2

The Effects of Falsified and
Substandard Drugs

A safe medicines supply is fundamental for public health. This chapter describes consequences of falsified and substandard drugs. Drawing on a range of examples from both academic literature and other sources, it discusses the relationships between drug failure and health problems at the individual and population levels. The chapter does not attempt to present an exhaustive analysis of every health consequence of substandard or falsified drugs, but it gives an overview of the kinds of health problems these products cause. The second section of this chapter analyzes the economic and social costs of a substandard drug supply, including loss of confidence in the health care system.

PUBLIC HEALTH CONSEQUENCES

A reliable, good-quality medicine supply is essential for health, but it is often missing in countries with weak regulatory systems (Ratanawijitrasin and Wondemagegnehu, 2002). The fallout of falsified and substandard medicines includes poisoning, untreated disease, early death, and treatment failure.

Poisoning

Some of the most compelling stories of pharmaceutical fraud are those of frank poisoning. Between November 2008 and February 2009, 84 Nigerian children died from acute kidney failure brought on by the industrial solvent diethylene glycol in teething syrup (Akuse et al., 2012;



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2 The Effects of Falsified and Substandard Drugs A safe medicines supply is fundamental for public health. This chapter describes consequences of falsified and substandard drugs. Drawing on a range of examples from both academic literature and other sources, it discusses the relationships between drug failure and health problems at the individual and population levels. The chapter does not attempt to present an exhaustive analysis of every health consequence of substandard or falsi- fied drugs, but it gives an overview of the kinds of health problems these products cause. The second section of this chapter analyzes the economic and social costs of a substandard drug supply, including loss of confidence in the health care system. PUBLIC HEALTH CONSEQUENCES A reliable, good-quality medicine supply is essential for health, but it is often missing in countries with weak regulatory systems (Ratanawijitrasin and Wondemagegnehu, 2002). The fallout of falsified and substandard medicines includes poisoning, untreated disease, early death, and treatment failure. Poisoning Some of the most compelling stories of pharmaceutical fraud are those of frank poisoning. Between November 2008 and February 2009, 84 Nigerian children died from acute kidney failure brought on by the industrial solvent diethylene glycol in teething syrup (Akuse et al., 2012; 55

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56 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS Key Findings and Conclusions •  alsified and substandard drugs may contain toxic doses of danger- F ous ingredients and cause mass poisoning. •  oor-quality medicines compromise the treatment of chronic and P infectious diseases, causing disease progression, drug resistance, and death. •  s chronic diseases increase in low- and middle-income countries, so A will the need for reliable medicines. •  ubstandard and falsified medicines encourage drug resistance, S threatening the health of populations today and in the future. Polgreen, 2009). The contaminated product, My Pikin, was registered with the Nigerian regulatory authority and made in Lagos, the national manu- facturing hub (Akuse et al., 2012). Inspectors traced the problem back to deliberate fraud by a chemical dealer in Lagos, eventually leading to 12 prosecutions (Poisoned teething drug arrests, 2009; Polgreen, 2009). A similar tragedy unfolded on a larger scale the previous year in Pan- ama when a Chinese chemical manufacturer sold diethylene glycol, the ac- tive ingredient in antifreeze, as pharmaceutical-grade glycerin to a European company (Bogdanich and Hooker, 2007). The poison caused acute kidney failure in the people who ingested it, often as the solvent in cough syrup (Bogdanich and Hooker, 2007; CDC, 2009). The Panamanian government counted 219 deaths from kidney failure brought on by diethylene glycol poisoning (Núñez, 2011). Given that more than 60,000 bottles of cough syrup and some lotions were contaminated, the Ministry of Health and the World Health Organization (WHO) assume that these confirmed deaths are probably only a fraction of the total mortality (Rentz et al., 2008). The 2006 diethylene glycol poisoning was an international tragedy, and 18 of the causalities were Chinese (Bogdanich, 2007). In the early 2000s some sources called China “the world’s largest producer of bogus medi- cines”; Chinese newspaper accounts contain stories of similar mass poison- ings (Fackler, 2002). In 2001 reporters described the death of a southwest China mine owner from a poisoned albumin drip (Fackler, 2002). A decade later, the Chinese State Food and Drug Administration (SFDA) found that 13 percent of capsule manufacturers are making drugs containing unsafe levels of chromium, a toxic metal (Rickman, 2012). The SFDA identified 254 separate companies as sources of the chromium-tainted medicines (Rickman, 2012). Though poisonous drugs are part of the story, the more insidious

