Antibiotic resistance in Mexico : a brief overview of the current status and its causes

As in many other developing countries, conditions that may foster antibiotic resistance in Mexico differ from developed countries, as does resistance prevalence. Fecal pollution and other characteristics of overcrowded, poor cities might create ideal settings for selecting, exchanging and maintaining resistance traits. Medical abuse of antibiotics, along with low-quality drugs, is also present as in many other developing countries. Self-prescription, a common yet unmeasured practice among the Mexican population, may also contribute to increased resistance rates. Pneumococcal resistance towards penicillin and macrolides are the highest in Latin American countries, as is resistance of Salmonella and uropathogenic Escherichia coli towards ampicillin and sulfamethoxazole-trimethoprim; about one-tenth of isolates of these gram-negative pathogens seem to produce extended-spectrum beta-lactamases (ESBL). High rates of multiple-drug resistant Mycobacterium tuberculosis are also found in Mexico, although there is no report of extensively drug-resistant strains. As to hospital-acquired pathogens, about a third of E. coli and Klebsiella isolates are ESBL-producers, and half of Staphylococcus aureus isolates are resistant to oxacillin (MRSA). Approximately 40% of Pseudomonas aeruginosa isolates are resistant to ceftazidime, imipenem or levofloxacin. Although community-acquired MRSA, vancomycin-resistant enterococci, and other resistance problems found in developed countries are not as common in Mexico, local issues are no small concern, and are disturbingly moving towards outpatients.


Introduction
Many articles on antibiotic resistance start with a statement about the threat it poses towards public health.This is, of course, true, but the threat differs among countries.First, the overall rate of resistance, which is often larger in developing than in developed countries, must be considered.Also, the kind of organisms in which resistance is dangerously growing is different: while rich countries are concerned with hospital-acquired pathogens such as the ESKAPE group including Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, Enterobacter, (with the exception being community-acquired methicillin-resistant Staphylococcus aureus, CA-MRSA), poor countries are additionally challenged with multi-resistant pathogens in the community, such as Mycobacterium tuberculosis, pneumococci, uropathogenic Escherichia coli (UPEC) or Salmonella.As to the clinical impact, overcrowded, poorly staffed and poorly equipped hospitals allow for a rapid spread, slow detection and grim outcome of multi-resistant infections much more often in developing countries than in the US or most of Europe.With malnourished patients that have scarce access to medical services and drugs, such infections are crippling or fatal much more commonly.Finally, the financial burden that resistance imposes upon health services causes more hardship in poor countries.All these have been very recently reviewed [1], not only with regard to bacteria, but also to other microbial pathogens that are gaining resistance and that pose particular threats to the public health in developing countries.The current situation in Mexico is briefly reviewed here.

Causes for the rise of resistance, different from antibiotic usage
Despite some subtle differences, real or apparent, on the biology of the emergence and spread of resistance genes that will be discussed shortly, there is no reason to believe that there is a significant disparity on the molecular basis of antibiotic resistance between Mexico (or the whole of Latin America) and richer countries.Perhaps some drugs that presumably promote the spread itself of resistance genes, such as quinolones [2] or tetracycline [3,4], are used more often in Latin America, hence enacting more than a mere selective pressure and increasing resistance rates when compared to low-usage countries.However, even if such a usage pattern difference exists, it is not likely to have a significant impact.Therefore, direct selective pressure is the most probable culprit of increased resistance in Mexico and other Latin American countries.Before going to the obvious selective pressure, i.e., the abuse of antibiotics, some other peculiar characteristics of developing countries that might, albeit indirectly, influence bacterial resistance should be discussed.
