Figure 1 summarises the key themes of our qualitative analysis and illustrates the pathways (depicted in green) through which the CRP POCT trial outcomes (dark blue) were affected by three inter-related domains of contextual factors (light blue). The first domain was perceived infectious disease risks, defined as treatment risks stemming from the disease environment as HCWs evaluate them in their routine practice (rather than “objective” measures of disease burden in the local area). Second, the health system context comprised health policies and guidelines that governed the work of healthcare workers, and the structure of the health system. Third, the demand-side context related to local healthcare-seeking behaviours and popular conceptions of illness and medicine, and the resulting utilisation of the health system among patients. We exemplified the concrete manifestations of these elements across our three case studies in Table 4 and described the main elements in detail in the remainder of this section, structured according to the three contextual domains.

Fig. 1 Contextual factors influencing C-reactive protein point-of-care test (CRP POCT). Source: Authors, derived from qualitative analysis. “Health systems” here comprise all formal and informal actors involved in promoting, maintaining, or restoring health according to the World Health Organization [91], which can include for example medicine-selling grocery stores alongside public and private hospitals Full size image

Table 4 Summary of contextual impact on outcomes of clinical trials Full size table

Perceived infectious disease risks

The first contextual influence involved HCWs’ perceptions and fears of potentially life-threatening infections and the extent to which they owned and managed the associated treatment risks (e.g. through referral). A doctor in Hanoi suggested for instance that antibiotic prescription decisions related partly to individual risks that the clinical users (i.e. HCWs) of CRP POCT faced in their treatment:

“If we prescribe antibiotics, we would not be blamed for any problem the patients might have. If we don’t prescribe antibiotics, the patients might get worse. In this case, we would not be able to explain to their relatives. And they would not accept our explanation.” (Doctor, Hanoi, FGD)

Perceptions of risks may thereby correspond only partially to the actual epidemiological environment. For example, a survey in Vietnam by Minh [60] detected very low rates of pneumonia of 1.2% among 563 outpatients with acute respiratory infections visiting a paediatric tertiary referral hospital [60]. Yet, doctors in Hanoi repeatedly expressed the need to protect themselves from potentially under-treating such infectious diseases and “co-infections of both viral and bacterial infections” by over-prescribing (Doctor, Hanoi, SSI).

We observed similar tendencies in the Yangon clinics, which catered especially to patients with tuberculosis (TB) and patients with HIV and which were situated among squatter populations with poor hygiene and environmental conditions [61, 62]. The participating doctors would thus describe common risks of co-infection and that: “If [the CRP test result is] low and [the patient’s] condition is bad, and there is bacterial infection, what we fear most in the bacterial infection is the pneumonia. So for that we would give [antibiotics] even if the CRP is low” (Doctor, Yangon, SSI). Considering the possibility of co-infection, antibiotics were also often prescribed as prophylactic treatment especially in patients whom the doctors considered to be high-risk groups (e.g. children, malnourished patients, or those from lower socio-economic backgrounds: “some [patients] are very weak, so then I give antibiotics, but for patients with asthma or heart failure by birth, or children, I give antibiotics even if they are not weak, because they are more prone to infection” Doctor, Yangon, SSI).

In contrast to the experiences from Yangon and Hanoi, respondents in Chiang Rai would only occasionally express a need for prophylactic prescriptions, considering the different patient profiles resulting for example from higher average wealth and access to improved sanitation facilities (e.g. access to improved sanitation in Thailand was 93% in 2015, compared to 78% in Vietnam and 80% in Myanmar [63]; see Additional file 1 for details). However, when for example, pneumonia was suspected, one nurse explained that: “mostly we’d have to refer and a medical doctor will take care of it because that’s something quite serious” (Nurse, Chiang Rai, SSI). Referral mechanisms therefore mitigated the remaining risks for the nurses when patients had low CRP but suspected pneumonia, which underlined the role of the health policy environment as a further determinant of the risks that HCWs perceived when not prescribing an antibiotic.

