel import

Parallel import is the sale of a pharmaceutical in a different country than the country which it was originally manufactured and released for (the direct imported medicinal product). If a pharmaceutical is to be sold in Sweden through parallel import, the product must be approved by the SMPA, repackaged/re-labelled and provided with an approved Swedish package leaflet. [23]

4.4.5 Pharmaceutical Distributors

The distribution once the products are delivered to Sweden can contain multiple steps before reaching the hospitals. Magnus Munge, head of operations for pharmaceuticals at Kronoberg region, explained the distribution chain in Sweden as follows (Interview, M.Munge, 2020-05-20):

Tamro and Oriola are the only two companies that stock pharmaceuticals for Sweden on behalf on the MAHs which sell them. However, it is the hospital pharmacies that are responsible to assure that the pharmaceuticals are distributed to have stable supply for the hospitals. The hospital pharmacies can chose to buy the pharmaceutical directly from Oriola or Tamro and have it delivered by them. In this case, the hospital pharmacies are responsible for the warehousing post delivery. Or, the hospital pharmacies can use an external company to handle delivery and warehousing, such as Apoex, APL or Apoteket AB. When the regions purchase the pharmaceuticals at Tamro/Oriola it is for the negotiated price that was agreed upon between buyer and the MAHs (if there is a

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negotiated price).

According to The pharmaceutical industry association (LIF), the stocks at Timro/O- riola are called "turnover stocks" and they aim to meet the need of normal consumption in Sweden. [24]

4.5 Common causes for pharmaceuticals shortages

It is not solely one reason behind shortages of pharmaceuticals. There are multiple actors in the supply chain, and deficiencies within these actors can lead to shortages.

Disruption in production processes If there is a limited amount of producers for a pharmaceutical it can be difficult to find replacements, should some producers have issues regarding quality or raw material. If the manufacturers for some reason runs out of API, the later actors in the supply chain will have to wait for production of more API.

Reduces margins The economic margins have been reduced for all participating actors of the supply chain. Not only for the API manufacturer, but also for warehousing, delivery and orders from healthcare and pharmacies. With reduced margins, even slight disturbances can have major consequences.

Shifting demand It is difficult to know how and when the demand will increase above the supply. For example, with the current covid-19 flu it will be diffcult to forsee the demand on needed medicines.

Warehousing It is not beneficial for suppliers, pharmacies or other storage actors to store pharmaceuticals. Partly because it is an economic expense, but also because of the fact that pharmaceuticals have limited durability. This is especially the case for refrigerated products. Thus, warehousing actors in the supply chain rarely wish to have an extra amount products on stock.

Free market mobility There is a free market of goods within the EU, meaning that goods can be traded freely between the members. Sweden is a small country with a small pharmaceutical market and low sales. Because of this, pharmaceutical companies might not find Sweden attractive for sales. [25]

4.6 Outsourcing

Outsourcing is defined as "the business practice of hiring a party outside a company to perform services and create goods that traditionally were performed in-house by the company’s own employees and staff. Outsourcing is a practice usually undertaken by companies as a cost-cutting measure." according to Investopedia (2019-06-25). Outsourcing can also be a way for the company to improve focus on certain aspects of the business, which

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increases with third-party logistics (3PL). These risks include contract risks if the 3PL fails to complete their obligations, management risks due to different management styles and information risks if information management from the 3PL is poor. Market, financial, relationship, asset and competence risks are also to be taken in to consideration. [27]

The geographical localisation for the 3PL can add additionally increase risks if it is located in a country at risk for corruption or natural disasters. Corruption can lead to bad working conditions and general instabilities, causing efficiency and monetary losses.

For example, India and China are highly corrupt as many other eastern countries. [4]

4.7 Availability

There are three types of availability statuses for approved drugs in Sweden. Either the drug is available, currently unavailable or back ordered. If available, there are no issues in supply or demand of the drug. The patient is not at risk of being unmediated. If a drug is currently unavailable it means that it can not be ordered at the moment. This is usually related to market causes. If a drug is back ordered it means that the company providing the drug is not longer doing so during a period of time. A back order can for example be a consequence of:

• Issues in the production process.

• Shortages of the active substance

• A sudden unexpected high demand on the drug

• The MAH can decide to terminate sales of the drug

In Sweden, the pharmaceutical company is responsible to inform pharmacies and hospitals if a back order occurs or is expected to occur. They are also obligated to report back orders to the Swedish Medical Products Agency (SMPA) by law. When a drug is expected to be or is back ordered the SMPA published information from the pharmaceutical company along with information for alternative drugs for affected patients.

There are different options for patients affected by back orders who still needs to be medicated. An equivalent replacement drug can be given if such drug exists. A new recipe can be prescribed if replacement is not an alternative. The recipe could be for another dosage form, strength or sometimes another drug. If there are no suitable options on the Swedish market the issue can be resolved with an exemption or licence application, which has to be approved by the SMPA. [28]

Even though a pharmaceutical company is responsible to inform pharmacies and hospitals if a back order occurs or is expected to occur, it seems that some companies fail to do so. According to Jesper Qvist-Pedersen, Head of Region Scandinavia at Orion Pharma (Interview, J.Qvist-Pedersen, 2020-05-20), some companies do not have the same routines or/and procedures when it comes to registration of back orders. In addition to this, there seems to be a difference in the exact definition of a back order depending on the country.

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4.8 Purchasing system for Requisition pharmaceuticals

The Swedish pharmaceutical market is divided in to smaller market groups, and antibiotcs which are given for incare treatment applies to requisition pharmaceuticals. Requistion pharmaceuticals that are used mainly at hospitals and clinics are generally ordered by the hospitals and paid for by their respective region. There are total of 21 regions in Sweden.

