Anti-Infectives for Systemic Use Prescribed in a Spanish Hospital Between 2009‑2013

Le Infezioni in Medicina, n. 1, 18-23, 2016 18 Original article

Anti-infectives for systemic use prescribed in a Spanish hospital between 2009‑2013

Gabriel Alberto March Rosselló1, Arturo Artero Mora2, Alberto Pérez Rubio3, José María Eiros Bouza3 1Service of Microbiology and Immunology, University Clinic Hospital of Valladolid, Spain; 2Faculty of Medicine, University of Valencia, Spain; 3Management of the University Clinic Hospital of Valladolid, Spain

SummaRY The overuse and misuse of antimicrobials contribute to expenditure of antibacterials decreased in the period the emergence of antibiotic-resistant bacteria. The aim 2009-2013. Antimycotics showed an upward trend in of this work was to analyse all the anti-infectives for expenditure and DDDs in the five-year study period, systemic use (J ATC group) prescribed at the Univer- but with major oscillations. The consumption of anti- sity Clinic Hospital of Valladolid (Spain) for the years virals was practically constant in the period 2009-2011; 2009-2013. Amounts of anti-infectives (antibacterials, in 2012, a significant reduction was observed and this antifungals and antivirals) used in the period 2009- reduction was conserved in 2013, although their ex- 2013 were expressed as defined daily doses (DDDs) penditure increased year by year. In conclusion, in the and as total expenditure, and the significance of the period 2009-2013, expenditure on anti-infectives in- difference in consumption of anti-infectives and the creased year to year. However, this increase in expen- relevant expenditure between years was evaluated diture resulted in a downward trend of DDDs. from the overlapping of the corresponding confidence intervals at 95% confidence level of DDDs and expen- Keywords: defined daily dose, anti-infectives, expendi- diture. The results obtained showed that DDDs and tures.

n INTRODUCTION penditures and 15% of overall health care spend- ing. Moreover, up to 50% of patients could receive he emergence of antibiotic resistant bacteria an antibiotic prescribed erroneously [3]. Tconstitutes a global threat towards the effec- In most developed countries, there have been tiveness of treatment of human infections. Be- efforts to supervise the use of antibiotics and re- sides, antimicrobials are currently considered as ports are published periodically [4]. However, at a non-renewable health resources given that the our region there are no studies on consuming of rate of development of resistances is higher than antibacterials, antimycotics and antivirals by the that the incorporation of new antibiotics [1]. With- population served by hospitals. In this context, in the causes of the development of antimicrobial the aim of this work was to analyze the overall resistance, an important one is the overuse and antiinfectives for systemic use (J ATC group) pre- misuse of antimicrobials [2]. These causes are prescribed at the University Clinic Hospital of Val- dominant within hospitals, where antibiotic pre- ladolid, Spain for the years 2009-2013. scribing represents almost 50% of pharmacy ex-

