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The table above shows that AMR will inevitably causes attenuation of the potential full health benefits of ART (HIV treatment) and adds cost to the programs. This will worsen the impact of HIV.

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AMR  poses one of the greatest threats to malaria control and results in increased malaria morbidity and mortality. This is seen in the graph which illustrates an increase in malaria case incidence, deaths, and case fatality after the introduction and spread of chloroquine-resistant malaria into sub-Saharan Africa.

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According to WHO, “drug-resistant TB is a continuing threat. In 2016, there were 600,000 new cases with resistance to rifampicin, the most effective first-line drug, of which 490,000 had multidrug-resistant TB.” In addition, the cost of treating a single case of MDR-TB or XDR-TB can be thousands of times more expensive than treating drug-sensitive TB. Once a drug becomes resistant, another drug must be developed, which cost even more mode. AMR creates a large economic burden and contributes to the health burden of TB.

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This website discusses how TB is exacerbated by AMR. It reveals that 29% of deaths caused by antimicrobial infections today are due to drug-resistant TB. Treating drug resistant TB is also more expensive than treat TB itself. AMR creates an additional burden.

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Antimicrobial Resistance

Antimicrobial resistance (AMR)-which occurs when microorganisms no longer respond to the drugs designed to treat them-is becoming one of the defining health issues of our time. The threat posed by "superbugs" to public health, safety, and the global economy is staggering.

While AMR is often associated with hospital-based infections, like MRSA (methicillin-resistant Staphylococcus aureus), about 29% of deaths caused by antimicrobial infections today are due to drug-resistant TB. In fact, the grim projections forecast for the "post-antibiotic age" are already a reality for many countries and patients who are experiencing the human and economic toll of multi-drug resistant (MDR-) and extensively drug-resistant (XDR-) TB.

"The advent of a better treatment regimen for MDR-TB would by itself quickly start to save a large number of lives, with more than 20,000 deaths being averted every year within three years of the new treatment's introduction."

MDR-TB:

MDR-TB, multidrug-resistant TB, is defined by resistance to the two most commonly used drugs in the current four-drug (or first-line) regimen, isoniazid and rifampin. It is the result of interrupted, erratic, or inadequate TB therapy, and its spread is undermining efforts to control the global TB epidemic. Drug-resistant TB develops when the long, complex, decades-old TB drug regimen is improperly administered, or when people with TB stop taking their medicines before the disease has been fully eradicated from their body. Once a drug-resistant strain has developed, it can be transmitted directly to others just like drug-susceptible TB. There are over half a million cases of drug-resistant TB each year. MDR-TB is such a global health threat because the medicines are very expensive, take years to work, and ultimately inadequate to stop the disease and its spread.

Antimicrobial resistance is dangerous in all its forms, however, MDR-TB yields a global threat to health and economic development. A recent report from a UK parliamentary group stated over the next 35 years, multidrug-resistant tuberculosis will kill 75 million people and could cost the global economy a cumulative $16.7 trillion - the equivalent of the European Union's annual output.

XDR-TB:

Extensively drug-resistant tuberculosis, or XDR-TB, is a strain of tuberculosis, airborne and infectious, that is resistant to four commonly-used anti-TB drugs. Until the US FDA approval of pretomanid as part of the BPaL regimen, there was no reliable cure for XDR-TB. XDR-TB has been confirmed in 127 countries around the world and represents about six percent of all MDR-TB cases. XDR-TB is emerging as an extremely deadly and costly global health threat that the world must mobilize rapidly to tackle.

"Drug-resistant TB is a continuing threat. In 2016, there were 600,000 new cases with resistance to rifampicin, the most effective first-line drug, of which 490,000 had multidrug-resistant TB."

Dire Costs

When infections become resistant to first-line drugs, more expensive therapies must be used to treat them. Lengthier treatment, often in hospitals, substantially increases health care costs as well as the economic burden on families and societies. The cost of treating a single case of MDR-TB or XDR-TB can be thousands of times more expensive than treating drug-sensitive TB. For example, in South Africa, drug-resistant TB consumed about 32% of South Africa's US$218 million national TB budget (2011), despite the fact that it only accounted for about 2% of all TB cases.

View the portfolio

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Antimicrobial resistance (AMR) is becoming one of the defining health issues of our time. The threat posed by "superbugs" to public health, safety, and the global economy is staggering, and TB accounts for more than 1 in 4 AMR fatalities per year.

