Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence

Abstract

There is growing universal concern regarding counterfeit medications. In particular, counterfeit antimicrobial drugs are a threat to public health with many devastating consequences for patients; increased mortality and morbidity and emergence of drug resistance. In addition, physicians treating these patients lose their confidence in the medications used and report high levels of bacterial resistance. The problem with fake and suboptimal medications got worse with the advent of the World Wide Web; a significant proportion of medications that are sold through Internet pharmacies is counterfeit. Various initiatives of the WHO (the International Medical Products Anti-Counterfeiting Taskforce) are hopefully going to tackle this very important public health issue. In this article, we review the available evidence in peer-reviewed articles and World Wide Web information resources regarding the issue of counterfeit antimicrobials.

low-quality antimicrobials, quality testing, fake antimicrobial agents

Introduction

Drug quality is currently receiving renewed international attention.¹ Over the past decade, there has been an increase in public awareness of the existence of counterfeit and substandard drugs,^2–5 which have been increasingly reported in developing countries where drug regulations are ineffective.^6–14 Although practically all types of pharmaceutical products have been shown to be involved, the existing data suggest that anti-infectious agents, particularly antibiotics and antiparasitic agents, are the most counterfeited products in developing countries.^1,15,16

To implement effective countermeasures against counterfeit and substandard drugs, there is a need for more data to define the extent of the problem. The issue of poor quality drugs has been discussed more in the mass media including newspapers than in the biomedical literature. Many reports that this topic are however anecdotal, which makes quantitative assessment difficult.^10,17 Few studies have been reported that systematically examine drug quality,^7–12 and have investigated poor quality drugs in terms of correct amount of active ingredient present. More specifically, although drugs that treat serious diseases such as malaria, tuberculosis, AIDS or other infections are more often the object of counterfeits,^18,19 there have been scarce reports that systematically review data of low-quality antimicrobials. Therefore, we performed a review of the available scientific evidence on counterfeit and/or substandard antimicrobial drugs. More specifically, we set out to explore the causes and prevalence of this problem and summarize the categories of antimicrobials that have been reported to be counterfeit or substandard. We then discuss the characteristics of these low-quality antimicrobials, their consequences to patients and in our society and finally what interventions have been put into place to cope with this menace.

Literature review

Two reviewers (T. K. and I. K.) independently performed the literature search, study selection and data extraction. The following terms were used in searches of the PubMed database (1966–2006): ‘counterfeit drugs’, ‘substandard drugs’, ‘fake drugs’, ‘substandard antimicrobial agents’, ‘fake antimicrobial agents’, ‘counterfeit antimicrobial agents’, ‘substandard antibiotics’, ‘fake antibiotics’ and ‘counterfeit antibiotics’. Magazine and newspaper articles were searched for with Google and we screened articles related to the initially identified publications to expand our data sources.

Definitions

The subject of overall drug quality has been addressed in several WHO publications.^20–22 Substandard drugs are genuine products that have not passed the quality testing protocols previously set for each product.²³ The testing protocols and specifications are published in official pharmacopoeias such as the United States Pharmacopoeia (USP), the European Pharmacopoeia and the WHO International Pharmacopoeia. In addition, many countries have published their own pharmacopoeias. More specifically, substandard drugs have incorrect quantity of active ingredient, which could be secondary to excessive decomposition of active ingredient as a result of high temperature and humidity, and poor quality assurance during the manufacture of pharmaceutical products in less-developed countries.

One special class of substandard drugs is the class of counterfeit drugs. Several countries have their own definitions as to what constitutes a counterfeit drug and there is no consensus. This poses a problem in that what may be considered a counterfeit product in one country will not necessarily be so in another country. The WHO has defined counterfeit drugs as those that are deliberately and fraudulently mislabelled with respect to identity and/or source.²⁴ Counterfeit products include drugs with the correct ingredients or with the wrong ingredients, without active ingredients, with insufficient active ingredient or with fake packaging.²⁵ According to a WHO report, analysis of the content of a drug preparation cannot therefore determine whether or not the sample is counterfeit, because the inclusion of inappropriate quantities of active ingredient during manufacture cannot be identified as deliberate.¹⁵

Using the above definitions, the variations in active ingredient and weight above or below the recognized limits found in different studies in the current report point to problems in good manufacturing practice, deliberate counterfeiting or poor retail management. Although it is very important to make a clear distinction between the various terms for poor quality medications such as ‘counterfeit’, ‘fake’ or ‘substandard’ drugs in the majority of reports reviewed herein, it was not clarified whether the substandard drug was counterfeit or simply the result of a defect in the manufacturing process.^7,12 Thus, although these two terms are indicative of different problems that must be addressed using different strategies, we use the term ‘counterfeit/substandard’ drug, whenever the cause of the poor quality medication is not clear.

Causes of poor quality drugs

The poor quality of drugs has been linked to counterfeiting of medicines,²⁶ chemical instability especially in tropical climates,²⁷ and poor quality control during manufacture.²⁸ Many factors contribute to the increased prevalence of substandard and counterfeit medications. Much of the counterfeit drug trade is probably linked to organized crime, corruption, the narcotics trade, the business interests of unscrupulous politicians and unregulated pharmaceutical companies.^29,30 According to the WHO guidelines, factors that influence the prevalence of counterfeit drugs in any particular country include weak or absent drug regulatory authority, absence of a legal mandate for licensing of manufacture/import of drugs, lack of regulation by exporters and within free trade zones, proliferation of small pharmaceutical industries, complex transactions involving many intermediaries, high demand for curative and preventive drugs and vaccines exceeding supply, high prices and inefficient cooperation among stakeholders.¹ The WHO Essential Drug Program has failed in most countries³¹ because of personal financial interests at local, national and foreign levels or a black market. Studies indicate that a country's capacity to restrict dangerous drugs depends heavily on its wealth.⁹ It is surprising that almost a third of WHO member countries have poor means of controlling counterfeit medications.³⁰ In these circumstances, the market for counterfeit and substandard drugs becomes a lucrative one. In addition, lack of good manufacturing practices (GMP) is common in local pharmaceutical industries in most developing countries because of many hurdles such as frequent power cuts and shortage of water.⁹ In addition to the existence of substandard drugs, assurance of the stability of pharmaceuticals marketed in developing countries (most of which have tropical climates) is a challenging issue as poor storage conditions, high temperature and high humidity conditions generally enhance chemical degradation and may alter the biopharmaceutical properties of the drugs,^32,33 as it has been shown for antibiotics such as tetracyclines.³⁴ Finally, medicine sellers often exhibit lack of concern about expiration dates and storage conditions, especially in poor settings and in the absence of national control, and this can increase the spread of substandard antimicrobials.^35,36 Manufacture of generic versions of patented drugs for humanitarian reasons may also be abused in developing countries.³⁷

In contrast, in developed countries such as the USA, other factors contribute to the spread of counterfeit medicines. For example, it is well known that underinsured or uninsured individuals and some states and local governments are turning to the Internet and foreign pharmacies, particularly what they believe to be safe, reputable Canadian pharmacies, to find less costly medications. However, Internet pharmacies, even licensed ones in Canada, are increasingly buying from foreign sources themselves to meet American demand³⁸ and thus import of counterfeit and substandard medications may be enhanced. Finally, certain antimicrobials such as artemisin derivatives are not only confined to Asia and Africa but also to other countries of the industrialized world as they have a natural plant origin and tourists commonly buy them in the tropics as a standby treatment and they are also readily available on the Internet.³⁹

Prevalence of counterfeit and substandard antimicrobials

The magnitude of the drug-counterfeiting problem is considerable and is difficult to gauge as any true estimate of prevalence is difficult. The WHO estimates that up to 10% of the world's pharmaceutical trade—25% in developing countries—consists of fakes,^18,40 whereas up to 25% of all drugs consumed in poor countries are thought to be counterfeit or substandard, according to the figures from the US Food and Drug Administration (FDA).⁴¹ Many studies have tried to provide estimates of prevalence of counterfeit/substandard antimicrobials [Table S1, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)].