Cities in developing countries are interesting playgrounds for a variety of humans' and animals' pathogenic and commensal bacteria.The lack of adequate urban infrastructure-along with overcrowding, stray animals, and improper management of garbage and wastewater-makes for increased levels of fecal pollution of urban dust.Aside from the direct health effects of chronic exposure to these contaminants, the chances for horizontal transfer of resistance and even virulence genes are increased by merely putting together bacteria that do not often interact [5].Furthermore, chemical pollution, another feature of developing countries due to under-regulation, underenforcement, or plain corruption, can play a role in the selection of resistant bacteria.Ozone, for instance, is a common air pollutant in large Mexican cities, derived from photochemical reactions of automobile exhaust fumes and household propane gas, and has been shown to select for bacteria with oxidant-response mechanisms that also confer a multi-resistant phenotype [6].This and other agents might be at play in selecting resistance to multiple antibiotics among E. coli isolates in urban dust in Mexico City, as well as low-level quinolone resistance in urban water bodies [7].It is even possible that such selective pressures are enough to keep class 1 integrons in E. coli, despite being a rather unstable mobile element in this species in the absence of antibiotics [8].Further research is needed in this mostly ignored area.

Antibiotic usage in Mexico
The use and abuse of antibiotics is regarded, however, as the most important cause of increasing resistance.Perhaps the first problem we have in Mexico is the lack of information about the amount of antibiotics used for both clinical and non-clinical purposes.A recent review published in the journal of the National Institute of Public Health of Mexico relied mostly on some few papers on prescription practices and antibiotic usage that are 10 to 20 years old [9].Furthermore, there is no mention of the agricultural use of antibiotics that amounts, worldwide, to more than half of the total antibiotics produced.Furthermore, documented information on the use of antibiotics in Mexico cannot be provided, but there is no reason to suppose that the agricultural use of antibiotics is less intense and reckless here than in any developed country, but rather the opposite.It is also commonly presumed that medical training is of lower quality in Mexico than in the USA or Europe.It is likely that Mexican physicians use antibiotics as badly as most of their colleagues abroad, i.e., wrongly in about half of the cases [10].Nonetheless, there is not sufficient local information on this matter.
The quality of antibiotics used clinically might have some bearing in promoting resistance.Generic drugs have been reported as having significantly less active antibiotic than the -original‖ counterpart [11,12].Again, this has been tested elsewhere, but there is no reason to think that generic drugs available in Mexico (most of which are manufactured abroad) are any better.Furthermore, for many years a third, rather odd, category of drugs existed in Mexico: -similar‖ drugs.Similar drugs are manufactured by a single company, owned by a -well-connected‖ individual, the brother of the -owner‖ of a mid-size national political party.This category of drugs was not tested, even in the minimal and obscure way that is requisite for generics, escaping external quality controls of any kind [13].It is easy to imagine that less potent drugs that fail to keep inhibitory concentrations in blood and tissues for as long as they are supposed to can potentially engender resistance easily, but that would also need to be tested.
Falsified drugs are not, apparently, as big a problem here as they are in other developing countries [14].A peculiar issue, however, is the mostly un-quantified black market of stolen drugs.These come from illegally sold samples that physicians are supposed to receive free of charge as well as from the two large public hospital networks in the country, from which a continuous flow of stolen drugs is allowed.Many of these drugs are improperly stored, possibly leading to partial or total inactivation, and are often sold past their expiration dates.Most of the drugs made available this way are costly, such as anti-neoplastic agents, but some intravenous antibiotics also make their way to the neighborhoods and towns well-known as cheap drugstores.How many of these drugs are sold and used, and what is the impact of this upon bacterial resistance, we might never know.
Self-prescription is another problem.As in many other Latin American countries (the exceptions being Cuba, Chile, Costa Rica and Venezuela), antibiotics of any kind, from ophthalmic chloramphenicol to intravenous linezolid, can be bought in Mexico without medical prescription.Self-prescription causes antibiotic abuse in a number of ways, not restricted to the use against non-infectious or non-bacterial diseases: self-prescribed antibiotic treatments are shorter and/or improperly dosified and also rely upon expired remnants of past, medically prescribed treatments.The easiest way to stop self-prescription is to make mandatory the presentation of a medical prescription (although in countries where such restrictions exist, as in the USA, antibiotics can be purchased from friendly pharmacists, immigrants, the internet, and even pet stores).That has been the path chosen by the few Latin American countries where antibiotics are no longer over-the-counter drugs.However, in countries such as Mexico, where many people do not have access to health care services, it is possible that self-prescription actually saves many lives.Before restricting the free-sale of antibiotics, it would be necessary to assess the cost of such a measure (denying access to life-saving drugs to lowand very-low-income people) against its benefits (decreased resistance and adverse drug effects).One can only hope that surveillance of resistance in those countries where restrictions have recently been put in place would answer the latter question.In any case, one of the very few published reports quantifying self-prescription in Mexico [15,16], indicates that it might amount for up to 28-43% of antibiotics sold at drugstores, still leaving medical prescription as the main source of antibiotic requests, and as the main risk of getting unnecessary antibiotics.