n MATERIALS AND METHODS Corresponding author Gabriel Alberto March Rosselló The University Clinic Hospital of Valladolid is a E-mail: [email protected] 762-bed academic tertiary hospital located in the Anti-infectives for systemic use prescribed in a Spanish hospital between 2009‑2013 19 32.7 *69.1 247.8 *100.9 *128.4 9991.1 7519.1 4081.3 1267.3 2024.2 3002.4 6233.3 3388.4 *2526.5 23921.5 21965.7 22049.4 55660.2 *30238.5 *48217.6 *79495.8 119632.5 112974.5 233220.1 255965.4 *290550.9 *109639.5 *753618.5 *143257.8 Expenditures Expenditures 2013 2013 - - - - *675 DDD DDD *902.3 *11120 *17820 *16600 *15800 910080 265657 619534 *1902.4 *212159 *408845 *218220 *95799.7 *52910.3 2.768375 135868,2 184772.1 345083.3 390458.3 *2893790 600.855.3 1523727.7 8754316.5 15660154.7 61.8 14.6 *28.4 270.1 *658.1 *130.1 8460.8 3779.9 1978.4 2973.7 7360.3 2096.3 *1262.2 11400.2 81107.7 27928.9 32180.6 10585.3 64302.7 21624.7 *39495.9 *53488.3 119648.1 129149.3 *242776.5 *253155.9 *603281.5 *242682.2 *97763.80 Expenditures Expenditures 2012 2012 - - - - *193 6140 DDD DDD 22564 *205.2 9789.5 *22520 *20800 933902 273607 237404 *2864.8 *177594 2915475 150165.8 *3158975 *118421.7 *195889.8 *594621.3 *207508.8 *331533.3 *387316.7 *630375.7 1596796.1 *8847572.5 *14611836.9 36.3 82.5 9884 3508 *27.8 *60.9 936.5 252.3 291.1 1832.1 6396.1 2935.1 *2514.8 48436.4 12905.2 23635.9 15343.9 67287.1 69366.9 20440.1 *65920.5 *85253.8 111853.1 189789.4 *118956.2 *119000.8 *484272.2 *359416.8 *635041.5 Expenditures Expenditures 2011 2011 - - - - *10 *218 DDD DDD *3973 18213 9449.1 *29320 *46750 909570 194086 476050 *1375.1 *280880 *314863 *262691 3551125 114890.8 689299.5 139062.4 *164483.7 *406266.4 3969198.3 729614.50 1652743.8 18649753.6 10044253.1 293 55,7 54.8 6954 *15.1 888.8 576.9 18323 4263.4 5833.5 2456.9 3620.2 2778.5 11198.4 75150.1 12800.8 77474.9 *36187.1 *17138.9 *50865.9 *88213.4 *74166.3 634259.8 149683.9 132926.4 *293724.7 *120582.8 *182052.7 *744395.4 Expenditures Expenditures 2010 2010 - - - - 382 *311 *739 8976 DDD DDD 46030 15062 33983 731099 325362 *7871.4 *871926 *187341 *445008 4039900 *21607.3 105156.3 178006.5 759380.2 *341533.3 *135305.3 *646655.8 4128936.7 1.657020.6 18349565.2 10303248.9 73 73.3 67.1 4248 2927 5835 311.8 571.2 393.3 23404 7251.2 5058.6 3857.6 1761.9 117392 154997 497250 75909.8 10984.7 27618.8 12758.1 60622.2 88931.5 35486.8 48824.6 662961.7 166953.5 240725.6 100192.1 Expenditures Expenditures 2009 2009 - - - - 146 193 1032 5120 4127 DDD DDD 47310 15,037 756933 728860 351504 166918 38966.7 4949640 101364.3 177957.9 178315.5 297866.6 100265.7 610445.6 348100.2 760916.7 4249966.7 1689157.7 16657898.9 10598863.7

Antibacterial class Antibacterial class Combinations of sulphonamides Fourth-generation cephalosporins Carbapenems Second-generation cephalosporins Third-generation cephalosporins Third-generation Monobactams First-generation cephalosporins Beta-lactamase inhibitors Beta-lactamase sensitive penicillins penicillins Beta-lactamase resistant Other antimycotics for systemic use Penicillins with extended spectrum Triazole derivatives Triazole Drugs for treatment of tuberculosis for treatment Drugs Hydrazides Imidazole derivatives Tetracyclines Antibiotics Antimycotics Imidazole derivatives for treatment Combinations of drugs Polymyxins Other antibacterials of tuberculosis for treatment Other drugs Glycopeptide antibacterials and trimethoprim of tuberculosis Lincosamides Fluoroquinolones Combinations of antibacterials Other aminoglycosides Macrolides ATC ATC ATC group group J01EE J01DE J01DH J01DC J01DD J01DF J01DB J01CG J01CE J01CF J02AX J01CA J02AC J04AB J04AC J02AB J01AA J02AA J01XD J04AM J01XB J01XX J04AK J01XA J01FF J01MA J01RA J01GB J01FA - DDDs and expenditures of antimycotics for systemic use (J02) dispensed by the University Clinic Hospital of Valladolid for the years 2009-2013. able 2 - DDDs and expenditures of antimycotics for systemic use (J02) dispensed by the University Clinic Hospital Valladolid - DDDs and expenditures of antibacterials for systemic use (J01) dispensed by the University Clinic Hospital of Valladolid for the years 2009-2013. able 1 - DDDs and expenditures of antibacterials for systemic use (J01) dispensed by the University Clinic Hospital Valladolid T T *Variation statistically significant compared to the value of the previous year. to the value of previous statistically significant compared *Variation year. to the value of previous statistically significant compared *Variation 20 G.A. March Rosselló, et al.