A search of the medical literature yields a limited number of primary published research reports concerning counterfeit drugs and much of the information is only found in the grey literature and newspapers. Few published studies describing the prevalence of counterfeit anti-infectives provided sufficient methodological details to interpret the results^{6,7,11,12,14,36,42–59} and to control for potential bias or other factors such as instability of some medicines,⁴² whereas only in very few studies, there was random sampling with adequate description of methods.⁷ In the current review, we analyse the major studies that have been published regarding counterfeit/substandard antimicrobials (Tables 1 and 2) and also describe the separate categories of these antimicrobials, which include antibiotics, antiviral and antiparasitic agents and vaccines.

Table 1

Major studies regarding counterfeit/substandard antibiotics

Year (reference)	No. of drugs analysed	Country	Category of drugs studied	Method of detection of counterfeit/substandard drug	Results	Characteristics of counterfeit/substandard drugs	Pharmaceutical companies involved/country of manufacture
Hu et al.159	NR	China	macrolides: erythromycin, clarithromycin, roxithromycin, azithromycin, erythromycin ethylsuccinate, kitasamycin, luecomycin A3, acetylspiramycin, acetyl-kitasamycin, midecamycin and meleumycin	FCIS consisting of two colour reactions based on functional groups in molecules of macrolide antibiotics and two TLC methods were developed for screening of fake macrolide drugs	two lots of capsules and one lot of granule had no active ingredients imitating erythromycin ethylsuccinate capsule and azithromycin granule, respectively, one lot of erythromycin tablets imitating roxithromycin tablets and two lots of meleumycin capsule imitating midecamycin capsule	no active ingredient, wrong ingredient, no colour change in sulphuric acid reaction	China
Kayumba et al.32	33	Rwanda and Tanzania	essential antimicrobials (amoxicillin capsules, metronidazole tablets, TMP–SMX tablet)	commercially available drug formulations, USP 24 dissolution tests, HPLC	at the time of purchase, the drug content of all the formulations was within the limits recommended by the USP 24, but after 6-month storage, the drug content of one sulfamethoxazole/trimethoprim was found to be substandard. Immediately after purchase, four formulations (three sulfamethoxazole/trimethoprim and one sulfadoxine/pyrimethamine combination) failed the USP 24 dissolution test. Except for three metronidazole, dissolution tests performed after 6 months of storage under simulated tropical conditions showed that drug release remained within the USP 24 recommended values. In total, 24% of the sampled formulations (8/33) failed the dissolution test	poor in vitro drug release profiles and dissolution [four formulations (three sulfamethoxazole/trimethoprim and one sulfadoxine/pyrimethamine combination)]. Some of the formulations tested were not stable in terms of drug content (one sulfamethoxazole/trimethoprim) and dissolution (three metronidazole formulations), upon storage under simulated tropical conditions	TPI (metronidazole), Holden Medica (metronidazole), Labophar (TMP–SMX, sulfadoxine and pyrimethamine), Shalina (sulfamethoxazole), ACE (TMP–SMX). Rwanda and Tanzania
Syhakhang et al.42	300	Laos	ampicillin, tetracycline	HPLC, potentiometric titration and ultraviolet spectrophotometry (UV). The identity was confirmed by TLC, UV or colour reactions	the percentage of substandard drugs decreased significantly from 46% to 22% (66 out of 300) between 1997 and 1999 (P < 0.001). Substandard ampicillin and tetracycline were reduced significantly from 67% to 9% and from 38% to 12%, respectively (P < 0.001). In total, 3% versus 1% contained no active ingredient, 12% versus 4% had too little or too much active ingredient and 35% versus 14% had weight variation outside pharmacopoeial limits	no active ingredient (ampicillin and tetracycline), too little (ampicillin) or too much (tetracycline) active ingredient, weight variation outside pharmacopoeial limits	24% (23 out of 97) of the drugs from Lao factories, 17% (24 out of 143) of the drugs from Thailand and 47% (17 out of 36) of the drugs of unknown origin were substandard
Prazuck et al.36	21	Northern Myanmar	antimicrobials (benzathine benzylpenicillin, ceftriaxone, chlortetracycline, ciprofloxacin, TMP–SMX doxycycline and erythromycin)	drug quantitative analysis was performed with titrimetry and visible UV spectrophotometry. Qualitative analysis was performed with TLC	among the 21 different specialty products, only 3 displayed the official ‘registered’ label. Three drugs were expired and the expiration date was not available for six others. One product did not contain the active drug declared (chlortetracycline) and did not show any in vitro activity against bacteria. Seven of 21 products (33%) did not contain the stated dosage (one more than stated dosage and six less than stated dosage). The highest deficit observed was 48% in two products (co-trimoxazole and benzylpenicillin). The dosage was not available for five drugs. As a result, only 8 of 21 products (38%) did not contain the stated dosage of active drug	inappropriate labelling, expired drug, no active ingredient (chlortetracycline), reduced active ingredient	Lombisin, Unicorn, China (chlortetracycline), Yong Fong, Myanmar (co-trimoxazole), China (benzylpenicillin), Helm Pharmaceutical GMBH, Hamburg, Germany (benzathine benzylpenicillin), Cadila Lab, Ahmedabad, India, Dr Reddy's Lab, Bollaram, India (ciprofloxacin), Remedica Ltd, Limassol, Cyprus (erythromycin and doxycycline), ICPA Lab Ltd, Bombay, India (TMP–SMX)
Taylor et al.12	581	Nigeria	antibacterial and antituberculosis drugs	HPLC	for all groups of drugs, antibacterial and antituberculosis agents, more than 50% failed to comply with specifications. For some individual drug preparations, all samples assayed were within pharmacopoeial limits. These included trimethoprim and sulfamethoxazole tablets. No metronidazole suspension met pharmacopoeial specifications. Several antibacterial preparations contained very low quantities of active ingredient (ampicillin and amoxicillin 24% to 40%), and for five metronidazole suspension preparations, no active ingredient was detected	zero (metronidazole suspension), or very low [ampicillin (syrup and capsules), amoxicillin (syrup), pyrimethamine and sulfadoxine (syrup), cloxacillin (syrup and capsules) and ampicillin and cloxacillin (syrup and capsules)] quantities of active ingredient	most drugs that failed to pass the test were manufactured in countries such as Malaysia, Switzerland, China, Holland, Nigeria, Pakistan, Romania, India, and UK or were of unknown origin
Okeke and Lamikanra160	5	Nigeria	five samples of ampicillin capsules		three of the five (60%) capsule samples from dispensing points were found to be of lower quality than the officially prescribed standards of pharmaceutical quality. The quality lapses observed were sufficient to bring about determinable differences in biological availability
Laserson et al.65	71	Colombia, Estonia, India, Latvia, Russia and Vietnam	INH and RIF single and FDC formulations	TLC kit	overall, 10% (4/40) of all samples, including 13% (4/30) RIF samples, contained < 85% of stated content. More FDCs (5/24, 21%) than single-drug samples (2/16, 13%) were substandard. Two RIF samples and one INH sample had an extra component	reduced content of active ingredient, extra component	NR
Kenyon et al.156	13	Republic of Botswana	FDC anti-tuberculosis (TB) drugs	TLC as a screening method, and UV or LC as confirmation	all 13 FDCs contained the stated drugs. However, four (31%) were substandard, including two (15%) with low rifampicin content, one (8%) with excessive rifampicin and one (8%) with excessive pyrazinamide. Both FDCs with low rifampicin contained four drugs and failed TLC screening. The FDC with excessive rifampicin was not detected by TLC screening. Using UV as the gold standard, the sensitivity of TLC for low rifampicin was 2/2 (100%) and the specificity was 9/10 (90%)	reduced (rifampicin) or excess (rifampicin and pyrazinamide) content of active ingredient	NR
Pillai et al.161	10 FDC formulations	South Africa	FDC anti-tuberculosis formulations	NR	Cmax for rifampicin in 7 of 10 FDC formulations was not found to be bioequivalent to the reference administered as loose (separate) formulations	the poor relative bioavailability of rifampicin from some FDCs has been documented. The implications for tuberculosis programmes are extremely serious and warrant urgent attention	NR
Stenson et al.48	366	Laos	ampicillin (tablets and capsules) and tetracycline (tablets and capsules)	three tests were used: identity, assay and measurement of weight variation. The identity was confirmed by TLC, UV and colour reactions. Titrimetric, UV and HPLC methods were used for assay. Potentiometric titration method	12 (3.3%) out of the 366 drugs contained no active ingredient, 42 (11.5%) had levels of active ingredient outside acceptable limits in assay, 128 (35.0%) had excessive weight variation and 4 (1.1%) were managed badly in the pharmacy, 67% of ampicillin samples and 38% of tetracycline had bad quality	no active ingredient (ampicillin), low concentration of active ingredient (ampicillin and tetracycline), weight variation outside pharmacopoieal limits (all), bad retail management (ampicillin)	out of the 61 samples that were found to contain no active ingredient or to be substandard according to the assay, only 37 were labelled. Of these, 20 originated from Laos, 5 from Thailand and 3 from Vietnam, whereas 9 were of unknown origin
Nazerali and Hogerzeil83	789 samples of 26 brands of 13 essential drugs	Zimbabwe	injectable benzylpenicillin, amoxicillin, ampicillin, doxycycline, phenylmethoxypenicillin and tetracycline	NR. Drug quality was measured by level of active ingredient as percentage of stated content and by compliance (pass/fail) with assay standards of the BP. Drug stability was measured by comparing mean assay values at central and rural levels and by paired analysis of central and rural samples of the same batch	poor initial quality accounted for problems in injectable ampicillin (2/10 central samples failed, with 87% and 91% content). An aqueous formulation of injectable procaine benzylpenicillin showed moderate instability with 4% (1% to 6%) loss after 4.3 months but the assay remained within pharmacopoeial limits	reduced level of active ingredient	NR
Shakoor et al.7	96 (81 Nigeria, 15 Thailand)	Nigeria, Thailand	amoxicillin, tetracycline, TMP–SMX, ampicillin–cloxacillin	HPLC	36% of samples from Nigeria and 40% of samples from Thailand were substandard with respect to British Pharmacopoeial limits. One amoxicillin sample from Nigeria contained no active ingredient at all	zero (amoxicillin) or very low (amoxicillin, TMP–SMX, ampicillin–cloxacillin) quantities of active ingredient	the countries of origin were Nigeria, Italy, India, Pakistan, Thailand and UK, but no patterns emerged with respect to quality of product and country of origin
Roy10	137 brands	Bangladesh	ampicillin, TMP–SMX	NR	a significant proportion of a variety of drug preparations was substandard (27%). Ten brands of ampicillin were found to be substandard in this study and 8 of them had already been assessed as substandard by the regulatory authorities. This was also true of the two brands of co-trimoxazole suspension found to be substandard	it appeared that active ingredients had been deliberately kept below the required levels	NR
Taylor et al.111	40	Nigeria	antibacterial capsules and suspensions of amoxicillin		two amoxicillin capsules (0% and 50%) contained ≤ 50% of the stated amount of active ingredient. Ten other samples outside the BP range had at least 90% or up to 126%	the reason why BP requirements were not met is unknown. Decomposition is not likely to be a major factor (no large amounts of decomposition products found), poor quality assurance probably plays a part but the very small amounts found in some samples point to fraudulent manufacture or tampering
Santosh et al.162	7 brands	India	tetracycline: chemical estimation of seven different marketed brands of tetracycline/HCl capsules for tetracycline content	fluorimetric method	chemical estimation of seven different marketed brands of tetracycline/HCl capsules for tetracycline content showed that six brands were not meeting the pharmacopoeia prescribed standards. The power content of four brands was well below the labelled amount of the standard drug. Comparative analysis of bioavailability of substandard versus standard product indicates that the use of substandard tetracycline products in undernourished subjects may lead to therapeutic failures and/or result in the development of resistant microorganisms	the dissolution rate and disintegration time of substandard drugs were in accordance with USP specifications. The bioavailability of substandard product as determined from 48 h urinary tetracycline excretion was significantly lower when compared with standard product both in well-nourished and in undernourished subjects. The plasma steady-state concentrations with the substandard product were below the generally recommended MICs, more so in undernourished subjects	NR