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THE EFFECTS OF FALSIFIED AND SUBSTANDARD DRUGS 57 problem is medicine that simply does not work. Ineffective medicines of- ten contain benign ingredients, such as chalk, pollen, or flour, instead of medicinal chemicals. More dangerously, some contain substances intended to mask the illness and feign treatment, such as paracetemol added to fake antimalarials to lower fever. Patients taking ineffective drugs die of appar- ently natural causes, making these products more difficult to identify. Untreated Disease, Disease Progression, and Death Medicine is intended to cure patients, or at least to relieve symptoms or slow the progression of a disease. There is also useful information in treatment failure. When prescribing medicines of known content and potency, the clinician may suspect inadequate dosing, drug resistance, or misdiagnosis if the patient does not respond to treatment as expected. These inferences are central to the practice of medicine. The Partnership for Safe Medicines, an American nonprofit, encourages doctors to suspect counterfeit1 drugs in cases of treatment failure (PSM, n.d.), but there is little published evidence to suggest they do so. Advising physicians to consider the possibility of medicine fraud suggests that they have a way to verify it. In parts of the world where such assays are too costly or too technologically complicated to pursue, this information is usually unknowable. Confirmed accounts of drug failure are only a fraction of the larger, mostly invisible, problem. Research at the medicine store can help illuminate these problems. A random sample of all known medicine shops in three districts of Ghana found the uterotonic drugs oxytocin and ergometrine to be of uniformly poor quality: 89 percent of the samples tested were below British Pharma- copoeia specifications though only 2 percent were expired (Stanton et al., 2012). Unicef, the United Nations Children’s Fund, estimates the maternal mortality ratio in Ghana to be 350 per 100,000 live births (Unicef, 2003), of which hemorrhage, a condition treated with uterotonic drugs, is the most common cause (Asamoah et al., 2011). Even in Ghanaian hospital studies, where one would expect hemorrhage to be an uncommon cause of death, it accounts for an estimated 17 to 22 percent of maternal deaths (Ganyaglo and Hill, 2012; Lee et al., 2012). Increasing access to emergency obstetric care is a key piece of any strategy to reduce maternal mortality (Campbell and Graham, 2006), one that lies on the assumption that lifesaving utero- tonic medicines are of reliable potency. Research suggests they are not, even in a middle-income country like Ghana. The type of study Stanton and colleagues undertook in Ghana is rare. 1  The Partnership for Safe Medicines uses the term counterfeit broadly, the way this report uses falsified. See page 23.

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58 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS They were able to draw conclusions about uterotonic drug quality because their data represented a random sample of drugs from an almost exhaustive sampling frame of known pharmacies, chemical shops, and other dispensa- ries in their study area (Stanton et al., 2012). The identification of falsified and substandard medicines is more often incidental, found in newspaper accounts or uncovered in research that had a different primary aim. Medications for Chronic Diseases In 2009 a southwest China newspaper reported on a substandard version of the diabetes drug glibenclamide (also called glyburide) found to contain six times the pharmacopeial standard dose (Xiang, 2009). The medicine was tested only after killing two people and injuring nine (Cheng, 2009; Xiang, 2009). Like oxytocin and ergometrine, glibenclamide is a WHO essential medicine, as is only one other oral diabetes drug, metformin (WHO, 2011c). Metformin too has been the subject of quality concerns. In a convenience sample of pharmacies in Lagos, Nigeria, researchers found that four of eight popular brands of metformin tablets failed one or more pharmacopeial tests of bioequivalence (Olusola et al., 2012). These are troubling findings, given that an estimated 80 percent of the world’s 347 million diabetics live in low- and middle-income countries, where medi- cines quality is most variable, and diabetes case-fatality exorbitantly high (Unachukwu et al., 2008; WHO, 2011a). Dora Akunyili, the former direc- tor of the Nigerian drug regulatory authority, worked against pharmaceu- tical fraud, a cause she committed to after her diabetic sister’s death from fake insulin (Cheng, 2009; Lemonick, 2005). Medication for other chronic diseases has been compromised in devel- oping countries. A Rwandan study on drug stability found that 20 percent of medicines in a sample of Kigali and Butare pharmacies were substandard at the time of purchase (Twagirumukiza et al., 2009). Two studies of the antihypertensive amlodipine’s quality in south Nigeria found problems: one study reported 30 percent of samples failed pharmacopeial tests for content uniformity (Eichie et al., 2011) and, in another, all samples failed (Olajide et al., 2010). The management of diseases such as type 2 diabetes and hypertension depend on maintenance medication and monitoring. The sheer amount of products used to treat these conditions raises the patients’ lifetime risk of encountering a bad product, even in countries with strin- gent regulatory authorities (see Box 2-1). The need for reliable medicines in low- and middle-income countries will become more pronounced as the burden of chronic disease increases in these countries. Already cardiovascu- lar disease is the main killer of adults in low- and middle-income countries,

