Mox 500 for toothache

( B ) Cephalosporins, which correspond to the ATC classification codes J01DB, J01DC, J01DD, and J01DE for the four generations of cephalosporins.

( C ) Macrolides, which correspond to the ATC classification for macrolides, lincosamides, and streptogramins (J01F).

( D ) Quinolones, which correspond to the ATC classification for quinolone antibacterials (J01M). All rights reserved (https://www.iqvia.com/solutions/commercialization/geographies/midas). Consumption of newer and last-resort antibiotic classes increased across all country income groups between 2000 and 2015. The United States was the largest consumer of glycylcyclines (tigecycline) and oxazolidinones (primarily linezolid as tedizolid was not introduced until 2014) through the late 2000s.

However, the antibiotic consumption rate of these drugs in the United States began declining in 2009 (Fig. 4 A and B ), and in 2015, Taiwan, Italy, Turkey, and Austria all had higher consumption rates for glycylcyclines than the United States, while India surpassed

the

The antibiotic consumption rate of carbapenems increased greatly in LMICs between 2000 and 2015 but remained far below consumption rates in HICs (Fig. Similarly, the antibiotic consumption rate of polymyxins (largely colistin) also increased in LMICs, particularly in LMICs-UM countries, but remained much lower than in HICs (Fig. The highest polymyxin consumption rates were in Spain, the United Kingdom, and Ireland, all of which had rates greater than 0.05 DDDs per 1,000 inhabitants per day in 2015.

Download figure Open in new tab Download powerpoint. Antibiotic consumption rate for HICs, LMICs-UM, and LMICs-LM of new and last-resort antibiotics in DDDs per 1,000 inhabitants per day.

( A ) Glycylcyclines, which correspond to the ATC classification for tigecycline (J01AA12).

( B ) Oxazolidinones, which correspond to the ATC classifications for linezolid (J01XX08) and tedizolid (J01XX11).

( C ) Carbapenems, which correspond to the ATC classification for carbapenems (J01DH).

( D ) Polymyxins, which correspond to ATC classification for polymyxins (J01XB). All rights reserved (https://www.iqvia.com/solutions/commercialization/geographies/midas). We found a significant positive association between GDP per capita and changes in the antibiotic consumption rate in LMICs ( P = 0.004),

although

Fixed-effects regression analysis of factors associated with global antibiotic consumption (DDD per capita): 2000–2015. Between 2000 and 2015, the estimated total global antibiotic consumption rate (including countries not reported in the IQVIA database) decreased slightly in HICs from 27.0 to 25.7 DDDs per 1,000 inhabitants per day in HICs and increased from 8.6 to 13.9 DDDs per 1,000 inhabitants per day in LMICs ( SI Appendix , Fig. Total global antibiotic consumption in 2015 was estimated to be 42.3 billion DDDs (15.8 DDDs per 1,000 inhabitants per day)—10.7 billion DDDs in HICs and 31.6 billion DDDs in LMICs.

In our baseline condition, where we assumed no policy changes and constant antibiotic consumption rates set at current levels of use, global antibiotic use is projected to increase 15% between 2015 and 2030.

If all countries continue to increase their antibiotic consumption rates at their compounded annual growth rates, we estimate that total consumption would increase 202% to 128 billion DDDs, while the antibiotic consumption rate would increase 161% to 41.1 DDDs per 1,000 inhabitants per day. Finally, if all countries converge on the global median antibiotic consumption rate in 2015 of 17.9 DDDs per 1,000 inhabitants per day by 2020, we estimate global antibiotic consumption would increase 32% to 55.6 billion DDDs (Fig.

Download figure Open in new tab Download powerpoint. Projected total global antibiotic consumption (billions of DDDs): 2000–2030. Estimated global antibiotic consumption in all countries in billions of DDDs for three scenarios: ( i ) all countries continue to consume at current per capita rates; ( ii ) consumption of all countries continues to change at current compound annual growth rates; and ( iii ) all countries converge to the global median antibiotic consumption rate. Estimates were produced using antibiotic use data for 2000–2015 from the IQVIA MIDAS database and World Bank DataBank population estimates and projections for 2000–2030. All rights reserved (https://www.iqvia.com/solutions/commercialization/geographies/midas). Using a global database of antibiotic sales, we found that antibiotic consumption rates increased dramatically in LMICs between 2000 and 2015, and in some LMICs have reached levels previously reported only in HICs.