NR, not reported; FCIS, fast chemical identification test; TLC, thin-layer chromatography; TMP–SMX, trimethoprim–sulfamethoxazole; USP, United States Pharmacopoeia; UV, ultraviolet spectrophotometry; INH, isoniazid; RIF, rifampicin; FDC, fixed-dose combination; LC, liquid chromatography and BP, British Pharmacopoeia.

Table 2

Categories and characteristics of reported counterfeit/substandard antibiotics

Category of antimicrobial	Countries where counterfeit/substandard drug was reported	Characteristics of counterfeit/substandard antimicrobials
		no active ingredient	reduced active ingredient	wrong active ingredient	inappropriate labelling	others
Penicillins
penicillin	Cambodia,80 Madagascar,46 Brazil,93 Northern Myanmar36	Madagascar,46 Brazil93	Brazil,93 Northern Myanmar36		Cambodia,80 Northern Myanmar36
ampicillin	Laos,42,48 Vietnam,163 India,164 Senegal,49 Sierra Leone,75 Bolivia,165 Lebanon,166 Indonesia,93 Nigeria,12 Zimbabwe,83 Bangladesh10	Laos,42,48 Senegal,49 Sierra Leone,75 Lebanon166	Bolivia,165 Laos,42,48 Indonesia,93 Nigeria,12 Zimbabwe,83 Bangladesh10	Vietnam,163 India164	Laos48	weight variation outside pharmacopoeial limits,42,48 bad retail management48
ampicillin–clavulanate/ampicillin–cloxacillin	Germany,81 China,167 Lebanon,166 Nigeria,12 Thailand7	China,167 Lebanon166	Nigeria,12 Thailand7
amoxicillin	China,167 Nepal,168 India,164 Thailand,7 Sierra Leone,75 Nigeria,7,12,111,169,170 Cameroon,46,169 Guinea91	Nepal,168 Sierra Leone,75 Cameroon,46 Nigeria,7 Thailand7	Nigeria,12,111,169 Thailand7		Guinea91
amoxicillin–clavulanate/amoxicillin–cloxacillin	Philippines,168 India77,171
cloxacillin	Nigeria12		Nigeria12
Cephalosporins
cefador	USA81
cefalexin	China,172 Sierra Leone,75 Brazil81	China172
cefazolin	Ukraine,76 Russia81	Ukraine76		Ukraine,76 Russia81
cefradine	USA29	USA79
ceftazidime	Vietnam,173 Phillipines,168,171 India,171 Mexico,174 Russia175	Vietnam,173 Russia175		Vietnam173 (streptomycin)
cefuroxime axetil	China,176 India164			China176 (cefuroxime sodium)
cefotaxime	Russia168			Russia168
Macrolides
erythromycin	India,159,171 Nigeria,169 China,159 Northern Myanmar36	China159	Northern Myanmar36
azithromycin	China,159 Russia,119 Ukraine,76 other165	China,159 Russia,119 Ukraine76
roxithromycin	India,159,171 China,159 Russia,76 Germany76		China,159 contained erythromycin
Chloramphenicol	Burma,6 Cambodia,80 India,77 Nigeria,169 Cameroon46	Nigeria,169 Cameroon46			Burma6 Cambodia80
Tetracyclines	Burma,6,36 Laos,42 Cambodia,54,57,80 India,77,171 Sierra Leone,75 Nigeria,169 Brazil,93 USA,155 Northern Myanmar36	Burma,6,36 Laos,42 Cambodia,54,57,80 Brazil,93 Northern Myanmar36	Brazil,93 Laos,42 Northern Myanmar36		Burma,6,36 Cambodia,54,57,80 Nigeria,170 Northern Myanmar36	unregistered product,59 26.6% of tetracycline tablets failed disintegration tests,59 too much active ingredient,42 weight variation outside pharmacopoeial limits,42 expired drug,36 reduced bioavailability and excessive degradation34,162
Sulphonamides co-trimoxazole	Thailand,177 Burma,6 Cambodia,47 Nigeria,169 Sierra Leone,75 Nigeria,170 Cameroon,46 Cote d'Ivoire,58 Rwanda and Tanzania,32 Nigeria, Thailand,7 Bangladesh,10 Russia178	Cambodia,47 Cameroon,46 Thailand,177,178 Russia178	Cote d'Ivoire,58 after 6-month storage, the drug content of one sulfamethoxazole/trimethoprim was found to be substandard,32 Nigeria, Thailand,7 Bangladesh10	Burma6	Cote d'Ivoire58	poor in vitro drug release profiles and dissolution for three formulations of sulfamethoxazole/trimethoprim32
sulfamethizole sulfamethazine155	Australia,92 Nigeria,170 sulfamethazine155	sulfamethazine155	Australia92	Australia,92 Nigeria170
trimethoprim	Ukraine175
Quinolones
ciprofloxacin	India,77,164,171,179 Nigeria,170 Germany,81 Haiti.92 Ciprofloxacin is a frequently faked drug often sold via the Internet,38 Northern Myanmar36	38		Northern Myanmar36	Northern Myanmar36	substandard drug induced bouts of diverticulitis,92 inappropriate expiration date36
ofloxacin	China,180 Pakistan,52 Germany81			China180
nalidixic acid	India171
Metronidazole	Cambodia,47 Nigeria,169 Nigeria,12 Cameroon,46 Rwanda and Tanzania,32 Kenya181	Cambodia,47 Cameroon,46 Nigeria12		Nigeria170		some of the formulations tested were not stable in terms of dissolution upon storage under simulated tropical conditions32
Aminoglycosides
gentamicin	Nigeria,169 Republic of Mauritius,99 USA,163 Europe,81 counterfeit gentamicin sulphate within the USA29,139,155	USA29,139,155,	USA29,139			investigation showed gentamicin eye drops to be contaminated—Pseudomonas aeruginosa and other virulent bacteria were cultured from these vials99
neomycin	Nigeria,169 Europe81				Nigeria,75 Europe81
amikacin	Cote d'Ivoire,58 India165				Cote d'Ivoire58
Lincosamides
clindamycin/lincomycin	Germany,81 China,159 Sierra Leone,75 Mexico29,79		Mexico drug diluted with contaminated water29,79