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THE EFFECTS OF FALSIFIED AND SUBSTANDARD DRUGS 59 BOX 2-1 Defective Glucose Test Strips In October 2006, the FDA recalled two batches of blood glucose test strips used in LifeScan, Inc. OneTouch Ultra brand blood glucose moni- tors after LifeScan notified the agency that it had received a number of customer complaints. The strips produced inaccurate blood glucose level readings, the results of which are used by diabetics to monitor their condi- tion and determine medication dosing (Bloomberg News, 2007). Diabetics rely on their blood glucose monitors to manage their self-treatment, and incorrect readings can lead patients to administer the wrong dosage of in- sulin or induce unnecessary panic. Improper insulin dosing is a potentially fatal error. In the LifeScan recall, the FDA identified the problem strips and instructed consumers to inspect the serial numbers on their boxes and replace any fake or unidentifiable strips (FDA, 2006; WHO, 2006). Investigation traced the strips back to Halson Pharmaceuticals in Shanghai. The manufacturer sold approximately one million substandard test strips to importers, and from there the strips went through the sup- ply chain to reach U.S. and Canadian pharmacies. Over the course of the next year, the test strips made their way to 8 countries and 35 U.S. states. The Chinese authorities eventually arrested and imprisoned Henry Fu, owner of Halson Pharmaceuticals (Bloomberg News, 2007). The LifeScan recall is a reminder that substandard medical products can find their way into countries with strong regulatory systems. The United States and Canada have systems in place for prompt recalls, al- lowing them to mitigate the threat the product poses to public health. Within 2 years the fake test strips were fully recalled in the United States, but between 2009 and 2011 customers and investigators still found them in other countries, including Egypt, India, and Pakistan (Loftus, 2011). As the prevalence of diabetes increases rapidly in the developing world, new, loosely regulated markets attract potential counterfeiters. India is home to more than 50 million diabetics, more than any other country, and the number is expected to increase dramatically over the coming years (World Diabetes Foundation, 2013). In 2007, not long after the first bad test strips appeared in the United States, there were ap- proximately 40.9 million diabetics in India; by the time they reached the country’s growing diabetic population the number had risen by more than 10 million (Mohan et al., 2007). As the chronic disease burden in- creases in developing countries, falsified and substandard versions of the expensive products used to treat them pose new risks.

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60 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS the proper medical treatment of which is often neglected (Gaziano, 2007; Yusuf et al., 2011). Maintenance medication for cardiovascular disease is a vulnerable target for fraud, but the need for these drugs is still unmet in much of the world (Gaziano, 2007). In developing countries, there has been a greater emphasis on controlling infectious disease, especially the infectious diseases of childhood. Considerable research indicates that the anti-infective drugs used to do this are often compromised in poor countries. Medications for Infectious Diseases Since 1999 the WHO has known that antibiotics are commonly falsi- fied or made improperly (Wondemagegnehu, 1999). In the 1990s antibiotics accounted for over 45 percent of the 771 cases of falsified and substandard medicines brought to the WHO’s attention (Wondemagegnehu, 1999). A more recent survey in Egypt, Jordan, Lebanon, and Saudi Arabia found more than half of antibiotics sampled to be substandard (Kyriacos et al., 2008). A similar survey in Burma uncovered substandard drugs in 16 per- cent of amoxicillin and 13 percent of ampicillin samples (Wondemagegnehu, 1999). More recently, a survey of amoxicillin in the capital of Papua New Guinea found all samples outside of pharmacopeial specifications; 14 per- cent had undetectable levels of active ingredient (Nair et al., 2011). Chapter 3 describes the depth of the problem of fake antibiotics in more detail. In most low- and middle-income countries β-lactam antibiotics, an inexpensive and widely available class of drugs that includes penicillin and amoxicillin, are the first-line treatment for dozens of bacterial infections, including scarlet fever, pneumonia, and respiratory and urinary tract infec- tions (Byarugaba, 2004). Pneumonia, for example, is the leading cause of death in children under 5 and accounts for 18 percent of all child deaths in the world (Unicef and WHO, 2006; WHO, 2011b). The pathogen Strep- tococcus pneumoniae causes most of the world’s pneumonia. Alone it ac- counts for as much as 12 percent of all child deaths worldwide (O’Brien et al., 2009). Unicef’s recommended strategy for preventing pneumonia deaths is recognizing sickness in the child, seeking medical care, and treating with antibiotics (Unicef and WHO, 2006). This will remain the best strategy un- til the pneumococcal conjugate vaccine becomes more widely available. The treatment of pneumonia and other devastating bacterial infections depends on effective antibiotic supply. No research to date has attempted to quan- tify the proportion of child deaths attributable to falsified and substandard medicines, but Table 2-1 presents the most common causes of child death and links them to verified reports of substandard medicines. Vaccines are also important in the control of infectious disease. Chapter 5 describes the medicines supply chain in developing countries; in