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Malaria is a dangerous and sometimes fatal disease that can be prevented. Since it can infect anyone, anywhere it is a major burden on global health. People from countries without malaria can become infected when they travel to countries with malaria. While there are effective antimalarial drugs available, drug resistance has become a major issue. Malaria is resistant to all but one of the five major classes of drugs and the resistance is driven by selection pressure of a specific drug. In LMICs with little to no surveillance or measurement of drug resistances, the ineffective drug will continue to be used and malaria infections will increase.

This article discusses the implications of the lack of resistance surveillance and malaria control. It acknowledges that AMR prevents malarial from being prevented and contributes to the global burden of disease.

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Citation: Anderson T (2009) Mapping the Spread of Malaria Drug Resistance. PLoS Med 6(4): e1000054. https://doi.org/10.1371/journal.pmed.1000054

Published: April 14, 2009

Copyright: © 2009 Tim Anderson. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This article was supported by grants from the National Institutes of Health AI075145 and R01 AI48071. The funders played no role in the decision to submit the article or in its preparation.

Competing interests: The author has declared that no competing interests exist.

Abbreviations: dhps, dihydropteroate synthase; PYR, pyrimethamine; SDX, sulfadoxine; SNP, single nucleotide polymorphism

Provenance: Commissioned; not externally peer reviewed

Linked Research Article

This Perspective discusses the following new study published in PLoS Medicine:

Pearce RJ, Pota H, Evehe M-SB, Bâ E-H, Mombo-Ngoma G, et al. (2009) Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria. PLoS Med 6(4): e1000055. doi:10.1371/journal.pmed.1000055

Cally Roper and colleagues analyze the distribution of sulfadoxine resistance mutations and flanking microsatellite loci to trace the emergence and dispersal of drug-resistant Plasmodium falciparum malaria in Africa.

Drug resistance is a recurrent theme in the history of infectious disease control. In the case of malaria, resistance to all but one of the five major classes of drugs is widespread [1]. Such resistance occurs because of the strong selection pressure associated with giving patients antimalarial drugs.

The most effective way to stall resistance would therefore be to eliminate selection by halting drug treatment [2], but this is rarely a feasible option. Hence alternative approaches to managing resistance are needed. First of all, we need to better understand the manner in which resistance evolves and spreads within populations.

Molecular methods provide the tools needed for investigating the evolution and the spread of resistance genes. These methods can be used to answer a multitude of pertinent questions: Do resistance alleles have few or many origins? Do they spread locally or globally? Do parasites form a single pan-African population, or are there barriers to gene flow? In turn, the answers to these questions can be used to make rational decisions about drug treatment policy.

Sulfadoxine Resistance

Sulfadoxine (SDX) forms one half of the drug combination sulfadoxine-pyrimethamine (Fansidar), which replaced chloroquine as the first-line drug in much of Africa, before itself being replaced by artemisinin combination therapies. Resistance to both SDX and pyrimethamine (PYR) has spread rapidly within Africa. Because the genetic basis of resistance to these drugs is well established-single point mutations within the enzyme active sites [3] -SDX and PYR treatment provide excellent opportunities for understanding resistance evolution.

In a new study in PLoS Medicine, Cally Roper and colleagues describe molecular variation in alleles at the dihydropteroate synthase ( dhps) locus, which is known to underlie resistance to SDX, in over 5,000 parasites from 50 locations during 2000-2007 [4]. They also examine sequence variation flanking this locus to determine the number of independent origins of resistance alleles. This unusually large data set provides an extraordinarily fine-grained view of the spread of resistance alleles across Africa.

Curious Distribution of Resistance Alleles in East and West Africa

The maps generated by Roper and colleagues show a striking distribution of dhps alleles in Africa. Parasites bearing amino acids SGE (underlining denotes amino acids conferring resistance) at codons 436, 437, and 540 in dhps are common in east Africa, while parasites bearing AGK and SGK alleles are common in west Africa. The demonstration (below) that each one of these alleles has multiple origins suggests the action of selection. However, there are no obvious differences in treatment or biology of malaria in east and west Africa that explain repeated origins of dissimilar alleles. An alternative explanation is that the same alleles have arisen on multiple occasions because they were present within parasite populations at low levels prior to initiation of SDX-PYR selection.

How Many Times Have Resistance Alleles Arisen?

The data from flanking microsatellite markers reveal that there have been a minimum of five independent origins of resistance, which show strong geographical clustering. SGE alleles have arisen at least twice in the east, with one lineage in Ethiopia and Sudan and the other spanning from Kenya to South Africa. In west Africa, there are three lineages of alleles; in each lineage both AGK and SGK are found on a common background, suggesting that one has given rise to the other. Once again, the three AGK/SGK lineages have a strikingly focal distribution; lineage 1 is found from Namibia to Gabon, lineage 2 in Cameroon, and lineage 3 from Nigeria to Senegal.