Categories of poor quality antimicrobials

There have been reports of substandard/counterfeit drugs in almost all categories of antimicrobials including antibiotics and drugs used to treat tuberculosis, malaria and HIV/AIDS. In the developing world, antibiotics and antiparasitic agents, the drugs that are most needed there, are the counterfeiters' favourites. Other pharmacotherapeutic groups were represented in almost equal frequencies.⁶⁰ There are 8–10 times more reports for counterfeit antibiotics and 2–3 times more reports for antiparasitic drugs in comparison with other counterfeit drugs.⁶⁰

Antibacterial agents

A wide range of antibacterial agents have been found to be substandard or fake (Tables 1 and 2). Although no part of the world is exempted, southeast Asia and Africa seem to be particularly plagued by counterfeited antibacterial agents. Especially ‘old’ antibiotics, such as penicillin, tetracycline, trimethoprim–sulfamethoxazole and chloramphenicol, are among the favoured counterfeited antimicrobials.⁶

Antituberculosis (anti-TB) drugs

A substantial number of anti-TB drugs from several countries, particularly fixed-dose combinations, were found to be substandard [Table S2, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. In contrast, some other studies have shown good quality of anti-TB drugs.^61–63

In contrast to other medications, anti-TB drugs are stable under storage conditions, so substandard levels are usually not caused by instability.^61,64 Specific, robust and simple colorimetric methods such as thin-layer chromatography (TLC) can be used for the detection of substandard TB medications, especially in many Third World countries with relatively modest laboratory facilities⁶³ where resources such as HPLC are not available or routine use is impractical.⁶⁵ These substandard anti-TB medications can lead to emergence of drug resistance. Patients receiving a lower therapeutic dose than would be required for their treatment due to a substandard anti-TB drug could lead to drug resistance and treatment failure, despite 100% adherence to the treatment regimen by patients.^65,66

Antiviral agents

Counterfeit antiviral agents such as oseltamivir and interferon and antiretroviral agents have been reported [Table S3, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. Most of these reports, however, are anecdotal. More specifically, the recent report of substandard/counterfeit antiretroviral agents either alone or in combinations is very alarming [Table S3, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. On the other hand, in one study, drug content among generic antiretroviral preparations containing the non-nucleoside reverse transcriptase inhibitor nevirapine has been studied, and no substandard preparations were identified.⁵¹ Importantly, the recent discovery of counterfeit antiretrovirals raises the prospect of a disastrous setback in the treatment of AIDS in areas such as sub-Saharan Africa, unless vigorous action is taken now.

Antiparasitic agents

Antimalarials

The quality of antimalarial drugs is especially crucial, given the widespread nature of the disease and its importance to global public health.⁶⁷ As more than 40% of the world's population is at risk of malaria, antimalarial drugs have become a favourite target of counterfeiters. In the last years, many articles reported examples of counterfeit and substandard antimalarial medicines in developing countries (Tables 3 and 4). In a WHO survey of seven African countries, 20% to 90% of antimalarial drugs failed quality testing.⁶⁸ Many studies have reported that a considerable proportion of antimalarial drugs obtained from east African countries is of poor quality^7,12,17,69 and that even counterfeits of new antimalarial drugs, such as artesunate and mefloquine, are circulating in southeast Asia.^14,70,71 Counterfeit artemisinins are a significant problem in southeast Asia^14,55,72 and are expected to become a serious problem in Africa where artemisinin combination therapy is being implemented.³⁹ The problem of antimalarial drug resistance as a result of counterfeit drugs has been addressed in recent reports.⁷³ Considering the importance of antimalarial treatment in the tropical developing countries, where malaria is endemic and is the first cause of death for children, the presence of counterfeit and substandard drugs on the pharmaceutical market is a risk to the life of millions of people.