region of Castilla y León, Spain, which provides coverage to 240,000 people. Data about antiinfec- *338.9 1403.1 tives dispensed by the hospital for the four-year 3547254 *46916.5 324567.3 2337288.6 1078130.1 Expenditures period 2009-2013 were kindly provided by Phar- 2013 macy Service. In Spain, antivirals, although are not considered as medicines intended for hospital *44 703 DDD *421109 *818043 2012395 *1862584

1972651.8 use, outpatients have to acquire them in hospital pharmacies because in this way it is possible to control their dispensation. These antiinfectives were grouped by the anatom- *116.7 1694.9 *92115.6 309607.5 379568.7 2244193.7 *1007908.5

Expenditures ical therapeutic chemical (ATC) classification sys-

2012 tem and are listed in Tables 1, 2, and 3. Amounts of used antiinfectives (antibacterials, antifungals 3.7 940 DDD and antivirals) for the years 2009-2013 were ex- *492573 2541914 *1912377 *1996430.4 *1718469.6 pressed as defined daily dose (DDD) and as total expenditures (including VAT). The DDDs were calculated according to the WHO’s guidelines *87.5 *2346.1 69208.4 295876.9 355348.7 716763.1

2133964.1 in which the ATC/DDD system is defined [5]. In Expenditures brief, the combinations of antiinfectives and the 2011 antiinfectives prescribed to paediatric population

2.8 were excluded. For the rest of them, DDDs were DDD *1535 *327637 2654355 1589082 2363383.9 *1130815.6 obtained by means of dividing the amount of active principle present at every pharmaceutical form by the corresponding DDD per route of ad-

*300.3 ministration assigned to an ATC code. Moreover, *4831.6 74270.2 750546.9 *310130.7 *340697.6 1995343.5 Expenditures the significance of the difference in consumption

2010 and expenses of the antiinfectives between years was evaluated from the overlapping of the corre- *60 DDD *3126 2049550 2279922 1437466 *724.706 sponding confidence intervals at 95% confidence *1324581.6 level of DDDs and expenditures. 22,2 73484.9 10.636,9 272027.9 385478.2 762048.3 1779029.9 n RESULTS Expenditures 2009 The overall DDDs and overall expenditures of 0.9 8372 DDD antiinfectives (including antibacterials, antimy- 552769 2202196 2185070 16193275 1178015.1 cotics and antivirals) dispensed at the University Clinic Hospital of Valladolid for the period 2009- 2013 are shown in Figures 1 and 2 respectively. As can be seen from Figure 1, the consumption data of antibacterials expressed in DDD remained relatively constant for the years 2009-2011, with- out variations statistically significant; however, a significant decrease took place in 2012 and this re- Antibacterial class duction was conserved in 2013. The consumption data of antimycotics expressed in DDD was not uniform; in 2010, it increased significantly com- Otherantivirals Nucleosides and nucleotides excl. Non-nucleoside reverse transcriptase Non-nucleoside reverse inhibitors Neuraminidase inhibitors Nucleoside and nucleotide reverse Nucleoside and nucleotide reverse transcriptase inhibitors reverse transcriptase inhibitors reverse Protease inhibitors Protease Phosphonic acid derivatives pared to 2009 and next year decreased significantly; in 2012 this downward trend persisted and, fi- ATC ATC