How can we explain this focal distribution of allelic lineages? One possibility is that resistance alleles have spread like ripples on a pond from a limited number of foci. In this scenario, the boundaries between parasites bearing different resistance allele lineages merely reflect meeting points between ripples, and these boundaries are expected to become blurred and disappear over time. Alternatively, the distinctive focal distribution could result from barriers to mixing and gene flow between parasite subpopulations.

How can the opposing "ripples on a pond" and "barriers to mixing" models be distinguished? One option might be to examine patterns of spread of resistance genes to other antimalarial drugs. If similar distribution patterns are observed at different resistance loci, then this may be indicative of common boundaries to gene flow. It will be extremely interesting to see if a pan-African analysis of dihydrofolate reductase ( dhfr), which confers resistance to PYR, shows similar patterns. Furthermore, if boundaries between allelic lineages correspond to physical barriers such as mountain ranges or linguistic barriers between human populations, this further bolsters the "barriers to mixing" model.

Inferring the presence of barriers between populations using genes that are known to be under strong selection is fraught with problems [5]. Perhaps a more convincing approach might be to use the thousands of single nucleotide polymorphisms (SNPs) discovered by parasite re-sequencing projects [6] to infer parasite population structure. These can be scored using microarrays or short-read sequencing (Solexa), and the majority will not be influenced by selection. The power afforded by use of thousands of markers may reveal discontinuities in parasite populations that were not evident in smaller previous studies [7].

Implications for Resistance Surveillance and Malaria Control

This new study provides a number of important lessons. First, it illustrates the practicality of routine measurement of drug resistance allele frequencies across malaria-endemic regions. Such measurement allows policy makers direct access to information required to make national drug policy decisions. This new study was done in a single laboratory, using samples from multiple countries, showing that centralization can provide a practical way to generate such databases. The alternative model-multiple regional laboratories generating such data-will be more expensive and less practical from a control quality standpoint. Notably, this work was done with quite simple molecular methods-hybridization on nylon membranes. Rapid SNP typing approaches now allow multiple resistance SNPs to be genotyped in a single assay at low cost [8], which can further streamline geographical mapping of multiple resistance determinants.

The distinctive differences observed between east and west Africa have clear clinical implications. The dhps alleles with two mutations (SGE) confer higher levels of resistance than those carrying single mutations (AGK and SGK) [9], suggesting that SDX-PYR treatment will be less effective in east than west Africa. Hence interventions that use SDX-PYR, such as intermittent preventative therapy for infants or pregnant women, might be expected to differ in efficacy depending on location.

Given that just one or two SNPs are required for resistance, and infected people may contain more than 10 ¹¹ parasites [10], the finding that resistance alleles have only five origins is surprising, but consistent with limited numbers of origins observed at other drug resistance loci in malaria parasites [11] and some population genetic models [12]. This observation bodes well for current control efforts using artemisinin combination therapies. If resistance has relatively few independent origins, then simple strategies like combination therapy may be extremely effective in stalling resistance evolution [10], [13]. On the other hand, if resistance arises commonly, then such measures are more likely to be ineffective.

Finally, Roper and colleagues' study generates a testable hypothesis that malaria parasite populations in Africa are divided into regional subpopulations separated by barriers to gene flow. Further data are required to substantiate this hypothesis. If true, this hypothesis has important implications as it suggests that malaria control needs to be tailored to regional parasite subpopulations rather than to the continent as a whole.

Author Contributions

ICMJE criteria for authorship read and met: TA.

References

1. 4. Pearce RJ, Pota H, Evehe M-SB, Bâ E-H, Mombo-Ngoma G, et al. (2009) Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria. PLoS Med 6: e1000055.

2. 5. Hartl DL, Clark AG (2007) Principles of population genetics. Sunderland (MA): Sinauer Associates.