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THE EFFECTS OF FALSIFIED AND SUBSTANDARD DRUGS 61 general, the vaccine supply chain is simpler, if only because Unicef manages the parts of the chain between the manufacturer and the national port of entry (Kauffmann et al., 2011). Cases of falsified and substandard vaccines are rare, but Box 2-2 describes some. If antibiotics are some of the oldest and most widely used medicines in the world, antiretrovirals are their opposites: new medicines, prescribed in complicated regimes, to a relatively small segment of the population. An exhaustive WHO survey of antiretroviral drug quality in seven sub-Saharan African countries and a variety of treatment centers found reliable good quality in HIV medications (WHO, 2007). Only 1.8 percent of the drugs tested failed to meet quality specifications, and even those were “[not] seri- ous failures, i.e., no critical deficiencies which would pose a serious risk to patients” (WHO, 2007, p. 19). BOX 2-2 Deaths from Substandard and Falsified Vaccines Vaccines are complicated to make, and there are relatively few manufacturers supplying the world market. Vaccines are generally pro- cured in bulk by governments or UN agencies in a supply chain with few intermediaries. Though cases are rare, substandard vaccines can permeate this supply chain. In 1995, during a meningitis epidemic, about 60,000 Nigeriens were injected with water disguised as meningitis vac- cine (Cockburn, 2005). The substandard vaccine caused about 2,500 to 3,000 excess deaths (BASCAP, 1996). More recently, in China, substandard hepatitis B and rabies vaccines killed or sickened about 100 babies (Jia and Carey, 2011). Precise infor- mation regarding the event is scarce due to the Chinese government’s denial of a connection between the vaccines and the incidents as well as its control over the Chinese media. According to the Associated Press, the original article in the China Economic Times that exposed the scan- dal stated that four children who died never had a precise diagnosis, but suffered from fevers and convulsions before their deaths; others who became ill were later diagnosed with encephalitis, among other conditions, and some suffered permanent damage (Associated Press, 2010a). About 200,000 doses of substandard rabies vaccine circulated in Jiangsu province in 2010 before a manufacturer recall (Associated Press, 2010b). These vaccines, like the falsified meningitis vaccine used in Niger, convey no immunity to the patient. When herd immunity is an important result of vaccination, there is no such benefit to society. Assuming the patients survive injection with nonsterile, unidentified liquids, they are still at risk for death from the disease they were not inoculated against.

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62 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS Some more recent reports suggest that falsified antiretroviral drugs may circulate in African countries. In September 2011, falsified and substandard versions of the triple combination therapy Zidolam-N surfaced in Kenya, many samples molding and crumbling in the packages (Taylor, 2011). A year later, in Tanzania, the regulatory authority uncovered falsified anti- retrovirals at a district hospital (Athumani, 2012). These failures put HIV patients at risk for disease progression and favor the selection of resistant virus strains (WHO, 2003). As their viral loads increase, these patients are also more likely to transmit the infection, impeding efforts to control the virus. Although data suggesting compromised antiretroviral drug quality are mixed, there is substantial evidence, presented in Chapter 3, that antima- larials are often of poor quality. Substandard and falsified malaria drugs are especially common in malaria-endemic parts of Africa and Asia. In 2003, substandard sulfadoxine-pyrimethamine was used to treat a malaria epidemic in northwest Pakistan refugee camps (Leslie et al., 2009). Re- searchers concluded that, as the strain of P. falciparum they identified was 90 percent curable when using standard sulfadoxine-pyrimethamine drugs, the substandard medicines, procured from local manufacturers because of drug shortages, were a causal factor in what initially presented as drug- resistant malaria (Leslie et al., 2009). In this example, the effects of the substandard medicine were promptly mitigated. Health workers diagnosed the parasite with microscopy, monitored drug resistance, and checked drug quality using procedures described in the U.S. Pharmacopeia monograph. Good care during initial infection and treatment with an effective second- line drug prevented any deaths, and the onset of cooler weather stopped transmission (Leslie et al., 2009). The prognosis for most people treated with poor-quality antimalarial drugs is worse. Not only will their malaria be untreated, but inadequate treatment favors the selection of resistant parasites, which threaten their entire communities. Treatment Failure Individual patients have much to lose from substandard and falsified medicines. These products also encourage drug resistance and thereby threaten population health today and for future generations. This is a par- ticular concern with substandard products where the dose of active ingredi- ent is low and variable and with falsified products diluted by criminals in an effort to pass screening assays. Drug resistance is common in pathogens with short life cycles: viruses, bacteria, and protozoa. Poor-quality anti- microbial medications, taken frequently and, in poor countries, generally taken without professional supervision, contribute to drug resistance.