group nally, in 2013 a significant rebound was observed. J05AX J05AB J05AG J05AH J05AF J05AE J05AD - DDD and expenditures of antivirals for systemic use (J05) dispensed by the University Clinic Hospital of Valladolid for the years 2009-2013. able 3 - DDD and expenditures of antivirals for systemic use (J05) dispensed by the University Clinic Hospital Valladolid T *Variation statistically significant compared to the value of the previous year. to the value of previous statistically significant compared *Variation The consumption of antivirals expressed in DDD Anti-infectives for systemic use prescribed in a Spanish hospital between 2009‑2013 21

Figure 1 - DDDs of the antiinfectives for systemic use (J Figure 2 - Expenditures of the antiinfectives for sys- ATC group) dispensed by the University Clinic Hospital temic use (J ATC group) dispensed by the University of Valladolid for the years 2009-2013. Clinic Hospital of Valladolid for the years 2009-2013 was practically constant for the years 2009-2011; penditures was the JO1XX, which includes the in 2012, a significant reduction was observed and active principles fosfomycin, linezolid and dap- this reduction was conserved in 2013. Overall, tomycin. Regarding antimycotics, Table 2 shows consumption of antiinfectives in DDDs was virtu- the DDDs and expenditures of the antimycotics ally the same for the years 2009-2011; and in 2012- for systemic use (J02). The most prescribed group 2013 a downward trend was registered, being sta- was the J02AC, which includes the azole antifun- tistically significant in 2012. gal; and the J02AX group, which includes flucy- As can be noted from Figure 2, in 2010, com- tosine and echinocandins, was the one with the pared to 2009, the expenditures of antibacterials highest expenditures. With regard to antivirals, increased significantly and the next three years Table 3 illustrates the DDDs and expenditures of their expenditures was reduced, the reduction be- the antivirals for systemic use (J05). The most pre- ing statistically significant in 2011 and 2012. Re- scribed group was J05AE (Protease Inhibitors) in garding antimycotics, an increase in expenditures 2009 and 2013, J05AF (Nucleoside and Nucleotide was observed in the period 2009-2011, the aug- Reverse Transcriptase Inhibitors) in 2010, and fi- mentation being statistically significant in 2010; nally J05AG (Non-Nucleoside Reverse Transcrip- in 2012 a significant decrease was achieved and tase Inhibitors) in 2011 and 2012. On the expendi- finally, in 2013 a significant rise was obtained. For ture side, the main group was J05AF for each year. antivirals, an upward trend of expenditures was observed for 2009-2013, being statistically significant in 2010 and 2012. On the whole, an upward n DISCUSSION trend of expenditures of antiinfectives was observed, with a significant increase in 2013. Indiscriminate use of antiinfectives is associated Regarding antibacterials, Table 1 illustrates the with an increase in routine care expenditures of DDDs and expenditures corresponding to the an- patients affected by microbial infections and with tibacterials for systemic use (J01). As can be seen, the increasing emergence of microorganisms re- the most dispensed group per year was the J01CF, sistant to antibiotics. In this way, available thera- which includes beta-lactamase resistant pencil- peutic options are reduced and unfavourable out- lins such as amoxicillin-clavulanate, cloxacillin comes for patients can be achieved [6]. Routine and piperacillin-tazobactam. However, the ATC measurement and display of information on con- group with higher expenditures in 2009 was the sumption of antiinfectives is the cornerstone for J01DH, which includes carbapenems; and in the increasing awareness of the importance of proper period 2010-2013, the ATC group with higher ex- use of these drugs [7]. From this point on, clini- 22 G.A. March Rosselló, et al.