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Mapping the Spread of Malaria Drug Resistance

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Citation: Anderson T (2009) Mapping the Spread of Malaria Drug Resistance. PLoS Med 6(4): e1000054. https://doi.org/10.1371/journal.pmed.1000054 Published: April 14, 2009 Copyright: © 2009 Tim Anderson. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Bacterial infections are one of the main causes of hospitalization and death in PLWH worldwide. Since PLWH have more frequent hospital admissions and clinic visits due to HIV. This leads to increased number of antimicrobial prescriptions and a higher

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Introduction

The discovery of antimicrobials has led to a 'golden age' in medicine which has enabled the effective treatment of a large number of once deadly infections. The emergence and worldwide dissemination of antimicrobial resistance (AMR) is threatening to overturn these advances, leading to increased morbidity, mortality and healthcare costs [

]. AMR is of particular concern in low- and middle-income settings where treatment options are limited due to cost and availability of drugs. Among the main drivers for AMR are inappropriate antimicrobial use, transmission of resistant pathogens in healthcare settings, and rapid dissemination of resistant pathogenic strains due to international travel and trade []. On an individual level, prior antimicrobial use, healthcare contact and underlying comorbid conditions are recognized risk factors for infection and colonization with resistant organisms [].

There are almost 38 million people living with HIV (PLWH) worldwide, with the highest prevalence of infection in countries in sub-Saharan Africa [

]. PLWH have more frequent hospital admissions, clinic visits and antimicrobial treatment courses compared to individuals without HIV infection, putting them at increased risk of the acquisition of and infection with resistant bacteria. Hospital admissions for acute bacterial infections are more frequent in HIV-infected than in HIV-uninfected individuals [,

]. Overall, bacterial infections (not including tuberculosis) are one of the main causes of hospitalization and death in PLWH worldwide, with almost a third of all hospital admissions and a quarter of all deaths due to bacterial infections []. More frequent hospital admissions may lead to an increased number of antimicrobial prescriptions and a higher risk of acquisition of resistant pathogens during hospitalization. Additionally, there is a higher prevalence of chronic conditions such as kidney and liver diseases, which also require more frequent clinic appointments and hospital admissions among PLWH [

,]. In the United States, prescriptions for multiple antimicrobial drug classes are more common among elderly HIV-infected individuals than in their HIV non-infected counterparts [

]. Furthermore, antimicrobial prescriptions are more frequent among HIV-infected individuals even before HIV diagnosis, as shown by a study from Denmark []. With the roll-out of widespread antiretroviral therapy (ART) and improved early diagnosis and treatment of HIV, the impact of these factors on the prevalence of resistance may have changed over time.

Antimicrobials such as co-trimoxazole, macrolides and anti-mycobacterial agents are also recommended as prophylaxis for PLWH [

,

]. The indication may vary by CD4 cell count, age, geographical setting and prior medical history. Use of co-trimoxazole prophylaxis in high-income settings is decreasing due to early diagnosis of HIV and ART use. However, in low-income settings co-trimoxazole prophylaxis is recommended by the WHO for all children with HIV, and for adults with advanced HIV infection or who are living in areas where malaria and bacterial infections are prevalent, irrespective of ART [

]. Thus, co-trimoxazole prophylaxis, which has significantly reduced mortality [], is currently widely used throughout sub-Saharan Africa.

Although HIV infection is not known to have a direct effect on the colonization and infection of an individual with resistant organisms, PLWH have a multitude of indirect risk factors. There are limited data on the association between HIV infection and bacterial AMR, and to our knowledge this has never been reviewed systematically.

The aim of this systematic review is to determine whether HIV infection is associated with colonization or infection with antimicrobial-resistant bacteria.

The review is focused on bacterial pathogens causing infection or colonizing individuals with HIV infection. Mycobacteria and organisms causing sexually transmitted infections were excluded because this association has recently been reviewed [

] and because of the differences in transmission pathways for sexually transmitted infections.

Eligible publications were identified using the search strategy described in the Supplementary Material Table S2. The search strategy was applied to MEDLINE, EMBASE, Web of Science and LILACS databases up to week 3 of 2020. The African Journals Online and PubMed databases were searched for additional publications. The search was updated to June 2020. References of included studies and other reviews were manually searched for relevant publications. Articles identified were imported into the bibliographic software manager Endnote X7 (Clarivate Analytics, Philadelphia, PA, USA). Titles and abstracts were screened for eligibility by IDO and KK in duplicate.

Studies were included if they reported resistance data for colonization or infection by HIV status and stratified the results by bacterial species and antimicrobials tested. Colonization and infection were considered as defined by the authors of the respective studies. Studies describing species from the same family-such as Escherichia coli and Klebsiella pneumoniae (Enterobacteriaceae)-which did not present data by bacterial species were grouped in the analysis. No restriction with regards to geographical region, language or year of publication was applied. Case series were excluded. The review followed the PRISMA guidelines. The study protocol was registered with PROSPERO (CRD42020178907). The search strategy and analyses are described in the Supplementary Material.