In summary, perceived infectious disease risks undermined user adherence with CRP POCT insofar as they created a fragile balance between clinical judgment and the fear of missing a bacterial infection. Perceived infectious disease risks when refusing patients antibiotics on the basis of a negative CRP POCT could include social pressure and adverse patient outcomes. Such situations appeared more pronounced in Yangon and Hanoi: doctors more commonly articulated fears of undertreating potentially life-threatening infections and they owned treatment risks to a greater extent than the nurses in Chiang Rai.

Health system context

Policy environment

The health policy environment related to three important themes in our data: (1) the supply environment of antibiotics, (2) the range of available alternatives to antibiotic treatment, and (3) the characteristics of HCWs as users of the CRP POCT.

First, the supply environment contributed to the liberty with which HCWs could prescribe antibiotics. With the 2007 Antibiotic Smart Use campaign and the 2017–2021 National Strategic Plan on Antimicrobial Resistance, Chiang Rai experienced a higher-level drive towards better stewardship alongside local initiatives like stricter monitoring of primary-care-level antibiotic prescriptions [64,65,66,67]. A health centre director described the situation as follows: “the policies from the ministry […] would focus [increasingly] on antibiotics. […] It’s the kind of work of which if we don’t reach the goal, our expenses or income and things like that from that particular performance will decrease” (Nurse, Chiang Rai, SSI). In this strict supply environment, the CRP POCT emerged as a complementary tool to help meet the policy requirement of lower antibiotic prescription.

In contrast, health policy in Myanmar and Vietnam had hitherto focused on expanding the availability of antibiotics, while existing AMR-related policies in Vietnam had remained largely unenforced (e.g. the 2005 Drug Law; [45, 50, 68,69,70]). One manifestation of the comparatively lax regulation was that HCWs experienced no supply restrictions when prescribing antibiotics (notwithstanding the limited spectrum of available antibiotics). A doctor in a non-governmental organization (NGO) clinic in Yangon described for instance that antibiotics were well-stocked compared to other medicines: “We may run out of stock for other medicines but not the antibiotics. Because I think that according to seasonal needs during these months it’s quite high and we have a lot more consultation” (HCW, Yangon, SSI). Such availability of antibiotics was even more pronounced in Hanoi, where some respondents experienced a supply glut of antibiotics to an extent that would render the CRP POCT almost superfluous:

“100% of patients have been provided with antibiotics as here are a lot of antimicrobials in stock that need to be dispensed. Depending on CRP results, I tell my patients to use the antimicrobial immediately or keep for another illness episode.” (Doctor, Hanoi, FGD)

In other words, adherence appeared to drop in conditions of lax regulation and abundant supply.

Second, the presence and promotion of alternatives to antibiotic prescription influenced adherence as well. When asked whether she would prescribe antibiotics to insistent patients, a nurse in Chiang Rai for example explained: “Sometimes I would change to herbal medicines instead because here we have herbal medicines. Instead of antibiotic, I can give them Fah Talai Jone [ฟ้าทะลายโจร] to avoid their antibiotic use, I can use that technique” (Nurse, Chiang Rai, SSI). In Chiang Rai, such alternatives were promoted by antibiotic stewardship initiatives and complemented both the strict regulatory environment and the CRP POCT intervention (another common technique was to defer prescription [47]). The opposite situation materialised in Yangon. The participating NGO clinics (specialising in TB and sexually transmitted infections) would stock only a narrow range of general medicine like cough suppressants. This meant that doctors had to rely on antibiotics for want of more appropriate choices: “If we can get other suppressants, other supported treatment, then we wouldn’t use antibiotics when we hear crepitations” (Doctor, Yangon, SSI). The limited range of non-antibiotic medicine for general patients therefore undermined doctors’ ability to adhere to a negative CRP POCT result.