Consequences: more antibiotic resistance
From the brief overview above, where antibiotic abuse and other conditions seem like an ideal setting for the emergence and spread of resistance determinants, we can surmise that antibiotic resistance in Mexico is high, more so than in other comparable countries.Indeed, the prevalence of resistance seems higher than that of developed countries, and even than that seen in other Latin American countries.
Therefore, some recent, representative results of susceptibility surveys from both, community-and hospital-acquired pathogens will be discussed next.Most relevant data are summarized in Table 1.
Respiratory diseases are the main cause of medical consult; the most common bacterial pathogen is Streptococcus pneumoniae, followed by Haemophilus influenzae, Moraxella catarrhalis and those causing -atypical‖ pneumonia (Legionella pneumophila, Mycoplasma pneumoniae and Chlamydophila pneumoniae).In a recent survey that included isolates from outpatients, mainly in Mexico City, up to 70% of pneumococci were not susceptible to penicillin (13% resistant, 57% intermediate), 71% were resistant to sulfamethoxazole-trimetoprim (cotrimoxazole), and 49% to clarithromycin (70% of them also resistant to clindamycin).Forty-five percent of H. influenzae isolates were resistant to cotrimoxazole, 33% to ampicillin (all of them producing beta-lactamases), and 21% to clarithromycin (Amábile-Cuevas and Arredondo-García, unpublished results).None of the strains (150 of each species) were resistant to fluoroquinolones, but there is a report of a 6.5% resistance to ofloxacin in Mexican pneumococci, the highest in the region [17].An older survey, reporting only MIC values for respiratory pathogens in Latin America, shows that Mexico, Venezuela and Chile have the highest MIC 90 of penicillin for pneumococci (2-4 µg/mL), and Mexico has the highest MIC 90 of clarithromycin (16 µg/mL) and of co-trimoxazole (8 µg/mL) for pneumococci [18].With different rates, Mexico is often cited as the Latin American country with the highest prevalence of penicillin-nonsusceptible penumococci: 51.6% (22.2% resistant) in year 2000 [19], and 57% in year 2007 [17].
Enteropathogens Salmonella and Shigella are common causes of disease in developing countries.In a small survey conducted in 2001-2002, Mexican Salmonella isolates were mainly resistant to tetracycline (82%), co-trimoxazole (66%) and ampicillin (66%) (Amábile-Cuevas, unpublished results), contrasting with a 14% resistance to cotrimoxazole and 27% resistance to ampicillin in 1994-1995 [16], and with a very low prevalence of resistance (2-3%) towards the two latter drugs in the whole of Latin America.Mexico, along with Colombia and Argentina, had the highest resistance prevalence in the region [20].Shigella strains had similar trends in 2001-2002, with 100% resistance to tetracycline and 81% to co-trimoxazole and ampicillin, up from 59% resistance to co-trimoxazole and 63% to ampicillin in 1994-1995.However, resistance to chloramphenicol remained steady, approximately 20% in Salmonella, and decreased from 37% to 11% in Shigella.A surprising 12% of Salmonella isolates were resistant to ceftriaxone; perhaps the worrisome presence of extendedspectrum beta-lactamases (ESBLs) in communityacquired pathogens, mostly reported in enteropathogens in Latin America [21], are already in Mexico.