Analyses were conducted using STATA (version 15, Stata-Corp, TX, USA). A descriptive analysis was performed for all eligible studies. If at least five studies reporting on the same organism (or group) and resistance to the same antimicrobial class were identified, then a random effects meta-analysis using the DerSimonian and Laird method was performed in STATA (using 'metan'). The meta-analyses were also stratified according carriage/colonization or infection. The pooled odds ratio estimates were grouped by organism, infection versus colonization and drug tested. Sensitivity analyses were performed to determine whether findings were consistent across different groups (Supplementary Material). Meta-analyses for proportions were performed using the package 'metaprop'. Heterogeneity of studies was evaluated using Cochrane recommendations [

] using the I ² statistic. Heterogeneity was considered substantial if I ² >50%.

Completeness of reporting was assessed using the STROBE checklist [], and for each item studies were graded into three categories: 'no information provided or unclear description', 'some information but insufficient', 'clear information provided'. The modified Newcastle-Ottawa scale was used to evaluate the quality of the studies [

].

Characteristics of identified studies

Of 21 489 unique citations identified by the search, 299 were selected for full-text review, of which 71 were suitable for inclusion in the main analysis. An additional 21 publications were identified from reference review. A total of 92 citations were included in the qualitative analysis ( Fig. 1). Most studies were from either the United States ( n = 32, 35%) or South Africa ( n = 21, 23%). Fig. 2 shows where the studies were conducted. About half of the studies were conducted in low- and middle-income countries ( n = 50, 54%).

Most studies described resistance in a single pathogen ( n = 83, 90%) while nine studies presented data for multiple organisms. AMR in Streptococcus pneumoniae was described in 28 studies (carriage n = 1, infection n = 27), Staphylococcus aureus in 47 (carriage n = 29; infection n = 18) and other organisms in 22 (carriage n = 6; infection n = 16). Studies in Enterobacteriaceae were on E. coli ( n = 6), Salmonella spp. ( n = 7), K. pneumoniae ( n = 3), and Shigella spp. ( n = 3). Supplementary Material Table S3 presents an overview of the studies included.

Patient characteristics

Studies included 40 625 PLWH and 17 187 704 individuals without HIV. Most studies were conducted in inpatients ( n = 44, 48%), or a combination of inpatients and outpatients ( n = 10, 11%); 18 studies (20%) reported on outpatients only, and six (7%) on other settings such as prisons ( n = 3), youth centres ( n = 1), shelters ( n = 1) and individuals recruited from the community ( n = 1) ( Supplementary Material Table S3). One study reported on isolates collected as part of laboratory surveillance and did not specify the source of the isolates; 13 studies did not provide details on the healthcare setting. Most of the studies were conducted in a single facility ( n = 54, 59%).

Most studies reported data from adults ( n = 53, 58%), while 15 (16%) included only children and 22 (24%) included both adults and children. For two studies, participant age was not reported.

HIV status was determined by performing an HIV test as part of the study procedures ( n = 26 studies) or was obtained from patient records or as part of the medical history ( n = 52 studies). In 14 studies, HIV status ascertainment was not clearly described.

Few studies reported on ART coverage ( n = 17, 18%) and co-trimoxazole prophylaxis ( n = 22, 24%) among HIV-infected patients. CD4 cell counts at the time of the study were reported for 39 studies (42%). Mean/median CD4 cell counts were <200 cells/μL in 12 studies (31%) and ≥200 in 25 studies (64%). For two studies the severity of the immunosuppression could not be determined. Forty-five (49%) of the studies collected data prospectively, while 43 (47%) extracted data from medical records or laboratory databases; one study used both prospective and retrospective data collection, and three (3%) did not specify how data collection was performed.

The pooled prevalence of resistance to selected antimicrobials by HIV status is shown in Table 1 and in Supplementary Material Figs S2 and S3.

Antimicrobial resistance in Staphylococcus aureus

Of the 47 studies describing AMR prevalence in S. aureus, 29 studies (62%) focused on colonization only (nasal: n = 23; multiple sites n = 6), and 18 (38%) on infections (bacteraemia: n = 5; skin and soft tissue infections: n = 5; respiratory infections: n = 2; multiple sites: n = 6). Among studies evaluating methicillin-resistant S. aureus (MRSA) colonization, six studies used methods enabling direct MRSA identification: chromogenic media ( n = 5) and molecular methods ( n = 1). Most studies reported predominantly on patients with community-acquired infections ( n = 10, 56%), while four (22%) included patients with hospital-acquired infections and four (22%) did not describe the type of infection. The studies included a total of 27 364 PLWH and 17 159 190 individuals without HIV infection. Half of the studies (24/47) and 89% of PLWH were from United States. Most studies (41/47, 87%) were conducted after the introduction of widespread ART. The proportion of individuals on co-trimoxazole prophylaxis was not consistently reported ( n = 11, 23%) and ranged from 0 to 89%.