However, some regions have collaborated in pharmaceutical purchasing which has lead to eight constellations of purchasing regions [29]. The pharmaceutical companies compete to obtain a contract with the regions by offering their product for the lowest price. The company that wins the negotiations with their offer will become the provider for that region and are responsible to provide the pharmaceutical and will be fined if they fail.

Because of negotiations the prices may vary in different counties. [30]

Ideally, the purchase system for pharmaceuticals should be as effective as possible, with plenty of competitors on the market which in turn lowers product prices. This in unfortunately not always the case in Sweden. It takes approximately four to six months after pharmaceutical orders to actually be delivered to its final destination. This time is not taken into consideration during the negotiations between buyer and supplier. This means that the supplier need to "guess" and pre-order a volume of product without knowing if it will even be sold. If the supplier does not win the negotiation they will be left with products in their stock which will be discarded. This is both an economic and environ- mental issue. The orders from buyer and supplier can also be rather vague. Sometimes, the suppliers are only left with an estimate in grams or milligrams of product, and no information regarding strength our size of packaging. This makes it hard for the supplier to assure delivery reliability since they do not know what is actually needed, and may results in fines for the supplier. Pharmaceuticals for in care treatment have a longer sales period (year/s) than prescription pharmaceuticals for out care treatment (month/s). The sales period is the period for which the company sells a product and the period is based on the tendered contract. Longer sales periods decreases the amount of competitors on the market, since there are not as many opportunities for other suppliers to make offers.

This non-effective and rather risky system makes it harder for smaller pharmaceutical companies to take part in the purchasing process. This can results in higher prices for pharmaceuticals due to less market competition and may also cause dependency for a limited amount of suppliers. [31]

Moreover, according to Magnus Munge, a region can purchase pharmaceuticals from a supplier if available. If the company can not give an offer for a pharmaceuticals it is likely due to the fact that they have a limit amount of product. It that case, it might be that the company decides to sell to the larger regions, such as Stockholm, which leaves the smaller regions without an offer. Without an contract price, the price for the pharmaceuticals increases for the regions healthcare. Magnus also explains that if a MAH cannot provide for a region, they are obligated by contract to suggest an alternative treatment and will have to pay the difference in price for the originally bought product and the alternative product . This does not apply in extraordinary times, such as during a pandemic.

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4.9 Health-Economic Consequences

4.9.1 Consequences of shortages

Antimicrobial drug shortages bring about a plethora of complications [32]. It is primarily the patients who are subject to the consequences of shortages. It requires, when available, patients switching to less optimal drugs. As a result they may receive sub-optimal treatments, delayed treatments, prolonged treatments and in some cases no treatment at all. Generally, drug shortages decrease the affected patient’s well-being and may contribute to disease progression and discomfort, and in more serious cases also increase rate of mortality. [33]

Shortages also give rise to severe economic consequences. The unavailability of drugs generates increased workloads for hospital workers and require substitutes drugs to be used instead, these are more often than not less effective and more costly. In an analysis from the Premier Healthcare Alliance in 2011, use of alternative drugs due to medicinal shortages in the United States caused an estimated 200 million dollar loss, annually [32].

4.9.2 Direct costs

There is a number of increased direct healthcare costs associated with managing the side effects of drug shortages. The alternative antibiotics are often not optimised for the treatments and thus require longer therapy time and more resources, and as previously mentioned, are often times more expensive [33].

Furthermore, it becomes necessary for hospital personnel to allocate more of their time to handle the complications shortages entail, such as finding substitute drugs and managing supplies. According to a study, it was required of individual US hospital pharmacists to spend nine additional hours per week on drug supply problems and, eight hours per week for hospital technicians [34]. Similarly, another study examining the extra labour associated with shortages in 6000 hospitals in the U.S. estimated drug shortages to require an extra 8.6 million personnel hours per year, amounting to a cost of roughly 359 million dollars yearly [35].

Additionally, in a study by Gundlapalli et al. A survey was issued to determine the impact of antimicrobial drug shortages on infectious disease physicians. The study revealed how lack of medicines increased the workload of physicians and expenses of hospitals.

They determined that the total time spent by hospital pharmacists on the management of shortages were on average estimated to 12.8 hours per week, whereof six hours per week on finding alternative treatments [36][37].

4.9.3 Indirect costs

As previously mentioned, treatments with alternative drugs, among other diverse effects, often lead to prolonged treatments or other difficulties. Indirect costs concern those costs for society which arises as a result of said complications, measured through the loss of productive labor that follows from individuals not being able to work as a consequence

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of treatment.

In a report by the Public Health Agency of Sweden investigating the consequences of antimicrobial resistances, the indirect costs through loss of production because of the unavailability of effective antibiotics (similar to the situations created by shortages of antibiotics) projected indirect costs to about SEK 26 million for the year 2030 and SEK 36 million for the year 2050 [38].

Antibiotic shortages also directly contribute to antibiotic resistance, since it necessitates sub-optimal usage of antibiotics and often requires one to replace narrow-spectrum antibiotic treatments for treatments with broad-spectrum antibiotics. Antibiotic resistance itself greatly burdens society. The Public Health Agency of Sweden has estimated that roughly 30-40 outbreaks of antibiotic resistance occur yearly, costing an estimated SEK 29 million per year [38]. Similarly, in a study by Cherici C et al. the estimated costs of antibiotic shortages In the U.S exceeded $22.5 million yearly [39].

5 Material and Method

5.1 Supply Chain

The API manufacturers were found using multiple websites. The websites used were FASS, the database EudraGMP, Pharmacompass and the FDA Drug Master File list.