Community-acquired, uropathogenic E. coli is a cause of growing concern as all three -first choice‖ drugs are facing high resistance prevalence.In a recent survey, 74% of isolates were resistant to ampicillin, 60.1% to co-trimoxazole, and 32.6% to ciprofloxacin.Furthermore, nearly two-thirds of ciprofloxacin-resistant strains had minimal inhibitory concentrations (MICs) of 128 µg/ml or higher, making them able to withstand concentrations attained in urine; also, 8.1% of isolates were resistant to ceftazidime, and three-fourths of them produced ESBLs [22].Resistance prevalences in other Latin American countries (Argentina, Ecuador, Guatemala, Paraguay, Uruguay and Venezuela) are similar: 53-79% resistant to ampicillin, 33-68% to cotrimoxazole, and 7-32% to ciprofloxacin.Interestingly, Mexico's neighbor, Guatemala, had strikingly similar resistance rates: 79%, 68% and 32%, respectively; the highest in the region [23].
Tuberculosis is a -disease of the poor‖; hence it is endemic in Mexico, with 12.8 cases per 100,000 inhabitants, and about 10 deaths per day, according to official records.A recent review places multi-drug resistance (MDR, to at least isoniazid and rifampin) at a median of 17% (ranging from 6.2 to 64%) in all cases, 4.5% in new cases and 35% in treated cases [24].No report of extensively drug-resistant (XDR, i.e., MDR that is also resistant to second-line drugs, such as kanamycin, amikacin or capreomycin plus a fluoroquinolone) strains was mentioned.Other reports place MDR at 2.4% in new cases, and 22.4% in treated cases, contrasting with 1.2% and 5.6%, respectively, in the USA, and 0.0% and 7.1%, respectively, in Cuba [25].
Nosocomial pathogens included in the Tigecycline Evaluation and Surveillance Trial (TEST; www.testsurveillance.com)show a partial picture of the resistance trends inside Mexican hospitals.Nearly 70% of E. coli isolates are resistant to levofloxacin, and 36% produced ESBLs, while 28% were resistant to amoxicillin-clavulanate; 32% Klebsiella pneumoniae isolates were resistant to levofloxacin and 28% produced ESBLs; 48% of S. aureus isolates were resistant to oxacillin (MRSA), and 49% were resistant to levofloxacin; 33% of Enterococcus faecium isolates were resistant to vancomycin; 20% of Pseudomonas aeruginosa were resistant to amikacin, 39% to ceftazidime, 43% to imipenem, 40% to levofloxacin and 28% to piperacillin-tazobactam; 40% of Acinetobacter baumannii were resistant to amikacin, 72% to ceftazidime, 51% to levofloxacin and 51% to piperacillin-tazobactam. Fortunately, there was no detectable carbapenem resistance among Enterobacteriaceae, vancomycin resistance among S. aureus or Enterococcus faecalis, nor linezolid resistance among gram-positive cocci; only one K. pneumoniae isolate, among 1,001 isolates tested, was resistant to tigecycline (Ponce de León A, Amábile-Cuevas CF and Benítez A,18th European Congress of Clinical Microbiology and Infectious Diseases, Barcelona, 2008).A comparison between regional trends within the TEST data show that, overall, antibiotic susceptibility is lower in Latin American and Asian countries, than it is in the USA and EU.

Concluding remarks
Antibiotics are the main selective and maintenance pressure for antibiotic resistance determinants amongst bacterial populations.Antibiotic abuse, once a worldwide trend, is slowly receding, but developing countries have, as with many other issues, a significant lag.Other features included in the euphemistic -developing‖ qualifier, might also increase the prevalence of antibiotic resistance.All these conditions are present in Mexico, along with a dramatic lack of information and of epidemiological surveillance.
Although rational use and sales restrictions are strongly recommended, it must be clear that resistance is in itself a trait that is resistant to elimination [26,27].In other words, the high prevalence of resistance is here to stay, and strategies designed to curtail antibiotic abuse will result in the stabilization of resistance at best.It is therefore imperative that such measures be taken immediately to prevent the growing loss of antimicrobial efficacy of our current drug arsenal.It is also important to realize that this is not a local, internal problem in Mexico: microorganisms do travel, and Mexico is both the main exporter of migrants worldwide and the obligated pathway for migrants from other Latin American countries.International pressure is needed to drive the regulatory changes regarding antibiotic usage that are long overdue in Mexico.
Antibiotic resistance in Mexico at a glance.