PLWH had 2.12 (95%CI 1.36-3.30) higher odds for colonization and 1.90 (95%CI 1.45-2.48) higher odds for infection with MRSA compared with HIV-negative individuals. Eleven studies evaluated co-trimoxazole susceptibility of S. aureus isolates. The pooled OR for co-trimoxazole resistance was 1.40 (95%CI 0.49-3.99) for colonization and 2.89 (95%CI 0.48-17.37) for infection, comparing PLWH with HIV-negative individuals. Heterogeneity in ORs was high across studies ( I ² range 82-98%, Fig. 3c,d). Among individuals with S. aureus colonization, the odds of MRSA carriage were higher among PLWH than in those without HIV infection ( Supplementary Material Fig. S4).

Antimicrobial resistance in Streptococcus pneumoniae

A total of 28 studies evaluated AMR in S. pneumoniae, including 9239 PLWH and 8368 individuals without HIV infection; South Africa contributed the majority of the HIV-positive patients (83%). Studies were mostly conducted before the widespread availability of ART ( n = 18, 64%). Reporting of ART (1/28) and co-trimoxazole prophylaxis (8/28) usage was very rare. Where described, the proportion of PLWH reported to take co-trimoxazole prophylaxis ranged between 0 and 67%. More than two thirds of the studies described invasive pneumococcal disease ( n = 20, 71%), while isolates were cultured from multiple sample types in seven studies (30%). One study reported on pneumococcal carriage.

Nine studies reported on co-trimoxazole resistance. S. pneumoniae isolates from PLWH had a 2.28 (95%CI 1.75-2.97) higher odds of having decreased penicillin susceptibility compared to isolates from individuals without HIV. The pooled OR for co-trimoxazole resistance was 2.29 (95%CI 1.31-4.00). Heterogeneity of studies was moderate to substantial ( I ² 60% and 75%, respectively, Fig. 3 a,b).

Antimicrobial resistance in Escherichia coli and Klebsiella pneumoniae

Four studies described resistance in E. coli, two in K. pneumoniae, and one in both E. coli and K. pneumoniae isolates from patients presenting with infections. These studies included 849 HIV-infected and 12 573 non-HIV-infected individuals. Isolates were from blood ( n = 3), stool ( n = 2), urine ( n = 1) and respiratory samples ( n = 1). The OR for the presence of resistance to third-generation cephalosporins and co-trimoxazole in E. coli and K. pneumoniae causing infections was 1.59 (95%CI 0.83-3.05) and 2.43 (95%CI 1.36-4.32) respectively ( Fig. 3e,f). Heterogeneity was high across studies for both third-generation cephalosporin resistance ( I ² 94%) and co-trimoxazole resistance ( I ² 78%).

Quality of reporting in studies included

Completeness of reporting according to the STROBE checklist was moderate in the majority of studies (66/92, 72%) ( Fig. 4). Sources of bias, sample size and generalizability of results were often not discussed. Also, most studies did not report on the number of participants or samples excluded from the analysis or the reasons for exclusion. When using the modified Newcastle-Ottawa Scale, most studies were of moderate ( n = 30) or low ( n = 57) quality. Only seven studies were of high quality.

Discussion

This review synthesizes for the first time data on AMR in PLWH compared to that in HIV-negative individuals. It shows that, for several important pathogens, PLWH are more likely to be infected or colonized with resistant bacterial strains than people without HIV infection. This holds true for two major Gram-positive and some Gram-negative organisms and for multiple antimicrobial classes. The higher prevalence of resistance among PLWH is of particular concern in low-income settings where alternative treatment options are limited by their availability and cost [

]. Co-trimoxazole may increase the risk of colonization with resistant Gram-negative and Gram-positive organisms [, ,

]. Therefore, resistance is not surprising given the wide use of co-trimoxazole as prophylaxis in PLWH in general; however, only a fraction of the studies presented data on co-trimoxazole use among their participants. The degree of immunosuppression and ART influence the risk of infection and hospitalization [], but less than 20% of the studies reported the proportion of PLWH on ART, and only 41% described CD4 cell counts among PLWH.