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THE EFFECTS OF FALSIFIED AND SUBSTANDARD DRUGS 63 Antimicrobial Resistance Antibiotics should be used only when indicated, in the appropriate dose, and for the correct length of time. Ensuring the proper treatment with the right combination of drugs is the underlying principle of Directly Observed Treatment–Short Course (DOTS), the internationally accepted method of tuberculosis surveillance and treatment (WHO SEARO, 2006). DOTS also depends on a safe and reliable drug supply. Poor-quality drugs have been cited as a causal factor for the rise of multidrug-resistant tubercu- losis (Kelland, 2012). Over time, the bacteria causing tuberculosis have be- come increasingly drug resistant. Multidrug-resistant tuberculosis precedes extensively drug-resistant tuberculosis, and finally, sometimes, totally drug- resistant tuberculosis (Udwadia, 2012). Extensively drug-resistant strains of tuberculosis account for about 6 percent of incident infections worldwide, but much more in China, India, and the former Soviet Union (Jain and Mondal, 2008). Figure 2-1 shows the increasing incidence of multidrug- resistant tuberculosis around the world. Drug-resistant bacteria often surface in hospitals, causing infections that are difficult to treat and are an important killer of adults in low- and middle-income countries (Okeke et al., 2005b; WHO, 2012a). It is difficult to estimate the burden of antimicrobial resistance in low- and middle-income countries, in part because of the dearth of data, especially from francophone Africa, the Asian Pacific, and the former Soviet Union (Okeke et al., 2005a). The data that do exist are grim. Multidrug-resistant staphylococcus, an emerging problem in India and sub-Saharan Africa (Parasa et al., 2010; Vincent et al., 2009), accounts for more than half of all nosocomial infections in parts of Latin America (Guzmán-Blanco et al., 2009). (See Figure 2-2.) In a qualitative study in Orissa, India, doctors, veterinarians, and phar- macists cited poor-quality antibiotics as a cause of drug resistance, but men- tioned it only in passing, focusing more on patient and provider behaviors (Sahoo et al., 2010). This is consistent with most public health literature, which gives great deal of attention to the overuse of antibiotics as contrib- uting to the rise of antimicrobial resistance in general (Byarugaba, 2010; Okeke et al., 2005b) and drug-resistant pneumonia in particular (Unicef and WHO, 2006). Comparatively little work, however, discusses the role of drug quality in encouraging bacterial resistance. Antibiotics that contain low doses of active ingredient cause low circulating levels of the drug in the patient. This contributes to treatment failure and selectively favors the growth of drug-resistant organisms (Okeke et al., 2005b). Resistance is most common among the oldest and least expensive families of antibiotics (Okeke et al., 2005b).

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64 MDR-TB among new TB cases (%) 0-2.9 3-5.9 6-11.9 12-17.9 > 18 No data Subnational data only Not applicable FIGURE 2-1 Increasing incidence of multidrug-resistant tuberculosis (MDR-TB). SOURCE: WHO, 2011b.