Table 3

Major studies of substandard/counterfeit antimalarials

Year (reference)	No. of drugs analysed	Country	Category of drugs studied	Method of detection of counterfeit/substandard drug	Results	Characteristics of fake/substandard drugs	Pharmaceutical companies involved/country of manufacture
Gaudiano et al.82	NR	Congo, Burundi and Angola	antimalarials (chloroquine, quinine and mefloquine)	a reversed-phase liquid chromatographic method	only 88.6% of declared active substance (quinine tablets) was found. Moreover, a high quantity of impurities was observed with respect to the reference preparation, indicating some degradation probably due to the bad storage conditions	in the majority of the cases, samples were without both primary and secondary packaging and tablets were packaged in a little plastic bag or enveloped with paper and the expiry date and strength of the active substance were written on a piece of paper. All samples were within the period of validity on the basis of the declared expiry date. Only for some samples, the company name and the lot number were available	Congo, Burundi and Angola
Lon et al.59	451	Cambodia	antimalarials [quinine sulphate tablets, chloroquine phosphate tablets, artesunate tablets, mefloquine hydrochloride tablets, tetracycline tablets/capsules, dihydroartemisinin (DHA) tablets and artemether tablets]	Mini-lab kits, TLC and disintegration tests	79% of these were not registered at the Cambodia Department of Drugs and Food (DDF). Twenty-seven percent of the samples failed the TLC and disintegration tests, all of them were unregistered products. The TLC and disintegration test results showed that the average failure rate of quinine was 71.7%, artesunate 19.7% and tetracycline 26.6%, followed by chloroquine 8.5% and mefloquine 7.7%. In this study, only 22 samples of DHA and 2 samples of artemether passed the tests. The overall result showed that 122 (27.1%) samples failed TLC and/or disintegration tests	unknown origins, wrong or incomplete labelling hologram similar to the genuine one, they were in different containers from the original ones, wrong active pharmaceutical ingredients, no active pharmaceutical ingredients, unregistered products	197 (43.7%) were labelled as produced in Thailand, 102 (22.6%) in China, 19 (4.2%) in Cambodia, 17 (3.8%) in Switzerland and 48 (10.6%) were claimed to be produced in Germany, India, Australia, France, Vietnam, Hong Kong, Korea, The Netherlands, England, Belgium, Cyprus and Malaysia. The remaining 68 samples were of unknown origin. Brainy Pharmaceutical, Guillin Pharmaceutical Works in China
Hebron et al.182	11 brands of one drug	Tanzania	antimalarials (11 brands of SP combination tablets)	HPLC, physical methods	all the brands passed all the quality specifications of the USP and BP in terms of hardness, friability, disintegration, assay and dissolution test, except for three brands that failed the hardness, disintegration or friability tests. One brand failed the hardness and disintegration test, one failed the hardness test, whereas another failed the friability test. All brands passed the assay test for the content of SP.	three brands that failed the hardness, disintegration or friability tests. One brand failed the hardness and disintegration test, one failed the hardness test, whereas another failed the friability test.	three of the brands were locally manufactured in Tanzania, whereas the remaining eight were imported. Four were from India, two from Kenya and two from Europe, where one of these was the innovator brand, Fansidar®
Amin et al.90	116	Kenya	antimalarials (SP and AQ)	spectrophotometric assay (AQ), HPLC (SP), dissolution apparatus	of 116 SP and AQ samples analysed, 47 (40.5%) did not meet the USP specifications for content and/or dissolution. Overall, ∼45.3% of SP and 33.0% of AQ samples were found to be substandard. Of the substandard SP products, 55.2% were suspensions, whereas 61.1% of the substandard AQ products were tablets. Most SP failures were because of the pyrimethamine component	reduced content of active component, reduced dissolution	Kenya
Dondorp et al.55	188	Southeastern Asia Myanmar (Burma), Lao PDR, Vietnam, Cambodia and Thailand	antimalarials (artemisinin derivatives and mefloquine)	Fast Red TR dye technique, HPLC, based on packaging characteristics	of the 188 tablet packs purchased that were labelled as ‘artesunate’, 53% did not contain any artesunate. Of the 44 mefloquine samples, 9% contained < 10% of the expected amount of active ingredient	fake hologram (artemisinin), the visual characteristics (mefloquine) of the fake tablets were undistinguishable from the genuine product	Guilin Pharma, Mepha Ltd, Aesch-Basel, Switzerland (mefloquine)
Basco53	284	Cameroon	antimalarials (chloroquine, quinine and SP)	a simple colour reaction test and semi-quantitative TLC	fifty (38%) of 133 chloroquine, 52 (74%) of 70 quinine and 10 (12%) of 81 antifolates had no active ingredient, an insufficient active ingredient, the wrong ingredient or unknown ingredient(s). The primary screening based on colour reaction showed that 42 (32%) of 133 chloroquine samples were counterfeit. Further analysis by TLC showed that 8 (9%) of 91 colour-positive samples contained < 80% of the reference standard. The colour reaction suggested that 63 (90%) of 70 quinine samples contained a quinoline-type drug, the other 7 samples were clearly counterfeit with unknown ingredients. However, on further analysis, 45 of 63 colour-positive quinine samples were substandard. Of 78 SP samples, 10 (13%) had a negative colour reaction. There were no substandard medications of SP samples on further analysis of positive colour reaction	no active ingredient, an insufficient active ingredient, the wrong ingredient or unknown ingredient(s)	could not be specified with precision—unknown origin in majority of cases
Kayumba et al.32	33	Rwanda and Tanzania	antimalarials (quinine tablets and SP tablets), antimicrobials (amoxicillin capsules, metronidazole tablets, sulfamethoxazole/trimethoprim tablet)	commercially available drug formulations, USP 24 dissolution tests, HPLC	at the time of purchase, the drug content of all the formulations was within the limits recommended by the USP 24, but after 6-month storage, the drug contents of one TMP–SMX and one quinine formulation were found to be substandard. Immediately after purchase, four formulations (three TMP–SMX and one SP combination) failed the USP 24 dissolution test. Except for three metronidazole and one quinine formulations, dissolution tests performed after 6 months of storage under simulated tropical conditions showed that drug release remained within the USP 24 recommended values. In total, 24% of the sampled formulations (8/33) failed the dissolution test	poor in vitro drug release profiles and dissolution [four formulations (three TMP–SMX and one SP combination)]. Some of the formulations tested were not stable in terms of drug content (one TMP–SMX and one quinine formulation) and dissolution (three metronidazole and one quinine formulations), upon storage under simulated tropical conditions	TPI (metronidazole), Holden Medica (metronidazole), Labophar (TMP–SMX, quinine sulphate, SP), Shalina (sulfamethoxazole), ACE (TMP–SMX), Elys Chemicals (quinine sulphate). Rwanda and Tanzania
Syhakhang et al.42	300	Laos	antimalarials (chloroquine)	HPLC, potentiometric titration and UV. The identity was confirmed by TLC, UV or colour reactions	of the 34 substandard chloroquine samples, 16 were manufactured as sugar-coated tablets by Lao factories and had tablet weight outside standard. Eight out of 35 chloroquine samples (tablets) from Thailand also had weight variation outside standard. Among these, one with high tablet weight had also very high content of active ingredient. One chloroquine from France contained too high a level of active ingredient	too much active ingredient (tetracycline chloroquine), weight variation outside pharmacopoeial limits	24% (23 out of 97) of the drugs from Lao factories, 17% (24 out of 143) of the drugs from Thailand and 47% (17 out of 36) of the drugs of unknown origin were substandard
Minzi et al.183	33	Tanzania	antimalarials (SP and AQ tablets)	TLC and HPLC	all samples passed the identity test. 12 of 33 (36%) samples were of poor quality. In total, 10 of 33 (30%) samples, i.e. eight of 33 SP and two of 33 AQ, did not meet the USP specifications for dissolution. Among the AQ samples collected, 2 of 15 (13%) failed the dissolution test but all passed the assay for content, whereas 2 of 18 (11%) and 8 of 18 (44%) SP samples failed the assay for content and dissolution tests, respectively	the major reason for a drug being substandard was because of low dissolution rate of the active ingredients, whereas two samples had low content of active ingredient	SP samples of poor quality originated from Cyprus, Tanzania, India and AQ samples of poor quality originated from Kenya