Many penicillins and cephalosporins are readily available, inexpensive drugs used to treat infections caused by a wide variety of organisms. For S. aureus, the methicillin resistance gene ( mecA) is especially problematic as it confers resistance not just to flucloxacillin but to almost all β-lactam drugs, including third-generation cephalosporins. Treatment of systemic MRSA infections is hence particularly challenging in low- and middle-income settings, as vancomycin and linezolid are not widely available and are expensive and difficult to use safely in PLWH.

This systematic review found that HIV infection is associated with methicillin resistance in S. aureus in studies predominantly from the United States and conducted prior to 2010. The steady decrease in MRSA infections in the United States since 2005 is attributed to the rigorous introduction of enhanced infection control programmes []. This decline was also observed in PLWH, although MRSA incidence remained higher than in the general population [

]. People who inject drugs and men who have sex with men are at increased risk for MRSA [,

]. Given that these populations are more likely to be HIV-infected than the general population in the United States [

,

], the higher prevalence of MRSA may be due to confounding by these factors. However, the association between HIV infection and MRSA was also found in studies from sub-Saharan Africa [] where heterosexual transmission of HIV is predominant, and therefore the association cannot be fully explained by this confounder. Previous studies have found that low CD4 cell counts and unsuppressed HIV viral load, injected drug use and identifying as a man who has sex with men are all associated with MRSA in PLWH [,

]. The high prevalence of MRSA colonization in PLWH may be attributed to hospital admissions caused by HIV-related immunosuppression [

]. On the other hand, the association between HIV infection and resistance may be confounded by the presence of high-risk sexual activities []. Most studies in this review reported on community-acquired MRSA infections reflecting the widespread dissemination of successful MRSA clones.

This review found that the higher odds for MRSA colonization and infection among people with HIV was consistent across different levels of immunosuppression, ART use and country income, although some comparisons may be limited by the very small number of studies in the respective subgroups.

Co-trimoxazole resistance in S. aureus occurs either by mutations in the dihydrofolate reductase gene or by acquisition of variant dihydrofolate reductase genes by horizontal gene transfer [

]. While in Europe the prevalence of co-trimoxazole resistance in S. aureus is relatively low [

], this is not the case for sub-Saharan Africa and Asia [,]. The higher prevalence of resistance in these settings may be explained by the widespread use of co-trimoxazole and other sulphonamide-based drugs for treatment and prevention of infections [,], and potentially by the expansion of particular clonal types within the HIV population []. This is also reflected by the findings of this review which suggest an association between HIV and co-trimoxazole resistance, although estimates varied widely across studies.

S. pneumoniae is a major cause of pneumonia and meningitis; individuals with immunodeficiencies are at increased risk for invasive disease []. β-Lactam drugs, namely benzylpenicillin or amoxicillin, are the mainstay treatment for pneumococcal disease. Recent antimicrobial use, young age, previous hospitalization, infection with certain capsular serotypes, and geographical location are all risk factors for resistant S. pneumoniae strains causing invasive disease [

]. The epidemiology of S. pneumoniae non-susceptible to penicillin varies geographically, and in the late 1990s the majority of invasive pneumococcal disease cases in the United States were attributed to pneumococcal conjugate vaccine (PCV7) serotypes [].

Prevalence of co-trimoxazole resistance also varies geographically and is influenced by prior exposure either to co-trimoxazole [

] or to other sulphonamides such as sulfadoxine-pyrimethamine which are used in Africa for malaria treatment and preventive therapy in pregnancy [].

Our review shows that HIV infection is associated with penicillin non-susceptibility and co-trimoxazole resistance in S. pneumoniae, with one in three isolates cultured from PLWH showing non-susceptibility to penicillin and co-trimoxazole, although this may be overestimated by preferential sampling of people with HIV infection. Given that all studies presenting co-trimoxazole resistance data were conducted in sub-Saharan Africa, it is highly likely that a considerable proportion of PLWH had received co-trimoxazole prophylaxis. Most studies on S. pneumoniae were published before the ART roll-out, and therefore these results may not reflect the current situation.

Our review identified only a small number of studies for the Enterobacteriaceae, but they suggest a higher odds of resistance to third-generation cephalosporins and co-trimoxazole in people with HIV infection, although the confidence interval crossed one for the former. Comparisons of AMR prevalence for other drug classes were precluded by the small number of studies identified. Given that third-generation cephalosporin resistance is associated with resistance to other drug classes, severe infections may require treatment with broad-spectrum antibiotics such as carbapenems. In contrast to high-income settings, where carbapenems usually are available but their use is restricted, these agents are usually unavailable in low-income settings or their use is cost-prohibitive.