Third, the policy environment also shaped the characteristics of HCWs, for example their awareness of antibiotic resistance. It was common in all three contexts for HCWs to ignore antibiotic resistance as a local problem relevant to their routine practice:

“I don’t think [antibiotic over-prescription] is a problem in health centres. Because you need to prescribe it anyway, it’s a principle. If you don’t, the patients cannot get better.” (Nurse, Chiang Rai, SSI)

“It is not the problem of my clinic. We do not have the pressure of prescribing antibiotics.” (Doctor, Hanoi, FGD)

“Doctors mainly have limitations [i.e. guidelines when using antibiotics], but I think that the drug stores are out of control. Doctors have their ethics so …” (Doctor, Yangon, SSI)

However, the comparatively active policy environment in Chiang Rai meant that the nurses had been widely exposed to the problem through national policies (“they want us to focus on [antibiotic] ‘Smart Use’ [a campaign to raise awareness and reduce antibiotic use];” (Nurse, Chiang Rai, SSI)), operational guidelines, and the media (“a lot of us [nurses] began to use social [media] now so that increases the knowledge for us;” (Nurse, Chiang Rai, SSI)), while also recognising a greater degree of public awareness (“the patients learn from the media [i.e. TV], as well” (Nurse, Chiang Rai, SSI)). The implementation of the CRP POCT in this environment resonated with the existing degree of antibiotic stewardship. We could not discern such a link in the weaker AMR policy environments of Yangon and Hanoi. A doctor in Yangon indicated for instance that, “Oh, we don’t have it here [i.e. initiatives to reduce antibiotic use]” (Doctor, Yangon, SSI).

A final example of health policy context was its influence on primary-care-level antibiotic prescribers’ prior experience with point-of-care and laboratory tests. Considering that only a few diagnostic technologies were available at the primary care level in Chiang Rai (e.g. finger-prick blood glucose testing [71]), the introduction of a novel point-of-care test was often received favourably by the participating nurses. For example, a nurse described that: “I check on the patients and they would feel, like, like, ‘Our hospital [i.e. health centre] is modern,’ you know? […] It’s like it’s upgraded our class to something higher, and we seem better” (Nurse, Chiang Rai, SSI). The technological enthusiasm was not echoed in Yangon and Hanoi, where the doctors were familiar with a range of diagnostic testing technologies and their hospital and specialised clinic environments offered a variety of testing facilities and routine blood tests (“frankly speaking, we can get X-ray and do something more informative;” (Doctor, Yangon, SSI)). Nuanced and conservative attitudes towards the intervention based on broader experiences with diagnostic technologies therefore suggested a lower degree of reliance on and adherence to the CRP POCT in Yangon and Hanoi.

In summary, our interviews indicated a strong link between the health policy environment and HCWs’ adherence to the CRP POCT intervention. The policy environment shaped the antibiotic supply environment and the monitoring thereof, the availability of alternatives to antibiotic treatment, and the characteristics of the primary-care-level users of CRP POCT. In Chiang Rai, this created complementary conditions for the intervention and reinforced nurses’ trust in and adherence to CRP POCT. The opposite was the case in Hanoi and Yangon, where unrestricted antibiotic supply together with a lax regulatory environment, limited concerns about antibiotic resistance in HCWs’ routine practice, and experience with a wide range of diagnostic technologies appeared to undermine adherence.

Health system structure

The primary healthcare centres hosting the Chiang Rai trial were free of charge (except for unregistered minorities) and commonly accessed by poorer segments of the population, provided that these facilities were neither overcrowded or out of reach [47, 72]. The Yangon study clinics provided free healthcare as well, but were located in poor sub-urban slums with widespread unregulated access to antibiotics and unlabelled medicine sets (so-called “drug cocktails” [61, 62, 73]). In Hanoi, the participating clinics were commonly accessed by the poor and people with health insurance, but the first and cheaper step during an illness was typically self-medication [48, 68]. Our qualitative analysis suggested that such health system configurations influenced patients’ adherence to CRP-POCT-based treatment, but they also determined the population groups who were excluded from routine access to healthcare and thus from the intervention.