Rimoy et al.88	2	Tanzania	antimalarials-sugar-coated (Dawaquin) and a plain formulation (Shellyquine) of chloroquine phosphate	HPLC	Shellyquine was significantly more bioavailable than Dawaquin (P < 0.001). Although the Cpmax for Dawaquin was higher than the required therapeutic level for sensitive Plasmodium falciparum, its blood levels may not guarantee a rapid clearance of parasites	reduced bioavailability of sugar-coated chloroquine phosphate	NR
Risha et al.84	22	Tanzania	antimalarials (SP, chloroquine)	HPLC, accelerated stability test	all formulations passed the pharmacopoeia requirements for the drug content. However, seven formulations (three acetylsalicylic acid, two SP and two paracetamol) failed to meet the USP 24 tolerance limits for dissolution. Another five formulations (three paracetamol and two chloroquine) failed to meet the dissolution tolerance limits after being subjected to an accelerated stability test under simulated tropical conditions for 6 months	reduced dissolution. Reduced stability to storage in tropical conditions for 6 months: chloroquine formulations that failed the stability test had a more than 40% reduction in the amount of drug released after 3 and 6 months of stability testing	Shelys, Flamingo (SP), Ellys (pyrimethamine), Rhône Poulenc Rorer, TPI (chloroquine tablets)
Newton et al.14	104	Southeastern Asia Cambodia, Laos, Myanmar (Burma), Thailand and Vietnam	antimalarials (artesunate)	Fast Red TR dye technique. Classification of samples based on physical characteristics including holograms, bar codes, printing and crimping (the impression of text into foil), packages by independent observer	of 104 shop-bought ‘artesunate’ samples from these countries, 39 (38%) did not contain artesunate and were counterfeit. Overall, 30 (29%) of the blisterpacks collected contained no artesunate. The results of examining the packaging of 84 samples gave complete agreement with the dye test. The authors suggest that in some tablets, artesunate may have been substituted with chloroquine based on the bitter taste of the tablets	superficially similar in colour, size and inscription, heavier than the genuine tablets, had disagreeable bitter taste, cheaper than their genuine counterparts, forged or no holograms on fake artesunate blisterpacks	Guilin Pharma (China) or repackaged by Atlantic Pharmaceuticals (Bangkok, Thailand)
Sulaiman et al.184	34	Sudan	antiparasitic agents (praziquantel)	NR	15 of the 19 brands were of satisfactory quality for all variables assessed (content of active substance, impurities, disintegration and dissolution). Three brands did not meet the standards of BP, USP or both, for impurities and formulation characteristics, but these issues were of limited magnitude and possibly not critical for safety and efficacy of the drug. One brand, however, was counterfeit and contained no active substance	reduced gross mean weight of each tablet, the accompanying leaflet was in poor English and did not identify the name or address of the manufacturer, no active substance	International Ltd Co., Canada
Taylor et al.12	581	Nigeria	antimalarials, anthelmintics (mebendazole)	HPLC	48% of the samples contained amounts of active ingredient outside the appropriate limits. For all groups of drugs, more than 50% failed to comply with specifications. For some individual drug preparations, all samples assayed were within pharmacopoeial limits. These included proguanil tablets, and quinine hydrochloride injection and syrups. No pyrazinamide tablets met pharmacopoeial specifications	zero (pyrazinamide tablets) or very low (pyrimethamine and sulfadoxine syrup) quantities of active ingredient	most drugs that failed to pass the test were manufactured in countries such as Malaysia, Switzerland, China, Holland, Nigeria, Pakistan, Romania, India and UK or were of unknown origin
Rozendaal71	NR	Cambodia	antimalarials (mefloquine, artesunate)	NR	most of the bottles with mefloquine tablets and about half of the artesunate blister packs sampled seemed to be fakes. For mefloquine and artesunate, two different varieties of fakes were found: a first-generation fake that was easy to distinguish from the genuine product and a second-generation fake that much more closely resembled the genuine product. A total of 242 drug vendors and pharmacies were mapped in 12 marketplaces, and 133, about half in each marketplace, were selected randomly for investigation. Fake artesunate was sold by 71% (86% sold the genuine product) and fake mefloquine by 60% (61% sold the genuine variety)	the fakes were frequently preferred by patients and village health providers because of the lower price. Given their widespread use, the fake malaria drugs are probably a major cause of mortality and morbidity due to malaria in Cambodia	mefloquine in Australia and artesunate in China
Ogwal-Okeng et al.69	53 tablets and 49 injectable forms	Uganda	antimalarials (chloroquine)	pharmacopoeial assays, visual and potentiometric analysis technique	up to 30% of the tablet samples and 33% of injection samples contained less than the stated amount of the active ingredient. 25% of tablet samples and 29% of the injection samples contained more than the standard concentration of active ingredient	reduced level of active ingredient, excess level of active ingredient	the majority of samples were manufactured in India (52%) and Kenya (18%). Other countries of origin were Uganda, China, Cuba and Pakistan
Stenson et al.48	366	Laos	antimalarials (chloroquine tablets)	three tests were used: identity, assay and measurement of weight variation. The identity was confirmed by TLC, UV and colour reactions. Titrimetric, UV and HPLC methods were used for assay	49% of chloroquine samples had bad quality	no active ingredient, low concentration of active ingredient, above indicated concentration of active ingredient, weight variation outside pharmacopoieal limits	most of the samples that were found to contain no active ingredient or to be substandard according to the assay were unlabelled. Those that were labelled originated from Laos, Thailand and Vietnam or were of unknown origin
van Wyk et al.185	3 brands	South Africa	anthelmintics (three rafoxanide products)	the drugs were tested against a known susceptible strain of Haemonchus contortus in sheep	one of the three commercial formulations (of highly reputable companies) was markedly substandard, with an arithmetic mean efficacy of 66.2% when compared with the efficacy of the other two, which also differed significantly from one another (Mann–Whitney, P = 0.01)	reduced efficacy, sources of supply of different batches of active ingredient (with the result that the companies buying anthelmintics from them have no way of telling when a source of supply is changed)	South Africa
Shakoor et al.7	96 (81 Nigeria, 15 Thailand)	Nigeria, Thailand	antimalarials (chloroquine)	HPLC	36% of samples from Nigeria and 40% of samples from Thailand were substandard with respect to BP limits. Five substandard preparations (two chloroquine samples from Nigeria and three chloroquine samples from Thailand) contained no active ingredient at all	zero (chloroquine) or very low (chloroquine) quantities of active ingredient	the countries of origin were Nigeria, Italy, India, Pakistan, Thailand, UK, but no patterns emerged with respect to quality of product and country of origin
Abdi et al.17	NR	Tanzania	antimalarials (chloroquine tablets of nine different brands)	NR	tablets were tested for active ingredients and for dissolution rate. All brands complied with the USP requirements for amount of chloroquine (>97%). The eight brands of ordinary tablets also passed the dissolution test, the sugar-coated tablets did not (only 39% dissolved in 45 min, required minimum 75%)	the sugar-coated tablets of chloroquine did not have appropriate dissolution rate. Dissolution is an important determinant of bioavailability and may have resulted in this reported chloroquine treatment failure in a patient with malaria	Tanzania
Petralanda157	12 samples (9 different manufacturers)	Amazonian region	antimalarials (primaquine)	NR	50% of the samples did not conform to the USP qualitative requirements and none conformed to the quantitative requirements. One of three samples analysed by the BP qualitative criteria did not conform to those either. Chemical concentration of the active ingredient varied from 19% to 168% of the concentration indicated on the label, which made the total dose of primaquine received by the patients either insufficient or excess (toxic levels)	insufficient or excess chemical concentration of the active ingredient, reduced quality	NR
Taylor et al.111	40	Nigeria	antimalarials (tablets and syrup formulations of chloroquine)		three samples of chloroquine tablets (0%, 0%, 42%) contained ≤ 50 % of the stated amount of active ingredient	the reason why BP requirements were not met is unknown. Decomposition is not likely to be a major factor (no large amounts of decomposition products found), poor quality assurance probably plays a part but the very small amounts found in some samples point to fraudulent manufacture or tampering	NR