FASS publishes current information about approved drugs in Sweden. EudraGMP is a database maintained and operated by the EMA and includes complete information on all pharmaceutical manufacturers, including the API-Manufacturers. A drug master file is a submission to the FDA which provides detailed and classified information about the production and manufacturing processes of human drug products. Pharmacompass is a free online database for global pharmaceutical information, such as APIs, inspection updates and dossiers. The APIs were not limited to any geographical area for this project.

In the attached package leaflet for a pharmaceutical one can find information regarding the MAHs and "manufacturers" for the pharmaceutical. Whilst the MAHs mentioned on the package leaflets are in fact the actual MAHs, the given "manufacturers" are not necessarily the API manufacturers as one might believe. It has shown that the given manufacturers in the package leaflets can be either API or FDF manufacturers, local representative or distributors. Thus, several sources were needed to ensure that actual API manufacturers were found.

The information about the MAHs for the antibiotics of interest were found from FASS and Article 57 database published by the EMA. The Article 57 database includes all medicines authorised within the EEA. The MAHs were limited to the EEA for this project.All of the FDF manufacturers where found on Pharmacompass with some excep- tions (some where found by coincidence while searching for API manufactures).

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The backorders for Vancomycin and Pipetazo were found by looking at SMPA’s lists called "Avlutade restnoteringar" and "Restnoteringar". These list cover all back orders from Februari 7th 2018 and forward. To get information about earlier back orders, SMPA was contacted and the earlier back orders were achieved by e-mail. The distribution in Sweden was limited to distribution of incare pharmaceuticals through hospital pharmacies. The distributors for hospital care pharmaceuticals were found from the Swedish Pharmacy Association’s Industry Report 2020.

To find information about earlier events which have caused back orders and unavailability of each drug, keywords were used while searching on Google. Withdrawn or suspended CEPs were found at Diapharm, a global service and consultation firm within healthcare and the pharmaceutical industry. Other deficiencies concerning managing and/or production were found using the FDA database for performed inspections. Note that the deficiencies are not always specifically for the researched antibiotic products, but for other products at produced the same manufacturing site. Representatives from each purchasing region in Sweden were contacted through e-mail to get information about the current MAHs with hold the current contract to provide the antibiotics for the regions.

5.2 Health-Economical consequences

Information about health economic calculations was acquired through readings of two pre- vious studies on the subject. One by FDA, drug shortage report 2019 and one by WHO, shortage report 2018. Furthermore, in the design process of the method, inspiration was taken from the model presented by Folkhälsomyndigheten for estimations of AMR costs in their report "Future costs of antibiotics" [38], along with interviews from experts on infectious diseases and medical issues (E-mail, H Hanberger , MD, PhD, Professor.

Department of Clinical and Experimental Medicine, Linköping university 2020-05-13) (E- mail, J Järhult, MD, PhD, Associate Professor, Lecturer, Consultant Infectious Diseases.

Zoonosis Science Center, Dep. of Medical Sciences Uppsala University 2020-05-19). Ad- ditional information about the supply chain and involved actors was retrieved through interviews with company representatives.

5.3 Model for calculation of costs of antibiotic shortages

The report’s result of the extra labor cost additional with the results of the treatment cost differences will thereafter be summarised to estimate the total direct cost according to the used method. Data pertaining to the indirect costs of Vancomycin and Pipetazo shortages were not available to a sufficient enough degree to be included in the economical calculations.

5.3.1 Staff costs

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(1) equation describing the sum total of staff costs across Swedish hospitals as the additional daily labor required during times of Vancomycin and Pipetazo shortage multiplied by a scaling factor and the average salary of the affected personnel.

The required labor times were determined based of one specific event in 2019 according to H Hangberger, where there was a shortage of Vancomycin in Region Östergötland in Sweden, from which data on the additional labor required in the time of shortage were obtained. There were no similar data to be found for Pipetazo, however, since both antibiotics are administered through either infusion or I.V injections, and since they are both antibiotics with no readily available substitutes, it was assumed that shortages of both Vancomycin and Pipetazo require roughly an equivalent response from medical staff.

As such, the same required additional labor time was applied for the estimation of staff costs for shortages of both PipeTazo and Vancomycin.

The Vancomycin shortage of 2019 required of medical personnel, that includes doctors, nurses, health care assistants, medical advisers, medical institution managers and pharmacists, in total roughly 60 hours of additional work over four days. Since it could not be discerned to what degree each employee was affected, that is, how much each one of the different staff members contributed to the 60 hours of additional work, it was assumed that the workload was distributed evenly, so that similarly, an average salary of all the positions could be used to determine the value of said 60 hours. 60 hours over four days, equalling 15 hours of general labor per day, accounts only for the work required in region Östergötland, which in turn constitutes only five percent of the Swedish healthcare system. Thus, to estimate the costs across the entire country, the daily hours were multiplied by scaling factor of 20.

5.3.2 Patient and treatment calculations

To estimate the number of patients treated with Vancomycin respective Piperacillin/- Tazobactam during the years 2014-2018, the amount of sold units were multiplied with the package weights and thereafter divided by the recommended total treatment doses according to equation 2. The sales units document were obtained from PLATINEA and the recommended daily dosages for Vancomycin and Piperacillin/Tazobactam from the report Swedres-Svarm 2018. The treatment duration was set to 10 days according regu- lar recommendations. Since the unit weights of Piperacillin/Tazobactam where given as e.g. 4g Piperacillin and 500mg Tazobactam, one unit was considered to weight 4,5g in the calculations. Since no relevant statistics regarding the amount of patients with renal impairment or children that have been treated with the antibiotics, all patients will be considered to be treated with the DDD and the same recommended durations. It will also be assumed that all patients are incare patients since both antibiotics are administrated intravenously. The same assumptions will be made in the treatment cost calculations.