Overall this systematic review shows an association between HIV infection and bacterial AMR across multiple pathogens and antimicrobial classes, although for co-trimoxazole, resistance may not be of clinical significance for some infections. Because of the diversity in study settings and populations, and the small number of studies identified, we were unable to assess the trend in AMR prevalence over time. Only 14 studies reported data collected after 2010 and five after 2015, thus precluding conclusions on the current epidemiology of AMR in these settings. Results were consistent across time periods, suggesting that the association between HIV infection and AMR is still relevant despite the relatively small number of more recent studies. This highlights the need for studies and surveillance to report on resistance prevalence according to HIV status, especially in studies from settings with a high HIV burden.

Despite the comprehensive search strategy, without restriction by language, year of publication and geography, only a small number of countries are represented in this review. For example, there were very few studies from South America and Asia. For individual pathogens, the majority of studies are from a single country; most of the studies of S. aureus were from the USA, and most of the studies of S. pneumoniae were from South Africa. Consequently, the results of this review may not be generalizable beyond these countries. Despite the high burden of HIV in sub-Saharan Africa, there are few data on HIV and AMR for most countries apart from South Africa. Additionally, there was substantial heterogeneity among studies which is not surprising given the differences in settings, patient populations, sample types and laboratory methods used for testing. Further heterogeneity may have been introduced by preferential sampling of people with HIV leading to more frequent diagnosis of infection as compared to individuals uninfected with HIV. The high heterogeneity between studies may impact on the generalizability of these findings. For most pathogens, a meta-analysis could not be performed because of the small number of studies. Because this review included observational studies, findings may have been affected by confounding.

This is, to our knowledge, the first systematic review evaluating the association between HIV infection and AMR in a wide range of bacterial pathogens. A comprehensive assessment of the quality of reporting was performed using the STROBE checklist.

The findings of this review underscore the need for further studies evaluating the association between HIV and AMR, especially from countries with a high HIV burden []. Most studies included were published before 2010 and were of moderate and low quality, which may affect the validity of our findings. This study further highlights the need for a better understanding of AMR prevalence in low-income settings and on the extent to which people with HIV may be at increased risk for infections with resistant bacterial pathogens, emphasizing the need for improved antimicrobial resistance testing and reporting. Increasing diagnostic capacity and AMR surveillance, as well as promoting further research into AMR and HIV, could ultimately lead to improved management of HIV-infected patients.

Transparency declaration

The authors declare that they have no conflicts of interest. IDO received funding though the Wellcome Trust Clinical PhD Programme awarded to the London School of Hygiene & Tropical Medicine (grant number 203905/Z/16/Z ).

Appendix A. Supplementary data

The following are the Supplementary data to this article:

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The association between antimicrobial resistance and HIV infection: a systematic review and meta-analysis

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The discovery of antimicrobials has led to a 'golden age' in medicine which has enabled the effective treatment of a large number of once deadly infections. The emergence and worldwide dissemination of antimicrobial resistance (AMR) is threatening to overturn these advances, leading to increased morbidity, mortality and healthcare costs [ ].

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Antimicrobials offer a treatment of deadly infectious diseases. Unfortunately, their effectiveness is hindered by antimicrobial resistance (AMR) in which treatment is no longer effective in preventing diseases like HIV, malaria, and tuberculosis. This leads to increased morbidity, mortality, and healthcare costs. There are solutions to AMR such as changing the drug being used to treat the patient or monitoring the frequency of AMR. However, in LMICs, there is limited availability of drugs or surveillance systems. This results in AMR contributing greatly to the global burden of disease.

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The goal of global health is to "improve public health and strength US National security through global disease detection, response, prevention, and control strategies" (CDC 2020). Disease prevention is a critical component of public health. Within this critical part, there are several global health initiatives for infections diseases such as HIV/AIDS, tuberculosis, and malaria.

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AMR presents a significant and dangerous barrier to disease prevention. It allows infectious disease to continue to spread despite global health disease prevention efforts and contributes greatly to the global burden of disease. While the estimates of its burden are not easily obtained due to inadequate information on geographical distribution, prevalence, and incidence (specifically in LMICs), example of its impact are apparent in the exacerbation of the burden of diseases like malaria, HIV, and tuberculosis. AMR’s worsening of the burden of these disease underscore the need to reduce its impact in order to achieve global health goals. Funding needs to be allocated to developing new non-resistant drugs and monitoring drugs that are developing resistance.