Local health system structures shaped the range of available healthcare choices for patients and thereby influenced their adherence to CRP-POCT-based treatment. For instance, patients who incurred a time-consuming and costly visit to a primary healthcare care facility often articulated an expectation to receive some form of medication to not leave the health facility empty-handed. This was particularly pronounced in Chiang Rai, where patients’ responses often reflected explicit expectations for medicines and a sense of entitlement (“I take time to go to the doctor, if they don’t give [medicines] I’d be sad” (patient, Chiang Rai, SSI)). Similar expectations were common in Hanoi (“Some patients requested for more drugs so that they would not have to come back to the clinics at next time of being sick” (Doctor, Hanoi, FGD)), also because health insurance coverage appeared to stimulate medicine expectations (“I go to the clinics because my house is very close to this clinic and medicines are covered by health insurance. So I don’t go to drug store because I have to pay for medicines” (patient, Hanoi, SSI)). The patients interviewed in Yangon had generic expectations of medicine (rather than antibiotics in particular: “The unofficial unprescribed medicines are not helpful so we come in hopes that medicines from here would cure us” (patient, Yangon, SSI)), but also seemed to access informal and private sources of medicine commonly prior to the clinic/hospital visit (“Before [coming to this clinic], I would just take the mixed medicines [“drug cocktails”], I didn’t go to the clinic” (Patient, Yangon, SSI)).

The health system structure also entailed target group heterogeneity in terms of exclusion from routine primary healthcare access, which shaped the potential population-level impact of the intervention. For example, a doctor in Hanoi described that: “Patients in rural areas which are far from the hospital could not come back for re-consultation, so [they] treated themselves with antibiotics at home” (Doctor, Yangon, SSI). In Chiang Rai, villagers living in mountainous areas would cite healthcare access constraints like: “If we don’t have money, we would borrow and go buy [medicines] near our house [rather than going to the hospital]” (patient, Chiang Rai, SSI). Also, seasonal constraints were mentioned, with the workload around the rice harvest meaning that: “most people would come [to the health centre] after they’re done harvesting” (Nurse, Chiang Rai). Access to formal healthcare (and thus to the CRP POCT intervention) would therefore be limited, especially for poor people in rural and mountainous areas and during harvest the season.

In short, the structure of the formal and informal health system determined whether other healthcare providers like pharmacies, private clinics, or even local grocery stores could absorb patients’ demands for antibiotics. Yet, healthcare access constraints like poverty and remoteness led to the exclusion of parts of the relevant target groups in all three case studies.

Demand-side factors

The third and final domain of contextual factors related to the demand side of healthcare services, influencing patients’ adherence to the CRP POCT and exclusion from the intervention. Patient adherence was affected when patients challenged the authority and decisions of HCWs. This was especially pronounced in Chiang Rai, where nurses rather than doctors were involved in the clinical intervention (e.g. “they’re not doctors here [at the health centre], they’re nurses” (patient, Chiang Rai, SSI); versus “I have gone to hospital whenever I am ill. I trust in doctors” (patient, Hanoi, FGD)). In addition, in both Yangon and Chiang Rai (for which we had more comprehensive qualitative data), patients with less formal education, from lower socio-economic strata, or with ethnic minority backgrounds would appear less assertive and more compliant with HCWs’ treatment decisions, stating for instance that: “I don’t have any knowledge, so I’d take anything. I’d take whatever they advise” (patient, Chiang Rai, SSI). Healthcare workers echoed this observation and described these patients as being “easy to talk to” (Nurse, Chiang Rai, SSI) and that they “don’t understand about medicines, so they do accept the treatment we give” (Doctor, Yangon, SSI). Based on these examples, we hypothesise that patient adherence is higher in settings where the distance in power between HCWs and patients is larger.

