Journal scan: A review of 5 recent papers of immediate clinical significance, harvested from major international journals, reviews on Doxycycline for Scrub Typhus

From Dharsshini. N, Clinical Pharmacist

(1). Gupta N, Boodman C, Jouego CG, Van Den Broucke S. Doxycycline vs azithromycin in patients with scrub typhus: a systematic review of literature and meta-analysis. BMC Infect Dis. 2023;23(1):884. Published 2023 Dec 18. doi:10.1186/s12879-023-08893-7

Orientia tsutsugamushi is a gram-negative organism belonging to the Rickettsiaceae family. Owing to its intracellular nature, scrub typhus can only be treated by antibiotics that accumulate in large quantities within the target cells. The first antibiotic used to treat scrub typhus was chloramphenicol. Due to its significant toxicity profile, it has been predominantly replaced by doxycycline and azithromycin. In this systematic review and meta-analysis, after screening a total of 744 articles published before March 2023, 10 articles were included in the final meta-analysis. This study included seven additional comparative articles not included in the previous meta-analyses. There was no significant difference between doxycycline and azithromycin concerning the time to defervescence, clinical failure, mortality and treatment-related adverse effects.

While both drugs act by inhibiting protein synthesis, there are significant differences in their mechanism of action. Doxycycline acts on the 30S ribosomal unit and inhibits protein synthesis, which might lead to a quicker reduction in the bacterial load. However, azithromycin, acting on the 50S ribosomal unit, may have a longer-lasting effect on bacterial replication, potentially explaining the comparable clinical outcomes in terms of time to defervescence. The two antibiotics also differ according to the WHO Access Watch and Reserve (AWARE) antibiotic classification. While doxycycline is classified as an ‘Access’ group antibiotic, azithromycin is classified into the ‘Watch’ group. This also has a bearing on the cost and availability of these drugs.

The time to defervescence with doxycycline ranged from 12 to 96 hours, while it was 21 to 96 hours for azithromycin. The clinical failure rates (Day 2-3) varied from 4-41% in doxycycline and 2-70% in azithromycin. When the cut-off for attaining defervescence was taken as five days to define failure, the failure rates in both arms varied between 0 and 7%. Mortality with doxycycline and azithromycin ranged from 0 to 10.9% and 0 to 12.2%, respectively.

Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus

(2). George M. Varghese, M.D., Divya Dayanand, M.P.H. https://orcid.org/0000-0002-8008-1810, Karthik Gunasekaran, M.D., Debasree Kundu, Ph.D., Mukta Wyawahare, M.D., Navneet Sharma, M.D et al,. Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus. N Engl J Med. 2023;388(9):792-803

In a randomized trial conducted in Thailand that enrolled patients with scrub typhus, leptospirosis, or murine typhus, investigators found that the administration of either 3 days of azithromycin or 7 days of doxycycline led to similar median durations of fever clearance at 48 hours.

Interventions and Randomization

Patients underwent block randomization in a 1:1:1 ratio. The first group received 200 mg of doxycycline twice daily on day 1 followed by 100 mg twice daily for 6 days. The second group received 500 mg of azithromycin twice daily on day 1 followed by 500 mg daily for 6 days. The third group (combination therapy) received both azithromycin and doxycycline in the doses mentioned above.

As compared with the doxycycline group, the time until bacterial DNA clearance of O. tsutsugamushi (PCR negativity) was shorter in both the combination group (hazard ratio, 1.33; 95% CI, 1.09 to 1.62) and the azithromycin group (hazard ratio, 1.28; 95% CI, 1.05 to 1.57). The time until PCR negativity was similar in the combination group and the azithromycin group (hazard ratio, 1.03; 95% CI, 0.85 to 1.26).

In this trial involving patients with severe scrub typhus, we found that combination therapy with intravenous doxycycline and azithromycin was superior to monotherapy with either drug with respect to the primary composite outcome of death at day 28, persistent complications at day 7, and persistent fever at day 5 in both the modified intention-to-treat and per-protocol populations. The superiority of combination therapy was mainly due to a reduced incidence of persistent complications at day 7, when the frequencies of respiratory, renal, hepatic, and central nervous system complications were lower in the combination-therapy group than in either of the monotherapy groups.

Why a combination of doxycycline and azithromycin should be more clinically effective in the treatment of severe scrub typhus than either of the drugs alone is a matter of speculation. Through different mechanisms, the two drugs inhibit messenger RNA translation at the bacterial ribosome. Azithromycin binds the 23SrRNA of the 50S ribosomal subunit at the polypeptide exit tunnel, and doxycycline prevents aminoacyl-tRNA binding to the 30S ribosomal subunit.23,24 The combination of the two drugs may result in a more complete blockade of protein synthesis with a consequently greater effect against O. tsutsugamushi. Better bacterial control during the critical first week of infection may result in prevention and faster resolution of severe manifestations of illness.

Because O. tsutsugamushi is an intracellular organism that proliferates and survives in endothelial cells and macrophages, adequate intracellular antibiotic concentrations are essential.25,26 Both antibiotics have excellent tissue penetration, and azithromycin accumulates intracellularly to concentrations that are 100 times as high as those in plasma.23,27,28 This penetration of azithromycin into eukaryotic and prokaryotic cells explains its broad spectrum of activity, specifically against intracellular pathogens. The more rapid clearance of O. tsutsugamushi DNA from the buffy coat in both of the azithromycin-containing regimens may reflect this factor and explain why adding azithromycin to doxycycline (the usual drug of choice for rickettsial infections, including scrub typhus) leads to improved clinical outcomes in severe disease.

