Treatment of rickettsial disease

Antibiotics: Treatment, antimicrobial susceptibility and resistance for rickettsial infections

Rickettsiae are intracellular bacteria insensitive to beta-lactam drugs. The cause for this has long been imputed to an absence of peptidoglycan and lipopolysaccharide (LPS) in their cell walls. Protein-synthesis inhibiting antibiotics are therefore preferred and doxycycline is considered the treatment of choice for all rickettsial infections. The standard regimen is 100mg twice daily for seven days. To reach maintenance levels more rapidly, an initial dose of 200mg can be administered. Importantly, recent findings of peptidoglycan-like structure in Orientia tsutsugamushi , accompanied by in vitro susceptibility to some cell-wall targeting antibiotics, seem to question this view so it is possible that other antibiotics (e.g. phosphomycin) might be used as treatment in the future[1]. The following paragraphs focus on the treatment of scrub typhus, murine typhus and the spotted fevers. The evidence base is poor and there is a need for randomised clinical trials, especially amongst children and for severe disease. There have been no trials of adjunctive, non-antimicrobial, treatment of rickettsial diseases.

Scrub typhus
For the treatment of scrub typhus, some alternatives to doxycycline have good evidence of efficacy: chloramphenicol, tetracycline, azithromycin and rifampicin[2-4]. Other drugs that have been successfully used but for which there is limited evidence are telithromycin and roxithromycin, though in a small case series from northern Thailand the latter seemed to be less effective than doxycycline or chloramphenicol [5, 6]. Some authors have advocated the use of quinolones. However, the clinical response seems slower when compared to doxycycline and a quinolone resistance gene (GyrA) has been found in O. tsutsugamushi, so this class of antibiotics should be avoided [7-9]. As a general rule, doxycycline should be considered the first choice; if it is contraindicated, azithromycin can be given. In case of failure to respond to doxycycline or azithromycin, chloramphenicol or rifampicin can be used but the scrub typhus diagnosis and/or the quality of the antibiotics used should be questioned. The evidence base for treating severe scrub typhus is meagre with no randomized clinical trials; nasogastric or intravenous doxycycline or chloramphenicol are generally used. Intravenous azithromycin is also used but many countries do not have intravenous azithromycin or doxycycline available.

Doxycycline resistance in scrub typhus
Starting from the 1990s, patients with scrub typhus poorly responsive to doxycycline have been reported, especially from northern Thailand. From two cases, O. tsutsugamushi isolates were obtained. They showed reduced response to doxycycline in a rodent model and in cell culture compared to the reference strain[10, 11]. It is not clear if such findings are related to increased disease severity, true antibiotic resistance, high strain virulence, or a combination of those[12, 13]. Because the reports of doxycycline resistance and the evidence behind this theory are limited, if scrub typhus is suspected, doxycycline should remain the treatment of choice.

Murine typhus
The treatment of choice for murine typhus is doxycycline. Although azithromycin and chloramphenicol are occasionally recommended as alternatives, a recent RCT comparing doxycycline to azithromycin showed a worse performance of the latter[14]. Similarly, a retrospective study hinted that doxycycline might superior to both chloramphenicol and ciprofloxacin alone[15]. Doxycycline should therefore be preferred. Murine typhus The treatment of choice for murine typhus is doxycycline. Although azithromycin and chloramphenicol are occasionally recommended as alternatives, a recent RCT comparing doxycycline to azithromycin showed a worse performance of the latter[14]. Similarly, a retrospective study hinted that doxycycline might superior to both chloramphenicol and ciprofloxacin alone[15]. Doxycycline should therefore be preferred.