Overall consumption has also greatly increased, and the total amount of antibiotics consumed in LMICs, which was similar to HICs in 2000, was nearly 2.5 times that in HICs in 2015. Rising incomes are a major driver of increased antibiotic consumption in LMICs.

Thus, although rates of antibiotic consumption in most LMICs remain below the general rate in HICs, barring major policy changes, they are expected to increase over time and converge, and possibly surpass, antibiotic consumption rates in HICs, in part due to the higher burden of infectious diseases in LMICs. Tracking rates of antibiotic use is vitally important because of the well-quantified relationship between antibiotic use and resistance. However, although data on the burden of resistant bacterial infections is limited, both in HICs and especially in LMICs (2), the magnitude of the challenge posed by rising antibiotic resistance levels has become increasingly visible. Despite the emergence and spread of nearly untreatable infections, the global response to this public health crisis remains slow

and

Reducing antibiotic consumption rates in HICs and slowing the growth rate of consumption in LMICs is urgently needed to contain the problem of resistance, particularly given the long timescales and resources necessary for development of new antibiotics. However, there is a need to balance access to essential medications, particularly in LMICs where the burden of infectious diseases likely still outweighs the burden of resistant

infections

Efforts to reduce unnecessary or inappropriate use based on awareness campaigns have resulted in lower antibiotic consumption rates in some high-consuming HICs (20). However, maintaining those efforts in the long run has proven challenging (21, 22), and the methods used in HICs may not be appropriate or feasible in LMICs.

Research is urgently needed to understand the most effective methods for implementing stewardship programs in LMICs from the local to the national level in a manner that does not restrict antibiotics from those most burdened by treatable diseases. Numerous studies have examined the drivers of consumption within and between HICs; however, the large variations in antibiotic consumption among countries are poorly explained. In our study, increases in the antibiotic consumption rate in LMICs were positively correlated with per capita GDP growth rates, but no similar relationship could be identified for HICs.

Increases in economic growth provide access to goods and services, including antibiotics, which provides the most likely explanation for the positive relationship found between increasing wealth and increasing antibiotic consumption in LMICs. However, GDP growth in LMICs is also linked with increasing urbanization, which can facilitate the transmission of infectious diseases (23) and may contribute to the link between GDP growth and antibiotic consumption. Increasing incidence of bacterial infections, such as enteric fever (24), has been associated with rapid urbanization and increased consumption of antibiotics. Furthermore, rising incidence of nonbacterial infections associated with urbanization, such as dengue, chikungunya (25, 26), and viral diarrheal illnesses (27), is a significant driver of inappropriate consumption of antibiotics in LMICs. Additionally, declining air quality associated with urbanization and continued use of solid fuels for cooking also drives antibiotic consumption in LMICs by increasing the incidence of acute respiratory-tract infections (28).

The lack of a relationship between economic growth and antibiotic consumption in HICs suggests that access is not the leading factor driving differences between countries.

Rather differences in consumption rates are driven by social and cultural norms regarding attitudes toward prescribing and use of antibiotics [see, e.g., Blommaert et al.

Therefore, embedding judicious use as a normative value in

LMICs

However, additional studies in LMICs are needed to identify the regulatory and policy factors that result in lower consumption across these settings and whether they differ from higher-income settings. We observed prominent differences in the rate of change in classes of antibiotics consumed in HICs and LMICs, particularly cephalosporins, consumption of which increased rapidly in LMICs while declining in HICs. These changes are concerning because the consumption of cephalsoporins, particularly third-generation cephalsoporins, is associated with emergence of extended spectrum beta-lactamase–producing bacteria (30).

Consumption of other broad-spectrum agents like fluoroquinolones, macrolides, and second-line agents like oxazolidinones also increased in LMICs and decreased in HICs.

In contrast, consumption of broad-spectrum penicillins, carbapenems, and polymyxins increased in both HICs and LMICs, although the rate of increase was faster in LMICs-UM than LMICs-LM. Changes in consumption patterns in LMICs likely reflect increasing access due to economic growth as noted above, as well as patent expiration, which reduces barriers to access as well as the cost of medications. However, the changing composition of consumption may also reflect alterations in patterns of resistance. For example, India, which had the greatest increase in antibiotic consumption in LMICs (65% between 2000 and 2015), had sustained economic growth (?10% annual increase in GDP) through the 2000s.