(3). George M. Varghese, M.D., Divya Dayanand, M.P.H. https://orcid.org/0000-0002-8008-1810, Karthik Gunasekaran, M.D., Debasree Kundu, Ph.D., Mukta Wyawahare, M.D., Navneet Sharma, M.D et al,. Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus. N Engl J Med. 2023;388(9):792-803 doi: 10-1056/NEJMoa2208449.

“Combination therapy with intravenous doxycycline and azithromycin is a better, more effective way to treat severe scrub typhus than monotherapies of either drug by itself. This new evidence will change treatment guidelines, leading to swifter recovery and potentially saving thousands of lives of people with scrub typhus in the future,” said INTREST study lead author Prof George M Varghese, Department of Infectious Diseases, Christian Medical College in Vellore, India

In the past scrub typhus has been treated with doxycycline or chloramphenicol, though in recent years the use of chloramphenicol has reduced because of its toxicity. Meanwhile, the use of oral azithromycin for mild scrub typhus has increased. Small trials conducted in Thailand and South Korea among patients with mild scrub typhus showed that both azithromycin and doxycycline have similar efficacy. However, systematic reviews of available trials reveal that there is no uniformity in the doses of drugs used or in the outcomes of patients within the studies conducted so far. Hence, it is not clear which drug or how much of it should be used.

Researchers do not know for certain why a combination of doxycycline and azithromycin should be more clinically effective in the treatment of severe scrub typhus than either of the drugs alone. The study found that when both azithromycin and doxycycline were administered together to patients with severe scrub typhus, the bacteria were cleared away quicker and patients improved faster. This could be because doxycycline and azithromycin stop the bacteria from producing proteins through different, but complimentary, mechanisms. As a consequence the combination of the two drugs may have reduced bacterial growth and multiplication, leading to quicker control of bacterial growth and more rapid resolution of symptoms.

(4). Chung MH, Lee JS, Im JH. Antibiotic Combination Therapy for Severe Scrub Typhus: Is It Necessary?. Infect Chemother. 2023 Jun;55(2):179-184. https://doi.org/10.3947/ic.2023.0055

To evaluate the dynamics of bacteria in the human body during antibiotic therapy, it is necessary to directly measure the number of bacteria by inoculating experimental animals or by quantitative polymerase chain reaction (PCR), but these methods are rarely adopted due to a lack of facilities. In 1949, Smadel and his colleagues inoculated mice with blood from patients and showed that O. tsutsugamushi was present in the blood only during fever and for 1 to 2 days before and after the fever. In a previous study, we evaluated the dynamics of bacterial numbers in a cell culture model whereby after cultivating O. tsutsugamushi in cell culture, media containing each individual antibiotic was added to the cell culture. Doxycycline, rifampin, and azithromycin each reduced the bacterial count to 6.2%, 8.8%, and 9.6% of the initial bacterial count after 3 days, respectively, which confirmed the high efficacy of antibiotics currently used in clinical practice. There have been few studies of antibiotic combinations for the treatment of scrub typhus.

Combinations of doxycycline−azithromycin, doxycycline−rifampin, and rifampin−azithromycin showed antimicrobial effects similar to their individual effects in cell culture. In addition, cefotaxime−azithromycin, cefotaxime−doxycycline, and cefotaxime−rifampicin all showed an antagonism. However, peptidoglycan, the main target of β-lactam antibiotics, was thought to be absent in O. tsutsugamushi at that time, making the observed antagonism difficult to interpret. Later, O. tsutsugamushi was shown to have a peptidoglycan-like structure, which can explain the above antagonism. Therefore, caution should be taken when cefotaxime, which is commonly used as the empirical antibiotic treatment for undifferentiated fever in clinical practice, is used in combination with doxycycline. Chloroquine and doxycycline have a synergistic or additive effect against O. tsutsugamushi, as in the treatment of chronic Q fever and Whipple’s disease.

(5). Erin Sirois, Clinical Outcomes in Scrub Typhus Similar With Azithromycin vs Doxycycline. Infectious Disease Advice. February 5, 2024

Researchers performed a systematic review and meta-analysis to compare the effects of doxycycline with azithromycin on clinical outcomes in patients with scrub typhus. They searched Pubmed and Embase databases for relevant studies published through March 2023. Overall, 10 studies were screened for eligibility and included in the meta-analysis. The primary outcome was time to defervescence. Other outcomes assessed included clinical failure, mortality, and treatment-related AEs.

The final analysis comprised 2856 patients. Of the 10 studies reviewed, 5 were conducted in India, and all studies included time to defervescence as either a primary or secondary outcome. Across all studies, patients were administered azithromycin (500 mg daily) and doxycycline (100 mg twice daily) at similar doses, with the exception of 3 studies in which loading doses were used. Both treatments were most commonly administered for 7 days.

Data captured from 9 studies showed no significant difference in time to defervescence between adult patients who received azithromycin vs doxycycline (mean difference, -3.37 hours; 95% CI, -10.31 to 3.57; P =.34). Similar findings were observed between adult and pediatric subgroups, as well as among those who received loading doses. However, azithromycin was associated with significantly shorter time to defervescence in patients with severe disease (mean difference, -10.15 hours; 95% CI, -19.83 to -0.46; P =.04; I2=47%).

Further analysis indicated no significant between-group differences in the risk for clinical failure (risk ratio [RR], 0.78; 95% CI, 0.58-1.05; P =.01) or mortality (RR, 0.82; 95% CI, 0.54-1.24). The risk for treatment-related AEs was similar between the groups (RR, 1.37; 95% CI, 0.62-2.94; P =.33).

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