NR, not reported; TLC, thin-layer chromatography; USP, United States Pharmacopoeia; BP, British Pharmacopoeia; SP, sulfadoxine–pyrimethamine; AQ, amodiaquine; UV, ultraviolet spectrophotometry.

Table 4

Categories and characteristics of counterfeit/substandard antimalarials

Category of antimicrobial	Countries where counterfeit/substandard drug was reported	Characteristics of counterfeit/substandard antimicrobials
		no active ingredient	reduced active ingredient	wrong active ingredient	inappropriate labelling/packaging	others
Chloroquine	Africa in Cameroon,53 Cote d'Ivoire,58 Guinea,46 Sierrra Leone,75 Sudan,17 Nigeria,7 Uganda69 and Tanzania84	7,17,46,48,53,59,91,111	7	46,53	59	very high concentration of active ingredient,48,58 poor dissolution due to storage,84 reduced bioavailability,17 weight variation outside the standard, especially in sugar-coated brands of chloroquine1
Primaquine	Amazon region of South America,157 Namibia186		157			excess active ingredient,157 different morphology of fake primaquine tablets186
Mefloquine	Southeastern Asia in Cambodia54,55,59,71 and in Burma,54,55 Thailand,55 Laos55 and Senegal92	59,71,187	59	54,59	59	low dissolution rate59
Sulfadoxine–pyrimethamine (SP)	Nigeria,26,188 Cameroon,46,53 Sierra Leone,75 Zambia,189 Cotè d'Ivoire,58 Nigeria,12,188 Tanzania,32,84,182 Rwanda,32 Kenya90	46	53	53	58	failed dissolution testing.182 In most reports, pyrimethamine accounts for a disproportionate number of dissolution and content failures50,89,90
Quinine sulphate	Southeastern Asia in Cambodia,47,54,56,57,59 in Vietnam,56 in Africa in Cameroon,46,53 Congo, Burundi and Angola,82 Rwanda and Tanzania,32 Nigeria190 and in USA191	54,190	82	59	82	high quantity of impurities,82 poor dissolution32
Artemisin (ART) derivatives artesunate	Southeastern Asia70 and more specifically in Burma,14,55 Burma/Thailand,14,39,55 Thailand,56 Cambodia,14,54–57,59,71,72,192 Vietnam,14,55,56 Laos,14,55,56,72 China56 and Africa in Cameroon39	14,45,55,56,72	39	39	39
artemether	Cambodia193	39,193,194	59	59	59	failed disintegration tests59 have altered physicochemical characteristics193
dihydroartemisinin	Cameroon39,194	39,193,194
Halofantrine	Nigeria, Ghana, Sierra Leone,104,118,195,196 and from WHO197	118,195		104

Other antiparasitic drugs

Except for antimalarial drugs, there are reports for substandard anthelmintics and other antiparasitic agents such as pentavalent antimonials [Table S4, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)], which contribute to poor compliance, therapeutic failure and the appearance of resistance in parasites.⁷⁴

Other antimicrobial agents

Substandard/counterfeit antifungal agents such as griseofulvin and nystatin have been reported in Sierra Leone⁷⁵ and Ukraine,⁷⁶ respectively. In addition, there have been reports about substandard antiseptics such as betadine.⁷⁷ Finally, substandard/counterfeit vaccines have been reported [Table S4, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)] and according to a study, only 3 of 10 vaccine-producing countries in the Asia-Pacific region were assessed to have internationally acceptable standards for vaccine production and quality control and effective regulatory mechanisms.⁷⁸

Characteristics of substandard/counterfeit drugs

Counterfeit drug products come in many variations. Some do not contain any of the active (pharmaceutical) ingredients (AI) or include the ingredient in harmful amounts. Other preparations come from an unacceptable source or are differently formulated, may contain unacceptably high levels of impurities or impurities such as mould or packaging that falsifies the product's true expiration date, whereas others contain a completely different active ingredient.

Inappropriate packaging

Fake pharmaceuticals often have the same appearance as the brand name and generic drugs they mimic. They are generally indistinguishable in their outward packaging, and pill colour, shape, size and markings; they even have electronic bar codes, which pharmacists scan to verify drug authenticity.⁷⁹ In developing countries, many of the purchased drugs without packaging were counterfeit.⁵³ Examples of antimicrobials with false packaging and labelling include antibiotics such as penicillin,⁴⁸ chloramphenicol,⁶ tetracyclines,^{6,36,54,57,80} co-trimoxazole,⁵⁸ quinolones³⁶ and aminoglycosides^75,81 and antimalarials such as chloroquine,⁵³ mefloquine,⁵⁹ quinine⁸² and artesunate.^14,44,61,70

Reduced stability and bioavailability

Several studies that have reported on the stability of essential drugs under real storage conditions in the tropics^27,33,83,84 in warehouses and in some wholesale pharmacies may not be satisfactory for ensuring the integrity of drug products.^85–87 Antibiotics in particular, e.g. ampicillin,⁸⁸ may degrade during transportation or storage at temperatures above 25°C and high humidity.³³ Other drugs, however, may be stable under such conditions⁸³ and there are studies that have shown that high storage temperatures do not affect adversely the content of many antibiotics including penicillins and tetracyclines^12,83 and this may suggest that the most likely cause of low quality is to be found during manufacturing.⁴⁸

Moreover, interactions may occur when products are stored at high temperature and humidity, consequently reducing the dissolution rate.⁸⁵ Although many substandard antimicrobials may contain the appropriate amount of active ingredient, they can have suboptimal activity and this may be due to reduced bioavailability. Examples include tetracyclines,³⁴ co-trimoxazole,³² metronidazole,³² pyrimethamine,^50,89,90 chloroquine⁹¹ and mefloquine.⁵⁹

Reduced concentration of active ingredient

Low concentration of active ingredient in antimicrobials may be the result of poor manufacturing or could be the effect of poor transport and storage conditions and often it is not possible to distinguish between these two causes (Tables 2 and 4). Decomposition was the cause of poor quality in a number of samples,^7,88 but as it has been shown that many antibiotics may be stable even under tropical conditions,⁸³ overall poor manufacturing appeared to be the prevalent cause of low quality.^7,48 However, the effect of storage conditions on drug quality has not been assessed in all studies.⁴² Finally, reduced concentration of active ingredient could also be the result of dilution of drugs with other substances such as contaminated water^29,79 or sugar.⁹²

Altered chemical content

Additionally, counterfeit drugs may be characterized by altered odour because they contain diluted active ingredients, or in many cases harmful additives. Sometimes, the counterfeit drugs are chemically identical to the real product, making them counterfeit generics; however, most fakes contain inactive or harmful ingredients. The capsules or tablets may contain, for example, a wrong antibiotic such as erythromycin,³⁹ or they may contain only worthless flour, starch or powder.^29,39,93,94 Notorious recent real examples include neomycin eye drops and meningococcal vaccine made of tap water, ampicillin consisting of turmeric and antimalarials and antibiotics containing no active ingredients.^14,26,71,95

Methods for the detection of counterfeit/substandard antimicrobials

Several methods have been used for the detection of substandard medications including inspection, dissolution assays, colorimetric methods and chromatography techniques such as HPLC, TLC, Mini-lab and mass spectrometry [Table S5, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. Visual control, dissociating tests or simple colour reaction tests reveal only very rough forgeries. Fast, easy, reliable and non-expensive methods of drug screening are essential, especially in developing countries in the setting of lack of systematic control of the pharmaceutical market and the absence of specific regulations. Finally, new technologies such as near infrared spectroscopy⁹⁶ and X-ray powder diffraction method⁹⁷ have been increasingly used for the detection of counterfeit antimicrobials.

Consequences of counterfeit and substandard anti-infectives

The use of low-quality drugs can result in adverse clinical outcomes such as lack of effect and treatment failure, risk of development of bacterial resistance, toxicity or side effects,^14,42,66 all of which contribute to the burden of disease and consequently to excess mortality and morbidity.³ However, to the best of our knowledge, there are no reports (e.g. cohorts) that have studied these consequences of low-quality drugs in a systematic approach using adequate scientific methodology. The potential risk of counterfeit anti-infectious agents for individual and community health includes clinical aggravation leading to complications and even mortality from either the disease itself or possible toxic components in the product and selection of drug-resistant bacteria and parasites. These risks have been described on the basis of cases, case series or even epidemics in one case.⁹⁸

Consequences for the patients

Counterfeit and substandard medicines could also cause adverse effects such as allergic or other side effects through excessive dose or due to the presence of potentially toxic active ingredients⁵³ or pathogenic contaminants,⁹⁹ as has been reported for some antimicrobials including antimalarials,^{53,93,100–106} especially in paediatric formulations or when the drug has a narrow therapeutic window.¹²

In addition, there are many reports that anti-infective drugs of poor quality such as anti-TB agents and antimalarial drugs may cause treatment failure^7,9,13,48 and can lead to substantial morbidity or mortality.^{71,93,100–103,107–109} Other studies report the number of deaths, which can be very high because of counterfeit drugs, such as the most well-known major incident concerning 2500 deaths in Niger in 1995 from a counterfeit meningitis vaccination.⁹⁸