Adherence to the CRP POCT results could be further undermined if patients’ conceptions of illness and medicine were at odds with the implicit logic of the intervention (viz. a conceptual distinction between bacterial and non-bacterial causes of illness to guide antibiotic prescription). With few exceptions, SSI and FGD respondents in Hanoi articulated a working concept of “bacteria” and “viruses” as disease-causing agents. This conception was less prevalent among our respondents in Chiang Rai and Yangon, who would often link illness to an “inflammation” of the body (Chiang Rai) or to an infection with generic “germs” (Yangon). Respondents in these two sites also had a wider range of notions of antibiotics, which would include “anti-inflammatory medicine” (Chiang Rai), “germ killers” (Chiang Rai, Yangon), or “pesticides” (Yangon), and some patients especially in Yangon did not: “quite understand what germ killers [i.e. antibiotics] are for” (patient, Yangon, SSI). As local conceptions of illness and medicine in Chiang Rai and Yangon more often contradicted the biomedical logic of the CRP POCT, the information to explain the test might have been less effective than in Hanoi. At the same time, we observed a common pattern in Chiang Rai and Yangon that patients misinterpreted and over-estimated the capabilities of the CRP POCT as a comprehensive blood test (e.g. the finger-prick test indicating: “[…] whether this disease is good or bad, or if it’s very serious or not. And we get to know what disease it is […]” (patient, Yangon, SSI)). Ironically, this discrepancy appeared to increase rather than undermine patient adherence (see [47, 73] for more discussion on this point).

Local conceptions of illness and medicine also affected exclusion from the CRP POCT: first, local approaches to self-treatment with antibiotics were common in all three sites, and they could potentially involve strategies as elaborate as described by a patient in Hanoi:

“Sometimes I give [my daughter] ampi [ampicillin], small capsule. After replacing it by cefexim, I found [the treatment] better. Since then, I often treat her with cefixim at home, normally for 3-5 days. If she doesn’t have fever, I will treat her at home or buy medicines from [the] drug store.” (Patient, Hanoi, SSI)

While self-treatment with antibiotics was shaped partly by local conceptions of illnesses and their corresponding remedies, it was also an expression of barriers to accessing healthcare: “If [the patients] are really a hill tribe member, I don’t see them participate [in the trial], I don’t think. Because it’s hard for them to come down [from the mountain], something like that. It’s hard, it’s inconvenient” (Nurse, Chiang Rai, SSI)

Second, a mismatch emerged in Chiang Rai and Yangon between patients’ expectations about antibiotics and the focal condition of the test: neither patients nor HCWs would commonly demand antibiotic treatment for a fever, unless accompanied by other symptoms (see [71] for an analysis of administrative primary-care-level data from Chiang Rai):

“Anti... anti-inflammatory [i.e. antibiotic]; if they have a fever only—fever or cold—I wouldn’t prescribe [an antibiotic]” (Nurse, Chiang Rai, SSI).

Question (Q): “Right. And when you have a fever, do you normally take anti-inflammatory [i.e. antibiotic]?” Response (R): “For just fever, no, only Para.” Q: “There has to be a sore throat.” R: “Yes, if there’s an irritation, I’d take it right away.” (patient, Chiang Rai, SSI).

“Here they don’t ask for germ killers [i.e. antibiotics]. Because people that come here don’t have much knowledge, they might not even know that what they are taking are germ killers.” (Doctor, Yangon, SSI).

“I don’t take medicine [for a fever]. I usually have a sponge bath, if I have doubts [that I have fever], I take a sponge bath. I don’t usually take medicine.” (patient, Yangon, SSI).

Owing to the incongruency between fever and antibiotic demand, a doctor in Yangon reflected that: “I don’t think that it [i.e. CRP POCT] can change much the amount of antibiotics [on the clinic level] based on whether or not to give antibiotics to those 5 or 10 people [out of 200 patients/day]” (Doctor, Yangon, SSI).

In summary, a smaller distance in power between HCWs and patients and discrepancies between the intervention logic and the local conceptions of the target population appeared to undermine patients’ adherence to the CRP POCT results. In addition, incongruencies between local forms of antibiotic use and the disease/healthcare provider focus of the CRP POCT intervention could diminish the potential overall impact at the population level.