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The amount of treated patients calculated by equation 2 will then be used to estimate the costs of Vancomycin and Pipetazo treatments per day, aswell as the alternative substances that can be used during shortages. The prices of the antibiotics will be recieved from the Price list of contract medicines Region Stockholm 2019 and the recommended doses from Swedres-Svarm 2018 and FASS. The cost will be calculated by using equation 3. Some of the antibiotics in the price list are sold in different doses, whereupon only the package price with the highest amount of substance will be used in the calculations to determine the price of one gram of each substance. That price will then be multiplied with the DDD, the recommended treatment duration (days) and finally the average of the estimated amount of treated patient per day from equation 2. Thereafter, the differences between Vancomycin respective Pipetazo and their alternative treatments can be separately calculated by simple subtraction.

6 Results

An overview of the results regrading the supply chain of the two antibiotics can be seen in Figure 1.

6.1 Supply Chain

Figure 1: Summary of the supply chain results

6.1.1 Vancomycin

API: There are in total 18 API manufacturers of Vancomycin hydrochloride world wide.

Out of the 18 manufacturers, eight are located within the EEA, nine in Asia and one

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in the US. All of the API manufacturers are listed in table A1 and can be seen in Figure 2.

5 out of the total of 9 API manufacturing companies in Asia have shown deficiencies in quality or/and GMP since 2013. The deficiencies include withdrawn or suspended CEPs (Concord Biotech Ltd, Hetero Ltd x2, North China Pharmaceutical Co Ltd (NCPC)) and significant objectionable conditions in drug quality assurance and other violations according to FDF (Zhejiang Medicine Co., Chongqing Daxin Pharma. Co) Located in the same area as the Vancomycin production, NCPC has an additional cite for their Semi-Synthetic pharmaceuticals where many deficiencies could be found. Including serious deficiencies concerning documentation according to WHO, accusations of discharging pharmaceutical effluent into the environment and other serious manufacturing deficiencies. [40][41][42][43][44][45]

One out of 8 API manufacturing cites in Europe have shown deficiencies since 2016.

This includes significant objectionable conditions in drug quality assurance and other violations according to FDF (ACS Dobfar S.p.A) [43] The API manufacturer Hospira Inc (located in the US and owned by Pfizer) received a warning letter from the FDA after an inspection in 2016 due to "significant violations" at the Hospira Unit. A voluntary nationwide recall for a lot on Vancomycin injection was issued by Hospira Inc in 2017 due to presence of particular matter within a single vial. [46]

Figure 2: Location and amount of API manufacturers for Vancomycin

FDF There are a total of 28 FDF manufacturers globally, all listed in table A2 and visually presented in figure 3. 14 located in North America (US and Canada), five in the EEA and nine in asia, mainly India. Another five potential FDF manufacturers were identified on Pharmacompass but are not included because of lacking proof of actual FDF

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Figure 3: Location and amount of FDF manufacturers for Vancomycin

MAH: There are a total of seven MAHs for Vancomycin located in the EEA which are authorised to sell Vancomycin in Sweden. These MAHs are listed in table A3. Be- sides these seven MAHs there is an additional 43 MAHs which are authorised to sell Vancomycin or Vancomycin hydrochloride to other countries within the EEA. According to representatives from the different regions in Sweden, there are four main MAHs that currently obtain contracts and are responsible to provide Vancomycin for hospital care within the regions: Orion Pharma AB, MIP Pharma GmbH, Xellia Pharmaceuticals and STADA Nordic.

Availability According to FASS, there are currently four unavailable products of Van- comycin on the Swedish market. All four are listed in A4. A medical expert at Mylan AB stated that their Vancomycin products are registered in Sweden, but he believed that the product had never actually existed on the market. The company had begun to discuss costs after registration of the products, but they are not available because the company chose not to sell on the Swedish market due to low or no profits. There are other companies which currently hold the Swedish market for Vancomycin which are responsible for its supply .

There are currently no back orders on any of the Vancomycin products registered on the Swedish market. However, Vancomycin Orion by Orion Corporation was back ordered 2019-05-29. The back order was expected to be ceased by 2019-08-05, but did not until 2019-09-06. According to Jesper Qvist-Pedersen, Head of region Scandinavia at Orion Pharma region Scandinavia, Orion had contracts with some regions to supply Van- comycin Orion at the time. But in the summer of 2019, other suppliers for Vancomycin for other regions experienced shortages. This in turn increased demand for Vancomycin Orion as the regions sought to buy their product instead which caused the back order.

Vancomycin Xellia was also back ordered once in 2014. Though the reason for this is

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unclear, it seems most likely that is was due to lack of packaging according to the report from SMPA.

There is a total of 14 deregistrations of Vancomycin according to FASS. Four of these were made between 1998 and 2008. Since 2013, one dregistration has been made every year up until 2019.

Parallel import: According to the SMPA Vancomycin is not delivered to Sweden though parallel import.

Xellia Pharmaceuticals Out of the four main MAHs, a complete supply chain was found only for Xellia Pharmaceuticals. Xellia have their own API and FDF manufacturers of Vancomycin. The two API manufacturers are located in Taizhou, China and Budapest, Hungary. The FDF manufacturer is located in Copenhagen, Denmark. Drug Quality inspections by the Office of Regulatory Affairs (ORA, part of the FDA) has not shown any objectionable conditions or practices for neither of the sites during recent inspection.

[43] Civica Rx is a US based company established in 2018 by health systems with the aim to reduce and prevent drug shortages. Xellia became the first supplier partner for Civica Rx and manufactures essential antibiotics such as Vancomycin, which will be sold as Civica labeled generic drugs [47]. In addition to Xellia, Civica has begun a partnership with Hikma Pharmaceuticals to increase access to 14 essential sterile injection medicine which are "often in short supply". Details of the 14 medications have not been announced.