A large portion of this increase in consumption was due to an increase in the use of cephalosporins, which was likely due not only to economic growth, but also to changing prescribing practices for respiratory tract infections, skin and soft tissue infections, gonococcal infections, and enteric fever, where cephalosporins have replaced penicillins and quinolones for infection management due to rising resistance (31). Similarly, with increasing quinolone resistance in Salmonella Typhi (32), cephalosporins have become the treatment of choice for this infection in both outpatient (cefixime, cefpodoxime) and

inpatient

LMICs, with higher disease burdens, may be more sensitive to rising rates of resistance, which may drive local changes in antibiotic

consumption

However, a lack of surveillance for resistant infections makes it difficult to ascribe consumption changes to infectious disease burdens or resistance changes to overall consumption levels. Increased surveillance for resistance and infectious disease burden can improve the scientific basis for reducing antibiotic consumption.

Globally, the consumption of last-resort antibiotics—carbapenems and colistin—has been increasing.

This rise is consistent with a well-documented increase in the number of infections resistant to carbapenems and colistin (34, 35).

Given the recent finding that plasmid-mediated colistin resistance is spreading globally (35), this drug should be used prudently in humans and animals.

Although consumption of the newer second-line drugs glycylcyclines and oxazolidinones declined in the United States after the Food and Drug Administration warned of a higher risk of death compared with other drugs used to treat similar infections (36, 37), globally the consumption of these drugs has increased. With rapidly growing incomes in LMICs, continued high disease burden, and increasing rates of resistance, an accelerated uptake of these and other new drugs can be expected compared with prior uptake rates for older drugs.

This may lead to shorter time frames of effectiveness for new drugs, and as newer drugs are often less well-tolerated, an increase in adverse drug-related events.

While rising incomes provide increased access to medications, in resource-limited settings, financial barriers continue to restrict access to antibiotics particularly for the most vulnerable.

This is further compounded by rising resistance to affordable first-line treatments, which already prevents the most vulnerable populations

from

Innovative pricing mechanisms should be developed to improve access to lifesaving drugs for vulnerable populations (38) without compromising their future efficacy (31). Reducing the burden of disease is an alternative mechanism for reducing antibiotic consumption, particularly in countries where antibiotics are used as surrogates for other infection control measures (39).

Investments in sanitation and improved hygiene measures were a major driving force in reducing the burden of infectious diseases in HICs in the 20th century. Large infrastructure projects in LMICs that improve the delivery of clean, safe water could reduce the burden of disease without increasing the use of antibiotics. For example, a recent study in India demonstrated that improved water quality could significantly reduce the burden of childhood diarrheal diseases, which in turn would reduce antibiotic consumption (40). Improved quality and quantity of water would likely improve hand hygiene compliance, particularly in healthcare settings. In HICs, numerous studies have found that improved hand hygiene helps reduce the consumption of antibiotics in the clinical setting (41).

Access to vaccines and point-of-care diagnostics could similarly reduce unnecessary antibiotic consumption in resource-poor settings (42), both directly through vaccination against bacterial illnesses, such as the PCV (43, 44), or indirectly by reducing viral illnesses that often are treated unnecessarily with antibiotics. Policies to promote these alternatives to reduce consumption should be a major part of efforts to reduce antibiotic resistance. To aid policy development in this arena, future research efforts should quantify the economic benefit of investments by developed countries in these types of interventions relative to investments in the discovery of new antibiotic compounds.

To the best of our knowledge, IQVIA currently provides the only source of harmonized data on global antibiotic consumption. Without an alternative surveillance system to estimate global consumption, it is not possible to assess potential systematic bias in the database used for this study; however, our estimates are strongly correlated with data from the European Surveillance of Antimicrobial Consumption Network (ESAC-Net) ( SI Appendix , Fig.

S3), as well as others that have reported global antibiotic consumption (14, 16). While the DDD consumption data that we report permit our estimates to be directly compared with other sources of antibiotic consumption, including those from ESAC-Net, DDDs are not a perfect outcome measure of antibiotic prescribing, particularly for penicillins (14, 45). Indeed, for these drugs, the DDD is much lower than the actual prescribed dose, therefore overestimating antibiotic consumption. Also, the number of units per package and the amount of active substance per unit has increased over time in Europe and perhaps also in other continents (45). Despite these limitations, reporting of antibiotic consumption rates on a global scale is critical for carrying out effective policies to reduce consumption, such as setting and enforcing targets for antibiotic consumption based on current consumption levels (46) and inducing change by identifying the heaviest consumers of antibiotics (13).