Emergence of drug resistance

Other consequences of the problem of counterfeit and/or substandard antimicrobial drugs include the substantial effect on the growing global problem of antimicrobial resistance,^7,9,13,48 especially for diseases that are treated with combination therapy such as tuberculosis,^6,65,108 malaria due to Plasmodium falciparum^39,45,109 and HIV. Most drug failures are due to lower contents or dissolution scores, which is comparable with taking low doses of the drug. As a result although some bacterial agents are still susceptible to common antibiotics in industrialized countries, in some other developing countries, the proportion of multiresistant strains in various bacterial species has greatly increased.³⁶

Moreover, substandard narrow-spectrum antibiotics may create the wrong impression that the antibacterial agents themselves are ineffective and, thus, lead prescribers to unnecessarily opt for newer broad-spectrum antibiotics that have not yet been copied by unscrupulous manufacturers as their first-line treatment for many infections.⁹⁹

According to WHO, the consequences of this are obvious: (i) relatively cheap drugs will become ineffective; (ii) the loss of such drugs will require new drug development, which will be more expensive and will further disadvantage patients in the developing countries; and (iii) selection of drug-resistant pathogens will lead to increased morbidity, mortality and a significant economic burden on developing regions of the world.¹¹⁰ Another risk of using counterfeit drugs is that with the increased mobility of persons, the transmission of drug-resistant strains of diseases from country to country and within regions will also increase.

Examples of substandard antimicrobials that lead to spreading of resistance include chloramphenicol and co-trimoxazole⁶ and antimalarials¹¹¹ such as artemisinins,^39,112 chloroquine^113,114 and mefloquine.¹¹⁵

Other consequences

The counterfeiting of pharmaceuticals has serious consequences for consumers, healthcare providers, drug manufacturers and governments.¹¹⁶ There can be significant decline in confidence in public health systems, healthcare professionals and in government agencies involved in distributing drugs.¹¹⁶ Health practitioners can also lose confidence in the medications that they rely upon because of false reports of drug resistance.^45,117 On the other hand, the financial consequences of counterfeit medicines for the companies producing the genuine product can be enormous.^118–120 Finally, the financial impact for consumers can also be significant, mostly due to higher prices for drugs, especially in countries like the USA.¹¹⁶

Interventions

There is clearly no simple solution to the problem of counterfeit anti-infectives and several strategies are required. WHO has established guidelines against counterfeiting,¹²¹ which require cooperation between government organizations, health workers, industry and civil society.^{1,81,122–124} The Declaration of Rome, arising from the WHO International Conference on Combating Counterfeit Medicines, calls for the formation of an International Medical Products Anti-Counterfeiting Taskforce.^125,126 Moreover, as a response to the increased threat of counterfeit drugs in the USA and throughout the world, the US FDA established the Counterfeit Drug Task Force. Task force strategies for combating drug counterfeiting include using advanced technology, security business practices and regulatory requirements, creating rapid alert and response systems, developing education and public awareness programmes and addressing international issues.^68,127–130 FDA has also issued many measures to combat counterfeit antimicrobials in many publications.^{127,130–141} WHO has issued guidelines for combating counterfeit medications,^{1,6,15,22–25,46,50,57,77,95,98,122,126,142–150} but their effect in reducing counterfeiting of medications has not been assessed by studies.

However, although guidelines have been produced,⁹⁵ most developing countries do not have the infrastructure and financial resources to implement them.^1,12,75 For example, in Nigeria, efforts to control this problem were not very successful.¹⁵¹ In contrast, other research efforts were more effective. Interventions developed by WHO to reduce fake antimalarials in southeast Asia involved drug packaging such as blister packaging, public information campaigns and assessments of drug quality and improved drug compliance.¹⁵²

Increased legal measures,¹⁵³ including even death penalties (e.g. in China),¹⁵⁴ and increased inspection and drug regulation from governments have also been implemented as means to combat counterfeit drugs. However, there is only one published study examining the efficacy of such interventions,⁴² in which the quality of antimicrobials was examined in districts in Laos before and 2 years after random allocation to either regular or enhanced drug inspection. Although drug quality improved substantially over the 2 years, no significant differences were found between the regular and enhanced drug inspection districts.⁴² Prosecution of counterfeit antibiotics has been successful in some of the cases, e.g. in China.¹⁵⁵

On the other hand, increased public awareness of the problem of counterfeit drugs is of paramount importance and governments and companies have issued warnings about specific counterfeited products. For example, Nigeria and Thailand have developed informative web sites and such campaigns had some success, e.g. in Cambodia.⁴⁵ WHO has issued guidelines that consumers should follow, such as to check for abnormal appearance of packaging, to avoid buying suspiciously inexpensive medicines and to buy only from licensed pharmacies; however, their effectiveness is unknown.¹

Finally, interventions related to quality control and good manufacturing practice are necessary to reduce the prevalence of substandard drugs, but these are not complicated by criminal motives as is the case with counterfeit drugs.

Limitations of the review

Our review has several limitations including the inclusion of only studies in the English language and the search of only the PubMed database and major newspaper articles and Internet web sites found through the Google search machine. In the current manuscript, we could identify few studies with sufficient methodology and as a result, conclusions regarding low quality of specific classes of antimicrobials could not be made in some cases. In many reports on the quality of drugs in developing countries, the terms counterfeit and substandard drugs have been used interchangeably and the authors often do not distinguish between counterfeit and substandard drugs. Many studies measure the percent of available drugs that do not meet minimum pharmaceutical standards or do not possess the proper quantity of active ingredients, but, in most of them, there was no criminal investigation on the source of the medications so it was not specified whether the substandard medications were also counterfeit.^53,156

In addition, although in some studies the source of the low-quality antimicrobial agent is reported (Table 1), this source is not specified in the vast majority of the reports published and it is not possible to distinguish whether the reference is to a generic or to the original trade name product. This makes studying of the problem of substandard antimicrobials problematic with regard to application of GMP and the implementation of international standards in the manufacturing part of the industry.

Moreover, variability in definitions between different studies using different pharmacopoeial standards often makes direct comparisons difficult. Many of the previous reports on counterfeit drugs have been based on case reports on failure to attain the expected therapeutic effect, or reports investigating a small sample of products belonging to different classes of drugs.^10,15,157 Counterfeit drugs exist on the market sporadically, and the absence of counterfeit drugs in some studies could be due to the sampling window or sample size. Other reports constituting the WHO database have remained confidential, unpublished or published for limited distribution.¹⁵ Finally, many of these studies had methodological limitations specifically with regard to sampling and data analysis and were not necessarily representative for the whole country that was studied.

Thus, despite the scale of the problem of low-quality medications, there is little research on poor quality drugs. There are very few studies on the prevalence of counterfeit and substandard drugs with sufficient methodology including random sampling.¹² Future research efforts are needed to clearly study the problem of low-quality medications with adequate design to avoid bias. Publications describing drug quality should also provide manufacturer's names as stated on the packaging,¹⁰⁸ but only a small portion of published studies provide this information.¹⁵⁸ Such data are required to better define the problem by providing reliable prevalence estimates and by examining the effectiveness of interventions to confine this menace.

Conclusions

In summary, the data of the reviewed studies suggest that the problem of counterfeit and/or substandard antimicrobial drugs has a large dimension with considerable direct and indirect effects on global public health. The use of low-quality drugs can result in adverse clinical outcomes such as lack of effect and treatment failure, risk of development of bacterial resistance, toxicity, side effects and even deaths. This problem can have important implications on the everyday practice of healthcare providers because not only physicians but also patients lose confidence in the effectiveness of antimicrobials. In the current manuscript, we have summarized the body of scientific evidence in an effort to define the problem more clearly. Several strategies are required to combat the problem of counterfeit anti-infectives including cooperation between government organizations, health workers, industry and civil society and WHO has announced specific guidelines. However, many of these measures cannot be implemented in many developing countries because of the lack of resources and therefore there is need for international coordination to fight the menace of counterfeit/substandard antimicrobials.

Acknowledgements

This study received no funding.

Transparency declarations

None to declare.

Author notes

†

The first two authors have equally contributed to the work.