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THE EFFECTS OF FALSIFIED AND SUBSTANDARD DRUGS 65 According to a recent Tufts University estimate, it costs more than $1.3 billion to bring a new drug to market (Kaitin, 2010). Antibiotics in particular offer pharmaceutical companies a low return on investment; pa- tients take them for only a week or two, in contrast to lifetime regimes of maintenance drugs. There would be even less monetary incentive to develop antibiotic for only the poorest parts of the world. Preserving antibiotics is imperative and depends on maintaining drug quality as much as on encour- aging rational use. Antimalarial Resistance Through a conceptually similar mechanism, selectively allowing the growth of drug-resistant parasites by exposing them to subtherapeutic doses of medicines, falsified and substandard drugs favor survival and spread of resistance to antimalarial medicines. Drug-resistant parasites of particular concern are the malaria parasites Plasmodium falciparum and Plasmodium vivax. Artemisinin combination treatments are effective in treating falciparum malaria (WHO, 2011d). They have been the recommended first-line treat- ment for falciparum malaria everywhere in the world since 2001 (WWARN, 2012d). In areas where these drugs are available and appropriately used, malaria deaths have dropped dramatically (WHO, 2011d). Drug resistance could undo the success that artemisinin therapies have won, however (see Box 2-3). A recent review estimates that about 35 per- cent of the antimalarial medicines in Southeast Asia are substandard, and 36 percent can be classified as falsified (Nayyar et al., 2012). The same researchers found similar patterns in sub-Saharan Africa, where about 35 percent of antimalarials are substandard and 20 percent are falsified (Nayyar et al., 2012). In both regions, underdosing the active ingredients is far more common than overdosing (Nayyar et al., 2012). Already, 8 of the 12 major antimalarial drugs used in the world have been falsified, including products labeled as of mefloquine, but containing sulphadoxine- pyrimethamine and no mefloquine, and a product labeled as artesunate, but containing 6 percent chloroquine and no artesunate (Newton et al., 2006). Poor-quality medicines supply a subtherapeutic dose that selectively encour- ages the emergence of partially resistant pathogens (Talisuna et al., 2012). Underdosing with antimalarials causes low concentrations of ac- tive drugs in patients and selective pressure to breed resistant parasites (Dondorp et al., 2011; Sengaloundeth et al., 2009; White et al., 2009). In Thailand investigators have observed a progressive lengthening of the time it takes for patients to clear malaria parasites from their bloodstream dur- ing treatment, suggesting that the parasites are becoming more resistant to artemisinin (Phyo et al., 2012). Resistance is heritable from one generation

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74 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS such widespread and serious fraud can occur undermines confidence in gov- ernment, but the effects are so diffuse and uncertain that they are unlikely to generate an organized political response” (UNODC, 2009, p. 6). In many parts of the world, falsified and substandard medicines further erode the already weak political infrastructure that allows them to circulate, part of a vicious cycle of poverty and crime.

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TABLE 2–1 Medicines Used to Treat the Most Common Causes of Child Death Are Compromised in Developing Countries Known Falsified or Substandard or Common Pathogen Essential Medicine Both? Pneumonia Streptococcus pneumoniae Amoxicillin Yes a,b,c Amoxicillin + clavulanic acid Yes a,d Ampicillin Yes a,b,e Trimethoprim-sulfamethoxazole Yes a Pneumocystis carinii Trimethoprim-sulfamethoxazole Mycoplasma pneumoniae Erythromycin Yes a,f,g Haemophilus Influenzae type b Ampicillin Yes a,b,e Diarrheal Diseases Rotavirus Oral rehydration solution (ORS); zinc sulfate Campylobacter jejuni Oral rehydration solution (ORS); zinc sulfate Erythromycin Yes a,f,g Escherichia coli Oral rehydration solution (ORS); zinc sulfate Vibrio cholerae Oral rehydration solution (ORS); zinc sulfate Erythromycin Yes a,f,g Doxycycline Yes a,h Shigella Oral rehydration solution (ORS); zinc sulfate Ampicillin Yes a,b,e Trimethoprim-sulfamethoxazole Yes a Ceftriaxone Yes a continued 75

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76 TABLE 2–1 Continued Known Falsified or Substandard or Common Pathogen Essential Medicine Both? Malaria Plasmodium vivax/ovale/ Amodiaquine Yes i,j falciparum/malariae Artemether Yes i,k,l Artesunate Yes k,l,m Plasmodium vivax/ovale/ Doxycycline Yes a,h falciparum/malariae Mefloquine Yes k,n Sulfadoxine/pyrimethamine Yes l,j,o Quinine Yes j,k,o Artesunate + amodiaquine Yes l Artemether + lumefantrine Yes l Plasmodium vivax Chloroquine Yes f,k,p Primaquine Yes q,r Plasmodium ovale Primaquine

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