[48]

6.1.2 Piperacillin/Tazobactam

API: There are a total of 19 different API manufacturers for Pipetazo around the world (see table A5 and figure 4), three producing Piperacillin, four producing Tazobactam and the remaining 12 produce both of the active substances. As one can see in table A5, there are only five different API:s within Europe, three which are based in Italy and one in Spain and Belgium respectively. The majority of Pipetazo’s APIs are based in eastern countries, mostly in China and India.

Three out of the 19 API manufacturers have shown deficiencies in quality or/and GMP since 2009 according to FDA. Those deficiencies regards drug quality assurance. The sites are Fresenius Kabi (Italy, 2009), Istituto Biochimico Italiano Giovanni lorenzini (Italy, 2017) and Aurobindo Pharma (India, 2010 and 2019).

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Figure 4: Location and amount of API manufacturers for Pipetazo

FDF: When it comes to FDF manufacturers, Pipetazo has as much as 18 globally which are listed in table A6 and visually presented in figure 5. Another six potential FDF manufacturers were identified on Pharmacompass and FASS but are not included because of lack of further proof.

The two FDF manufacturers from Fresenius Kabi (see table A6) could not be com- pletely proven to be a FDF manufacturer for Pipetazo either. Judging by their websites, both sites handle "Infusion solutions such as antibiotics" but it does not say what kind of antibiotics. A Product Manager at Fresenius Kabi was contacted (E-mail, H Sultan 2020-05-13) regarding these FDF manufactures and confirmed that they were not able to leak any information about Pipetazo’s supply chain. Therefore the assumption was made that the two sites most likely are FDF manufacturers for Pipetazo since Fresenius Kabi also have their own API manufacturer and MAH.

When investigating all "manufactures" from the package leaflets, companies where contacted to confirm if the "manufacturer" was an API or FDF manufacturer. One company that did answer the given questions was Recipharm, which is the main company to the subsidiary Mitim Srl. Mitim Srl is a given "manufacturer" for Piperacillin/Tazobactam Fresenius Kabi according to the package leaflet found at FASS. A Technology Transfer Commercial Manager at Recipharm answered (E-mail, R Raffaele Addamo 2020-04-28) that their site Mitim Srl only manufacture injectable finished dosage forms and therefore only fills powder vials. Not only was it confirmed that Mitim Srl is a FDF manufacturer for Pipetazo, it was also told that this FDF manufacture did receive the most of their Pipetazo API from API suppliers in Italy. Since Fresenius Kabi have their own API manufacturer in Italy can one assume that’s where they get it from.

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Figure 5: Location and amount of FDF manufacturers for Pipetazo

MAH: There a are a total of six MAHs for Pipetazo within the EEA which has Swe- den as a product authorisation country (see table A7). Out of these six are two MAHs located in Denmark while remaining four are located in Sweden, Spain, Cyprus and Malta.

The total amount of MAHs within the EEA (all MAHs which have and do not have Sweden as a product authorisation country) are 32 and they are listed in table A8. The registered MAHs which is clearly subsidiaries (judging by name) from the same holding company are counted as one MAH in the table. According to representatives from the different regions in Sweden, there are two main MAHs that currently obtains contracts and are responsible to provide Pipetazo for hospital care within the regions: Stragen (1/8 regions) and Fresenius Kabi (7/8 regions).

Availability: According to FASS, is it only one product which are currently unavailable in Sweden. As one can see in table A9 is the MAH for this product located in Cyprus [49]. Despite this one unavailable product of Pipetazo, there are currently not any back orders or otherunavailable products on the Swedish market according to FASS.

According to the SMPA list called "Avslutade restnoteringar" Piperacillin/Tazobactam Fresenius Kabi has been back ordered seven times since February 7th 2018. In fact, four of the seven mentioned back orders have occurred since October 2019 with one more upcoming back order in the end of May 2020. A product manager at Fresenius Kabi was contacted (E-mail, H Sultan 2020-05-13) to comment on the repeated back orders for Piperacillin/Tazobactam Fresenius Kabi. According to him it is the relatively low amount of API manufacturers in proportion to the high demand on the market which leads to repeated back orders of the drug. He means that because of this, the market for

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of Pipetazo up until now. A big explosion at the API manufacturer Qilu Pharmaceutical in China (October 2016) lead to unavailability of Pipetazo globally [50] [51]. According to him Qilu Pharmaceutical was a rival API manufacturer but the incident affected all producers of of the drug; "After this accident it has been hard to provide the market’s need of Pipetazo, not only for us but for our industry colleagues.". Malin Grape, head of department at the Swedish Puplic Health Authority, says in an article at Sveriges Radio (May 2017) that the explosion is a great example of how fragile the whole system is and that the drug access is not secure at all. She means that Sweden may not be the most important country on the market and that happenings like this forces drug companies to prioritise which countries to deliver to.

The explosion in China did not only affect the Swedish market for Pipetazo. In Ger- many the unavailability of the drug was a serious problem since the whole country’s importation of the drug relied on one API manufacturer, Qilu Pharmaceutical. [50]

To return to the seven back orders for Piperacillin/Tazobactam Fresenius Kabi, Fre- senius Kabi did give an explanation regarding one of the first back orders in 2018. The explanation stated that "the company had manufacturing problems where some batches have not been approved at the release from the factory. Due to the high demand globally, back orders have emerged". What was meant by "manufacturing problems" was not clarified. [52]

Five additional back orders that occurred before 2018 were found. Piperacillin/Ta- zobactam Sandoz, Piperacillin/Tazobactam Stragen, Piperacillin/Tazobactam Reig Jofre, Piperacillin/Tazobactam Fresenius Kabi (x2). All back orders except for one of the two from Fresenius Kabi, were registered the same week in April 2017. The one back order from Fresnius Kabi that was not registered the same week, was registered in December the same year.

When it comes to deregistrations, there is a total of eight deregistrations of Pipetazo in Sweden according to FASS. The first one registered is from 2011 and the latest in 2019. Worth mentioning is that three of the products were deregistrated within two weeks in the middle of 2016, yet before the big explosion in Qilu Pharmaceutical.

In May 2018 Pfizer Inc recalled over 1.8 million vials of Pipetazo which was manufactured at their API site in India (see table A5). According to FDA all vials were going to be sold in the US but were recalled since they contained impurities that could decrease the potency of the drug. Not long after this incident AuroMedics Pharma LLC, an subsidiar- ity to Aurobindo pharmaceutical (another API manufacturer for Pipetazo, see table A5), voluntary recalled over 77 000 vials of Pipetazo. FDA reported that the recall happened

"due to presence of particulate matter as glass and silicone material". [53] [54]

Parallel import: According to the SMPA Pipetazo is not delivered to Sweden though parallel import.

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6.2 Health-economical consequences

6.2.1 Calculation of extra personnel cost of shortage in healthcare

The direct cost of shortage is mainly centred around the alternative treatments and the extra labor work that needs to be added when these antibiotics are in shortage. Additional labor is mainly required during the first few days of a shortage, as alternative treatments need to be found and approved by medical experts. The calculation shown in appendix table A16 poses the cost of 20 hours of added labor work per day during the first days of a shortage. The total costs of the additional labor required in Sweden amounts to SEK 400 000 daily and SEK 1 600 000 over four days.

6.2.2 Patient and treatment calculations

According to the given dosage information , each patient that is being treated with Van- comycin or Pipetazo can be assumed to consume 2g/day respective 14g/day in 10 days.

Therefore, it can be concluded that the two separate treatments requires 20g of Van- comycin and 140g of Pipetazo. The estimated amount of patients that were treated with the two antibiotics during 2014-2018 can be obtained in table A10 respective table A11 in the appendix.

The calculations of the Vancomycin and Pipetazo treatments, as well as the alternative antibiotics, were calculated by using equation 3. Although Vancomycin is a last resort antibiotic it can be substituted with the antibiotics Daptomycin, Linezolid or Teicoplanin [55]. The daily recommended dosages were found in Swedres-Svarm 2018, except the DDD of Daptomycin. The Daptomycin dosage was given as 6mg/kg once a day during one or two weeks [56]. Since the average weight in Sweden is 76kg, the average daily dose was estimated to 0,5 g/day [57]. All the DDDs, treatment durations and daily prices of the average amount of treated patients (according the results in table A10) can be obtained in table A13. Table A13 also shows the cost differences per day if Vancomycin is substituted during a shortage.

The examined replacement drugs that can be used instead of Pipetazo are Cefotaxim, Imipinem and Meropenem [58]. The DDDs, treatment durations, the daily prices of the average amount of treated patients and the cost differences per day if Pipetazo is substituted during a shortage can be obtained in table A14. The side effects of the alternative treatments of both Vancomycin and Pipetazo can be obtained in table A17 [56] [59] [60]

[61] [62] [63]. According to associate professor in infectious diseases J Järhult (E-mail, 2020-05-19): alternative treatments can lead to the risk of unnecessary resistance devel- opment in the patient’s normal flora. In addition, ’stronger’ options may also have more side effects.

6.2.3 Total direct cost of shortage

The total direct cost of Vancomycin respective Piperacillin/Tazobactam shortage were

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additional antibiotic costs could be SEK 81 916 - 202 997 daily, as show in table A13.

The total direct cost is therefore SEK 1 600 000 in fixed costs followed by 81 916 - 202 997 per additional day of shortage. Similarly, the total direct cost of a shortage of Pipetazo would be SEK 1 600 000 in labor work and SEK (-)286 230 - 923 650 per day for the extra antibiotic cost. If the treatment of an alternative drug is longer than the actual treatment and that hospitalisation would be extended, it would also add a cost of extra days of care. One day of care costs SEK 10 000 in Sweden [64].

6.2.4 VRE calculation

The number of patients treated with vancomycin 2018 was total 8543 (table A10), since approximately 5% are expected to have a resistance against vancomycin, the number of VRE patients are estimated to be a total number of 427 as seen in appendix table A12.

7 Discussion

7.1 Supply Chain

7.1.1 Vancomycin

The supply chain of Vancomycin consists of several actors located in Asia, USA and Eu- rope. The API manufacturers are located mainly in Asia and within EEA. There is a higher risk when outsourcing to Asia, as many management and production violations have taken place at several of the found API sites, mainly in China and India. There is an equal amount of API manufacturers within the EEA were violations seem to be less common. There are almost twice the amount of FDF manufacturers, the majority of which are located in the US. Since most APIs are located in the EEA and Asia, it is probable that the FDFs relevant for the supply chain to Sweden are the ones in Asia and EEA. There are seven MAHs, but only four that currently hold contracts to sell to the regions. All in all, there are multiple actors in each step in the supply chain which provides good conditions for Vancomycin to be produced, although some actors can po- tentially increase risks for shortages.

Vancomycin is an antibiotic of last resort and used almost exclusively in hospital care.

This, in combination with the fact that the Swedish pharmaceutical market is already small, leads to small purchasing volumes of Vancomycin. This is not attractive for possible MAHs, who wishes to sell out their stocks so that they do not have to discard expired pharmaceuticals. The consequences of this can be seen in the case with Mylan AB, a company that has a registered product on the Swedish market but are choosing not to sell due to low profits. It can also be seen in the other case with Xellia Pharmaceuticals.

The company has signed a contract to supply Vancomycin to the US, a major market, in order to prevent shortages. This will probably result in greater focus from Xellia towards the US rather than Sweden, because of a more attractive market with greater purchasing volumes. The large amount of deregistations compared to more commonly used antibiotics, such as Pipetazo, can also be a indicator for the unattractive market. The small

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market for Vancomycin in Sweden along with low profits seams to be the leading cause for the shortages of the product, rather than supply chain issues.

7.1.2 Piperacillin/Tazobactam

The fact that Pipetazo has as many as 19 API manufacturers is very good, since antibiotics are at higher risk of getting back ordered if there are a limited amount of APIs.

However, the location of the API manufacturers need to be taken into account for risk assessments. In this case the majority of Pipetazo’s APIs are located in eastern countries (China, Japan, Korea and India). Since those countries experience a higher risk of corruption, natural disasters and such, it is even more important that there exists other API manufacturing options. Undoubtedly it is not sustainable to have a high request market with a low amount of API manufacturers to rely on. The case in Germany after the big explosion in China showed the importance of starting to strengthen the now so sensitive market for Pipetazo. The market is in high need of a dependency control to ensure patient safety in cases of manufacturing accidents.

As for the back orders for Pipetazo, it is Fresenius Kabi that stands for the majority of them. They have a total of nine back orders in the past and one more to come in May 2020, a worrying pattern. As the product manager at Fresenius Kabi explained it has been hard for the company and their industry colleagues to provide the market with Pipetazo since the big accident in China occurred. The question still stands why Piperacillin/Tazobactam Fresenius Kabi keeps getting back ordered even though Qilu Pharmaceutical is not Fresenius Kabi’s API manufacturer but their rival’s. One possible reason to this could be the fact that other regions in Sweden can still purchase Pipetazo from Fresenius Kabis stock without a contract with the MAH. This makes it nearly im- possible for Fresenius Kabi to adapt their supply to demand. Another reasons could be the fact that there are different guidelines and standard for registration of back ordered in different countries. Thus, there can be other companies with repeated back orders other than Fresenius Kabi which have not registered their back orders.

Other than Fresenius Kabi, Pipetazo is also produced by Stragen, Reig Jofre and Sandoz which all registered back orders in April 2017, six months after the explosion in China.

There is not doubt that these back orders are connected to the explosion since it generally takes four to six months for pharmaceutical orders to be delivered. Considering Fresenius Kabi admitted that Qilu Pharmaceutical was not their producers of Pipetazo API. How- ever, one can draw the conclusion that the API manufactorur in China might be the API supplier to either Stragen, Sandoz or/and Reig Jofre. There is a chance that all the three last named companies could import their API from the same API manufacturer. In that case, the Swedish market for Pipetazo has a huge dependency on the same manufacturer.

This of course increases the risks of unavailability in cases of manufacturing problems.

7.1.3 General discussion regarding both antibiotics

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lower production cost in order to obtain competitive prices on the market, and can do so by outsourcing to countries with lower labour costs. Outsourcing may lower costs, but can increase risks, product recalls due to inferior quality and harmful consequences for the patients. Especially when outsourcing to countries with higher corruption and with risks of natural disasters. The margins are not only reduced during production but for warehousing as well, causing a limited stock for pharmaceuticals with no extra product on hand during shortages.

There is a free market mobility within the EU, which allows goods to be traded freely between member countries. Because Sweden is a smaller country, the demand for pharmaceuticals will also be smaller compared to larger countries. This affects Sweden negatively, since our market is less attractive and less prioritised. It has shown that some MAHs may be dependent on the same manufacturers, leading to greater consequences in case of accidents or malfunctions. In cases like these, supplies may be limited and the Swedish market will most likely not be prioritised. There is currently no way to check for manufacturing dependencies because the supply chain is considered as confidential information.

There are multiple MAHs within the EEA that have the right to sell Pipetazo and Vancomycin to other countries that does not include Sweden. Those MAHs are still important to take into consideration since the drug can be imported to Sweden through parallel and licence import. In cases of back orders or accidents which forces manufacturers to prioritise countries, is it important that pharmaceuticals can still be imported to Sweden but with a foreign label.

The current purchasing system in Sweden is also affecting the supply of pharmaceuticals negatively. It is ineffective, risky and sales periods are long. This makes for an unattractive system, especially for smaller generic pharmaceutical companies. The pharmaceutical stocks are held at Timro and Oriola, from where the pharmaceuticals are purchased by regions for the negotiated price. But the fact that a region can still buy the equivalent products from other MAHs stocks if the MAH which they have a contract with run out of stock creates a domino effect and repeating patterns of back orders. This is was observed for both Fresenius Kabi (Pipetazo producer) and Orion Pharma (vancomycin producer). This shows that the latter steps in the supply chain also have a great effect on back orders, and not only the primary manufacturing.

7.2 Health-Economical consequences

7.2.1 Quantitative aspects

The results of the labor work and additional treatment costs indicates that shortages of Vancomycin or Piperacillin/Tazobactam are a major burden on the Swedish healthcare economy. According table A15, the lack of antibiotics requires that a number of healthcare personnel with different professions work extra hours. It is an extensive national problem, if not greater for the individual regions that must be able to provide this type of labor.

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As described in the background, Vancomycin is a last resort antibiotic and not as fre- quently used as Pipetazo. The estimation of the amount of treated patients corresponds to this, even though it is a rough estimation and the method does not take treatment differences into account. However, considering the preconditions for this study, the results of the patient calculations are acceptable and useful for the cost estimations of the alternative treatments. The majority of the alternative treatment costs were more expensive than the corresponding Vancomycin respective Pipetazo treatment. All replacement drug costs of Vancomycin would require higher expenses, in the case of replacement with Te- icoplanin it would also increase the costs of care days since the treatment duration would be extended (see table A13). Regarding Pipetazo, Imipenem and Meropenem were more expensive and Cefotaxim had a lower price. Since an alternative antibiotic can extend the recovery of the patient, a less expensive treatment does not necessarily imply a lower shortage cost. It is also important to keep in mind that the costs of alternative drug use assumes that only one alternative drug is being used for all Vancomycin respective Pipetazo patients, but in reality patients might receive different alternative antibiotics depending on their indications. The total direct costs of Vancomycin respective Pipetazo shortages is severe and it is urgent that the Swedish healthcare develop proactive methods to avoid additional labor and alternative treatment costs.

7.2.2 Qualitative aspects

The qualitative effect on patients during shortage can be severe. As seen in table A17, the different alternative treatments for both Vancomycin and Pipetazo obtains several side effects which can have serious impact on the patient’s health. Some of the alternative treatments such as Teicoplanin, may extend the hospitalization with 11 extra days, this does not only have a financial load but also an impact on the patient’s life, job and family.

The indirect cost includes the loss of workdays for patients when they are hospitalized, in this aspect an extended treatment due to less effective alternative drugs puts a larger financial load both for the patient and the society. However, the specific cost is not presented in this report because its not as significant as the direct cost and has too many parameters that needs to be included regards to the patient’s personal life.

The quality of the alternative treatments is not as effective or appropriate to its cause.

Because of shortages, some patients do not have the opportunity to receive the proper treatment since the alternative antibiotic may be prioritized for more sensitive patients.

This also means that patients who do not receive the proper treatment may remain at the hospital longer than anticipated. There are many factors that needs to be in consideration when observing the qualitative aspect of the issues for alternative options. If a patient needs to be hospitalized longer than estimated, there is a high risk of developing a further resistant against the antibiotic. As mentioned earlier the enterococci bacteria advances a resistant against Vancomycin (VRE), unfortunately the hospital environment provides the easiest prospect to receive VRE. Since VRE cases increases each year the risk of higher mortality appears as a response to it, these cases affects the quality of the healthcare system in Sweden. As seen in table A12, 5% of patient treated with Van-

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as a result a higher assumption for more deaths. Sadly, Vancomycin is usually the last resort option which means that approximately 427 people may die due to bacteria resistance each year.The deaths caused by VRE adds to the financial burden to the Swedish healthcare.This can be very costly.

The probability of an increased AMR is massive when patient lack of proper treatment, as the alternative treatments are not as effective or suitable to the patients as Vancomycin or Pipetazo. This validates that shortage of these antibiotics has an indirect effect on expanded bacteria resistance and can be incorporated in the healthcare economics as an indirect cost.

7.2.3 Method limitations

There is a great difficulty in designing a model for calculation of economic costs of shortages that arises from the intricate nature of the management process. The impact that the shortages have on medical staff is heavily dependent on the drug in question. For drugs that are easily substituted for alternative drugs, the effects of a shortage might not be so severe, however, for drugs where alternatives are not so easy to find and need to be adapted to the patient’s condition, like Vancomycin and PipeTazo, shortages may require a great deal of additional work to handle.Therefore, to give a more realistic estimate, it was sought after to the highest degree possible to base the model of calculation on specific events within the recent history of Swedish healthcare where shortages of precisely Vancomycin and PipeTazo took place. As such, the economic calculations were largely based on the events following the shortage of Vancomycin during a weekend in region Östergötland in 2019.

Although this method allows for a good general estimation of the scale of the economic consequences of shortages of Vancomycin and PipeTazo. To get a better estimate, one would need to have access to more detailed information regarding the distribution of workload during shortages.

8 Conclusion

The supply chains for both of the antibiotics consist of numerous manufacturing actors, most of them located in countries which can increase the risk of shortages. The supply chain already has reduced economic margins and because Sweden is a small country with low pharmaceutical sales the Swedish pharmaceutical market is unattractive. The market is not prioritised by sales actors (MAHs), and this could be the reasons behind the low amount of MAHs for both antibiotics. The reasons behind shortages of these antibiotics are due to several obstacles, errors and accidents which can occur for multiple actors in the supply chain. The purchasing system for in care pharmaceuticals in Sweden is ineffective and because of this it is hard for the supplier to fulfil supply demands and back orders may also occur because of this.

Shortages can cost the healthcare system a total of SEK 1 600 000 in fixed costs followed by up to SEK 202 997 per day and up to SEK 923 650 per day for Vancomycin

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and Pipetazo respectively. Additionally, there are also negative impacts to patient health which can affect their daily life. The shortage effects the medical staff in terms of sig- nificantly increasing their workload and they further disease progression among patients and contribute to AMR. This leads to more VRE cases which already is estimated to be around 427 cases per year.

9 Acknowledgement

First and foremost, we would like to thank PLATINEA for providing us with an inter- esting, educative and important assignment. We would also like to thank our supervisors Enrico Baraldi, Simone Calligari and Petter Bertilsson Forsberg for supporting us during this thesis with guidance and useful material. Last but not least, we would like to express gratitude to all doctors providing us with data and information during these difficult times and for making it possible for us to finish this thesis.

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Empirisk antibiotikaterapi pa Akademiska sjukhuset och Lasarettet i

An Investigation of Aspects Affecting Availability and the Health-economical Consequences of Shortages ofVancomycin and Piperacillin/Tazobactam