Excessive use of antibiotics is a significant public health concern with several severe implications for the development of Antibiotic Resistance and its impact on Gut Microbiota. It is widely recognized that the optimal use of antibiotics can help to reduce the burden of antimicrobial resistance¹⁾. CRP is an acute-phase protein that is raised in infection and inflammation. A finger prick blood test measures it and can be used as a POC test^2-4). It is suggested that the CRP-POC test can reduce initial antibiotic prescriptions and thus improve antibiotic prescribing in respiratory tract infections for adults and children in primary care settings⁵⁾ and avoid unnecessary antibiotic prescriptions, helping to reduce bacterial resistance^6,7). Many studies have explored the role of CRP as a point-of-care tool to assist in decision-making and improve the efficiency of antibiotic prescribing practices among healthcare professionals in primary care settings^8-12). We review the role of C-reactive as a potential point of care test in primary healthcare settings to optimize the use CRP as POC tool for antibiotices prescription.

C-reactive Protein (CRP) is non-specific, acute-phase reactant whose levels increase in response to infection or inflammation due bacterial and viral etiologies¹³⁾. It is produced by the liver in response to acute inflammation, following the release of IL-6 by macrophages and T cells¹⁴⁾. CRP functions in activating the complement system during infectious conditions. The usual range of CRP is less than ten mg/L, but cutoff values for clinical decision-making can vary depending on the condition. Levels between 10 and 40 mg/L are often associated with viral infections, while levels above 40 mg/L are typically seen in bacterial infections. However, severe viral infections, such as those seen during the COVID-19 pandemic, can exceed 100 mg/L of CRP. CRP levels can also increase with age, in liver disorders, and non-specific inflammatory and autoimmune diseases. CRP levels rise within a few hours of the onset of inflammation and peak within 48 hours. The half-life of CRP is approximately 19 hours, and its levels decrease rapidly after the resolution of inflammation.

Several trials have demonstrated the efficacy of POC CRP testing in reducing antibiotic prescriptions. Cals, 2010¹⁵⁾ reported less incidence of antibiotic prescriptions (43.4%) compared to the control group (56.6%) with an RR of 0.77, 95% CI: 0.56–0.98. They emphasized the importance of clinical judgment, suggesting that CRP results can be disregarded, when necessary, based on the clinician's assessment. Do, 2023¹⁶⁾ reported a more significant reduction in the prescription of antibiotics in the intervention group (POC CRP group) (Adjustable RR 0.64 [95% CI 0.60–0.70]. These two studies were mainly focused on respiratory tract infections and in selected patients. Francis, 2020¹⁷⁾ reported that in the POC CRP group, 57% were prescribed antibiotics compared to 77.4% in the control group (adjusted OR 0.31, 95% CI 0.20–0.47). This study focused on patients with Chronic obstructive pulmonary airway disease with acute exacerbations. Interpretation of CRP in these patients is complex as COPD patients already have raised CRP values. Althaus, 2019¹⁸⁾ reported that the odds of prescribing antibiotics were significantly lower in the POC CRP group compared to controls with adjusted OR 0.80 (95% CI 0.65–0.98). This study focused on all acute febrile illnesses, excluding those with malaria, urinary tract infections, skin infections, and many other diseases where CRP is known to rise. However, this study reported severe adverse events in the CRP group, with 23 hospital admissions and one death. Minnaard, 2016¹⁹⁾ reported that antibiotic prescription did not differ significantly with CRP testing. However, POC CRP helped change the decision of antibiotic prescription in 27% of the patients. They have taken patients with acute cough, and POC CRP was explicitly used for clinically ambiguous cases where the need for antibiotics was uncertain. Even in those cases, CRP levels of intermediate level, again the clinical judgment is decided to be the key. The cutoff values of CRP varied across as some stuides using a threshold of <20 mg/L to rule out the need for antibiotics while others used < 10mg/L. Studies also used a higher threshold ranged from 40 mg/L to 100 mg/L.

Likopa, 2022²⁰⁾ did not observed a significant difference in antibiotic prescription rates between the POC CRP testing group and controls, howver, the authors noted a significant reduction was noted in rural areas, with 29% in the POC CRP group and 37.8% in the control group (p= 0.001). They included children with various respiratory, gastrointestinal, and urinary tract illnesses. They suggested that the minimal overall impact on antibiotic prescriptions was due to the lower antibiotic prescription rate by the physicians in that area compared to rural areas. They also emphasized that the cutoff values of CRP are not defined well in children, and the clinicians had to rely on their interpretation of CRP values for antibiotic prescription. Schot, 2018²¹⁾ reported a reduction of antibiotic prescription POC CRP testing at 30.9% versus 39.4% in controls (OR 0.6; 95% CI=0.29 to 1.23).

Severe cases requiring hospitalization and mild instances in which clinical judgment alone is sufficient were not tested. Even in borderline cases, only CRP levels below 20 mg/L or ten mg/L led to the exclusion of antibiotic prescriptions, while the decision in other cases remained dependent on the clinician's judgment. In studies where no significant results were observed, physicians' low baseline antibiotic prescription rates were highlighted, suggesting that clinician training might be more impactful than relying on a non-specific test to decide on antibiotic use. A lack of standardization in CRP cutoff values and variations in testing kits makes cross-study comparisons and systematic reviews difficult.

The main benefit of POC CRP testing is its ease of use, providing results within 2 to 3 minutes from a simple finger prick, which is optimal for an outpatient clinic. It helps in clearly identifying patients for whom antibiotics are not necessary. In doubtful cases, patients can be followed up for reassessment, and antibiotics can be prescribed later if needed.

Various biomarkers, such as C- C-reactive Protein (CRP) and pro-calcitonin, have been explored to reduce unnecessary antibiotic prescriptions for common ailments. Many trials and systematic reviews support using POC CRP tests at the primary healthcare level to decrease antibiotic prescriptions²²⁾. However, some studies have questioned the role of POC CRP testing. While several studies demonstrate reductions in antibiotic use with POC CRP testing, there are many controversies around those need to be resolved, including the cutoff values of CRP for antibiotic prescription, whether CRP can differentiate bacterial and viral etiologies, and whether a single CRP level can reflect the disease state.

The current studies provide a scope for the future and emphasize the need to find out the answers to many questions. CRP may not reliably distinguish between viral and bacterial infections, but higher levels may indicate the need for more aggressive management. In mild bacterial infections, CRP levels may not rise significantly. For patients with intermediate CRP levels, serial testing after 24 to 48 hours can help indicate the trend. An increasing trend may suggest the need for antibiotics, while a decreasing trend may indicate that they can be omitted. CRP testing should be reserved for specific cases where the need for antibiotics is uncertain, as determined by clinical judgment. This approach can be cost-effective and reduce unnecessary testing and antibiotic use in erroneously high CRP levels. Training physicians, alongside CRP testing, may improve the selective prescription of antibiotics. There is we still need to find out the answers to many questions, like

• Can CRP reliably distinguish between bacterial and viral infections? Even in mild bacterial infections, are antibiotics always necessary for treatment?

• Is a single CRP level sufficient to guide treatment decisions, or are serial CRP measurements needed?

• Should CRP testing be reserved for cases where the clinician is uncertain about starting antibiotics, or should every patient with mild symptoms be tested, and treatment decided based on CRP levels in the mid-range or equivocal range?

• To reduce antibiotic prescriptions, is training physicians at the peripheral level more effective than relying on CRP testing for every individual?

There is a lack of standardized guidelines regarding CRP levels for different age groups, especially children, suggesting more research is needed to optimize its application in clinical practice for antibiotic prescription writing in primary care settings. Despite its ease-of-use POC CRP testing cannot be viewed as a standalone tool for antibiotic prescriptions. It needs to bo used in conjunction with clinical assessment, particularly in cases of diagnostic uncertainty. Future research needs to focus on developing uniform guidelines for interpreting CRP levels and evaluating whether serial CRP measurements, physician training, especially in primary care and rural settings, to reduce overprescribing. Ultimately, while POC CRP testing can support antibiotic stewardship, its utility must be carefully balanced with sound clinical judgment.