cal microbiologists can actively become part of tibiotics could have reduced in many cases and decision-making processes of new strategies for probably, the emergence of strains resistant to car- administering antibiotics and, moreover, antibi- bapenems could have been delayed. On the other otic resistance patterns can be monitored. hand, there have been only five ATC groups that In this manuscript we described, for the first time, have not shown variations statistically significant the use of antiinfectives for a 5-year period in the in the consumption and expenses in the period University Clinic Hospital of Valladolid. DDDs 2009-2013. These groups are: J01CA, J01EE, J01FA, per 100 bed-days were not calculated because J04AC and J04AM. Moreover, it is worth to men- some antiinfectives were prescribed to patients tion that the groups J04AC and J04AM are practi- who were not hospitalized. Besides, taking into cally not used in clinical practice. account that the calculated DDDs did not include Regarding antimycotics, during an upward trend the antiinfectives prescribed to paediatric popu- of expenditures and DDDs in the period 2009- lation, in order to expose the overall use of anti- 2013, these parameters have shown pronounced infectives in the hospital, expenditures of them oscillations. Besides, it should be noted that these were reported. In the interval 2009-2013, the ex- variations have been statistically significant in penditures of antiinfectives increased year to year. most cases (Table 2). These data do not correlate However, this increase of expenditures results in a with the isolation of yeast and fungi in the clinical downward trend of DDDs. This fact is due to that microbiology laboratory, which has been practi- prescription of antiinfectives tends to administrate cally constant in the same period. On the basis of drugs with low amounts of active principles, such these data, particular attention should be given to as cloxacillin, cefexime and azitromycin. the administration of antimycotics at our hospital. Antibacterials represent the most prescribed Antivirals represent the group of antiinfectives group of antiinfectives at our hospital. Their with the highest expenditures. Besides, their ex- DDDs and expenditures have been decreased penditures have been increased year by year. The for the period 2009-2013, mainly due to the re- group J05AF (which includes zidovudine, didan- duction of the administration of tigecycline and osine, savudine, lamivudine, abacavir, tenofovir, fluoroquinolones, and to the reduction of price of adefovir and entecavir), J05AG (which includes carbapenems. The reduction of use of tigecycline nevirapine, delavirdine, efavirenz and etravirine) resulting from the FDA Drug Safety Communica- and J05AE (which includes saquinavir and oth- tion, issued in September 2010, where was stated ers) have shown a constant prescription in the pe- that tigecycline increases risk of death compared riod 2009-2013. According to national guidelines to other antibiotics used to treat similar infections for the treatment of acquired immune deficiency [8]. However, it was in 2012, two years after the syndrome (AIDS), these antivirals are used to emission statement, when the reduction of use of treat the majority of patients [9]. Taking into ac- tigecycline was statistically significant. So, a con- count that very few new cases of AIDS are report- trol in administration of antibiotics supervised by ed annually in the hospital, it could be expected the Service of Microbiology would have reduced that these group of antivirals showed a constant the administration of tigecycline earlier; in this use. However, the J05X group (which includes the way, the safety of patients could be improved antivirals for the treatment of AIDS maraviroc, and an important expenditure saving could be raltegravir and enfuvirtide) has shown important achieved. The use of fluoroquinolones has been oscillations, many of them with statistical signifi- reduced because currently the bacterial strains cance (Table 3). These antivirals are used when causing urinary tract infections resistant to this some adverse reactions are observed or when group of antibiotics move around 40%. Regarding the clinicians consider them appropriate to im- carbapenems, their price has been progressively prove patients’ outcome. Besides, in most cases, reduced in the interval 2009-2013. As a conse- there is a lack of information about their effective- quence, their use in 2012 increased nearly doubled, ness [10]. These data suggest the convenience of but, in 2013 the consumption of carbapenems was that clinical microbiologist could be involved in significantly reduced because of the emergence of the decision-making process for the treatment of bacterial strains resistant to carbapenems in our patients with AIDS. Another group with impor- hospital. A more controlled administration of an- tant oscillations in prescription has been J05AB, Anti-infectives for systemic use prescribed in a Spanish hospital between 2009‑2013 23

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