The spotted fevers
The spotted fever group rickettsiae comprise a vast and ever-increasing number of species but with meagre evidence for optimal therapy. Doxycycline is considered the treatment of choice for all of them. However, almost all research concerning treatment has focused on two species: Rickettsia rickettsii (causal agent of Rocky Mountain Spotted Fever, RMSF) and Rickettsia conorii (causal agent of Mediterranean Spotted Fever, MSF). For RMSF, antibiotics other than doxycycline have shown inferior results and, especially since the disease is severe compared to the other spotted fevers, should be avoided. In cases of severe allergy to doxycycline, the CDC proposes rapid desensitization procedures in an inpatient setting as an option for RMSF. If this is not possible, the only alternative treatment for RMSF, albeit with worse clinical outcomes, is chloramphenicol. For the treatment of MSF, clarithromycin, josamycin and azithromycin showed results comparable to doxycycline and the available evidence suggests that they be used as alternatives[16-18].

Contraindications to doxycycline treatment
Doxycycline is classified as a class D drug by the FDA (“potential benefits may warrant use of the drug in pregnant women despite potential risks”), so most authors recommend prescribing an alternative antibiotic in pregnancy. However, it must be borne in mind that the teratogenic potential of doxycycline has been inferred from the effects of tetracycline and there is hardly any evidence of direct teratogenic effects of doxycycline so the contraindication should be considered relative, especially in the presence of severe disease[19, 20]. Similarly, there have been concerns of tooth discoloration using tetracycline antibiotics in children less than 8 years old. When using doxycycline, recent reviews have not found any evidence of dental damage or any other serious toxicity so doxycycline should be considered a safe treatment option[21].

Atwal, S., et al., Evidence for a peptidoglycan-like structure in Orientia tsutsugamushi. Mol Microbiol, 2017. 105(3): p. 440-452.

Kim, Y.S., et al., A Comparative Trial of a Single Dose of Azithromycin versus Doxycycline for the Treatment of Mild Scrub Typhus. Clin Infect Dis, 2004. 39(November): p. 1329-35.

Watt, G., et al., Doxycycline and rifampicin for mild scrub-typhus infections in northern Thailand: a randomised trial. The Lancet, 2000. 356(9235): p. 1057-1061.

Wee, I., A. Lo, and C. Rodrigo, Drug treatment of scrub typhus: a systematic review and meta-analysis of controlled clinical trials. Trans R Soc Trop Med Hyg, 2017. 111(8): p. 336-344.

Kim, D.M., et al., Controlled trial of a 5-day course of telithromycin versus doxycycline for treatment of mild to moderate scrub typhus. Antimicrob Agents Chemother, 2007. 51(6): p. 2011-5.

Lee, K.-Y., et al., Roxithromycin treatment of scrub typhus (tsutsugamushi disease) in children. The Pediatric Infectious Disease Journal, 2003. 22(2): p. 130-133.

Tsai, C.C., et al., Levofloxacin versus tetracycline antibiotics for the treatment of scrub typhus. Int J Infect Dis, 2010. 14(1): p. e62-7.

Jang, H.C., et al., Inappropriateness of quinolone in scrub typhus treatment due to gyrA mutation in Orientia tsutsugamushi Boryong strain. J Korean Med Sci, 2013. 28(5): p. 667-71.

Tantibhedhyangkul, W., et al., Intrinsic fluoroquinolone resistance in Orientia tsutsugamushi. Int J Antimicrob Agents, 2010. 35(4): p. 338-41.

Watt, G., et al., Scrub typhus infections poorly responsive to antibiotics in northern Thailand. The Lancet, 1996. 348(9020): p. 86-89.

Strickman, D., et al., In Vitro Effectiveness of Azithromycin against Doxycycline-Resistant and -Susceptible Strains. Antimicrob Agents Chemother, 1995. 39(11): p. 2406-2410.

Wangrangsimakul, T., et al., Scrub typhus and the misconception of doxycycline resistance. Clin Infect Dis, 2019.

Kelly, D.J., P.A. Fuerst, and A.L. Richards, The Historical Case for and the Future Study of Antibiotic-Resistant Scrub Typhus. Trop Med Infect Dis, 2017. 2(4).

Newton, P.N., et al., A Prospective, Open-label, Randomized Trial of Doxycycline Versus Azithromycin for the Treatment of Uncomplicated Murine Typhus. