Comparison of short‐course versus long‐course antibiotic treatment for community‐acquired pneumonia: a meta-analysis of randomized-control trials

INTRODUCTION

Community-acquired pneumonia (CAP) is defined as pneumonia acquired outside the hospital setting, or that occurs within 48 hours of hospital admission.¹ CAP is one of the leading causes of mortality and morbidity all over the world.² The annual incidence of CAP ranges from 5 to 11 per 1000 adults and is associated with significant healthcare costs.^3,4 Several studies have projected a global rise in antibiotic resistance among CAP-related infections, with substantial clinical and financial ramifications.^4,5 Failure of antibiotic treatment because of inappropriate treatment choice and the resistance may enhance treatment costs if a longer stay in the hospital or a more expensive antibiotic class is needed.¹

Individuals diagnosed with CAP need efficient antibiotic therapy. The most commonly used antibiotics are fluoroquinolones, macrolides, cephalosporins, and beta-lactams.⁶ The selection of an antibiotic is frequently empirical, and individual research findings have not revealed significant differences in the efficiency of different antibiotics.⁷ Certain factors can impact decisions regarding treatment choices, including potential pathogens, their regional resistance profiles, and the safety and efficacy of individual antibiotics.⁸ Currently, several recommendations are there related to the treatment duration. However, treatment courses are mostly for 5 to 14 days.^6,8

Antibiotic therapy duration is vital in the management of patients with CAP. If the duration of antibiotic therapy is short, it will cause treatment failure. On the other hand, longer duration of antibiotic therapy is associated with substantial costs and contributes to increasing rates of antibiotic resistance.⁹ Increased prescribers' adherence to guidelines can cause a significant decrease in mortality and morbidity.⁴ Several studies have been conducted to determine the impact of the duration of antibiotic therapy on individuals with CAP. It has been found that shorter regimens are as effective as longer courses and are safe in reducing the spread of drug-resistant bacteria, improving compliance, limiting treatment-related costs and decreasing adverse events.^10-12 The duration of antibiotic treatment of CAP has been a topic of discussion in scientific communities because of the lack of evidence about the current regimen, i.e., 7 to 10 days of treatment. Besides this, several studies have been carried out to assess the impact of a shorter duration of antibiotic treatment in CAP patients. The present meta-analysis aims to compare the effectiveness of shorter-duration antibiotic treatment with longer-duration antibiotic treatment in patients with CAP.

This meta-analysis was conducted as well as the reported in accordance with the guidelines of the PRISMA statement.

LITERATURE SEARCH

Two authors carried out a scientific literature search on online databases, including EMBASE, PubMed and Cochrane library. The following keywords or corresponding MeSH were used for the search of relevant articles: “community-acquired pneumonia”, “antibiotics”, “drug therapy”, “short course”, “long course”, and "duration". We also manually searched the reference lists of the included studies and reviews. The search time limit was from the inception to 31st December 2022, and the search languages were limited to English only.

Literature screening and data extraction

Two researchers independently screened the literature and extracted data. Firstly, title and abstract screening were done after removing duplicates. Full texts of all eligible studies were retrieved and screened for eligibility criteria using pre-specified inclusion and exclusion criteria. Disagreements between the two researchers were resolved via discussion. Data were extracted using pre-designed data extraction forms designed using Microsoft Excel. Data extracted included the author's name, year of publication, groups, sample size and dose of the antibiotic.

Eligibility criteria

We included only randomized-controlled trials comparing short‐course antibiotic treatment with a more prolonged course in patients diagnosed with CAP. A short course of antibiotic treatment was defined as the treatment of 5 days or less, while seven or more days were defined as long-course antibiotic treatment. We excluded studies conducted on patients with comorbidities like lung cancer and chronic lung diseases. We excluded studies that compared two different antibiotics. We excluded studies that were conducted in children (under 18 years).

Outcome measures

The primary outcomes assessed in this meta-analysis were clinical efficacy (defined as pneumonia associated clinical signs and symptoms were resolved), microbiological efficacy (defined as eradication of bacterial cultures or reduction in the amount of bacterial colonies from baseline) and radiological resolution (areas of consolidation completely resolved), Other outcomes included mortality and drug related adverse events.

Risk of bias assessment

Risk of bias assessment of each included study was assessed by 2 authors independently using Cochrane Risk of bias Assessment tool. Any disagreements between 2 authors resolved by consensus and discussion. Seven domains were assessed and each domain rated as high risk, low risk/unclear risk of bias as per judgment criteria.

Statistical analysis

We used the review manager 5.4.1 software for data analysis. The heterogeneity among the study results was assessed by the I-square statistics. I-square is less than or equal to 50%, indicating low heterogeneity among the study results, and a fixed-effect model was used for data analysis. In case of heterogeneity of more than 50%, a random effect model was used. Outcomes were expressed as risk ratio (RR) and 95% confidence interval (CI). In the present meta-analysis, a p=0.05 was kept as a cut-off. Subgroup analysis was performed.

RESULTS

The process of studies selection is presented in Figure 1. We identified 324 articles through database searching. We excluded 180 articles based on titles and abstract screening. After reviewing 28 full-texts, we further excluded 22 RCTs based on the pre-specified inclusion and exclusion criteria. Eventually, 6 RCTs were included in the current meta-analysis. Table 1 shows the characteristics of included studies. Out of 6 studies, three compared levofloxacin, while gemifloxacin, amixicilin and Quinolones were assessed by one study each. Majority of patients in all studies were males. Figure 2 shows the risk of bias graph.

Comparison of short-term and long-term on rate of clinical efficacy, microbiological efficacy and radiological resolution

Six studies reported the rate of clinical efficacy between short-term and long-term antibiotic treatment. The clinical efficacy rate at the end of treatment in the CAP population was not significantly different between the shorter and longer antibiotic courses (84.23% versus 83.19%, RR: 1.01, 95% CI: 0.98-1.05, I-square: 12%) as shown in Figure 3. In the pooled analysis of the 3 RCTs that reported the microbiological efficacy, the microbiological efficacy rates were 92.11% and 94.61% in short-course and long-course groups, respectively (RR: 0.97, 95% CI: 0.93-1.02, I-square: 0%) as shown in Figure 4. In the pooled analysis of 3 RCT compared radiological resolution between two study arms, no significant differences were reported in terms of rate of radiological resolution (RR: 1.03, 95% CI: 0.91-1.16, I-square: 69%) (Figure 5).

Mortality and drug related adverse events

Two studies compared risk of mortality between two study groups. Incidence of mortality in patients randomized to short-term antibiotic regimen was 2% compared to 3% in long-term antibiotic regimen group (RR: 0.67, 95% CI: 0.28-1.62, I-square: 0%). Five studies assessed drug-related adverse events between patients randomized to short-term and long term antibiotic treatment. Meta-analysis showed that the risk of drug-related adverse events was not significantly different in two study arms (RR: 1.08, 95% CI: 0.96-1.23, I-square: 21%) as shown in Figure 6.

Subgroup analysis

In the subgroup analysis of the studies that used use dose of antibiotics and different dose across each study group, we found no significant difference between two subgroup in any of the primary outcomes (p>0.05). Results were similar to overall pooled meta-analysis as shown in Table 2.

DISCUSSION

The present meta-analysis found that adults with CAP had statistically similar clinical efficacy rates, microbiological efficacy rates, and radiological resolution rates in patients receiving short-course of antibiotics and long-course of antibiotics. In addition, there was no significant difference between the two groups in terms of drug-related adverse events. A meta-analysis conducted by Tansarli et al reported that the clinical efficacy rates were similar in patients receiving antibiotic treatment for a short duration (6 or fewer days) and longer duration (7 or more days).¹⁹

The efficiency of short-course antibiotic therapy for CAP reported in this meta-analysis is also supported by additional studies. There is growing evidence that a shorter duration of antibiotic use can be tried in other forms of respiratory tract infections without change in clinical effectiveness.^20,21 An observational study conducted by Montravers et al found that after three days of antibiotic therapy, infection was significantly reduced or cleared in many patients with ventilator-associated pneumonia.²² Current guidelines by American thoracic society and IDSA recommend that antibiotics can be stopped after minimum use of 5 days, if afebrile for 48-72 hours and no more than 1 sign of clinical instability.²³

Shortened antibiotic therapy can reduce the risk of antimicrobial resistance, antibiotic-related adverse events, the risk of bacterial superinfection, and individual and healthcare system-related costs.²⁴ Longer-course antibiotic therapy may reduce patients’ adherence to the prescribed regimen after the initial days or resolution of symptoms.^25,26 Reduced adherence can lead to enhanced exposure of pathogens to low drug concentrations, leading to drug resistance emergence.²⁷

Regarding the safety of short-course and long-course antibiotic therapy, a more recent systematic review showed no significant differences between the two groups in adverse events.²⁸ The present meta-analysis showed similar findings. However, a review conducted by Gundersen et al found that a shorter course of antibiotics was associated with reduced rates of adverse events compared to longer courses of antibiotics.²⁹

Moreover, some of the included studies used different antibiotic doses in the short-course and long-course antibiotic regimens. It reduces the comparability of RCTs and instead asks whether it is the duration of therapy or the dose of antibiotic that matters to the efficacy rate.

However, we tried to answer this question by performing a subgroup analysis, and the results were consistent with the overall pooled analysis.

The present meta-analysis has certain limitations. Firstly, none of the studies assessed the relationship between antibiotic course and the emergence of resistant microorganisms. Since we were unable to report on this finding, it may be stated that the risk of antimicrobial resistance may be reduced by reducing the duration of antibiotic exposure. Secondly, most studies used different doses in both groups, so it decreases the comparability of included RCTs. Therefore, in the future, more clinical trials need to be conducted that compare short-course and long-course antibiotic therapy with the same antibiotic type and with the same daily dosage.

CONCLUSION

The findings of the present meta-analysis showed that the treatment of CAP with a shorter course of antibiotic is as effective as a longer course of therapy as no significant differences were found between the two groups in radiological resolution, microbiological efficacy and clinical efficacy rate. In terms of safety, we did not find any significant difference in mortality rate and drug-related adverse events. However, only six RCTs were included in the present meta-analysis; therefore, more clinical trials need to be conducted to determine the optimum duration of antibiotic treatment in CAP. These studies need to compare treatment with the same type of antibiotic and the same dose of antibiotic. In addition, studies should focus on adverse events as well, like the development of resistant bacteria to aid in development of recommendations to treat CAP in outpatient clinics.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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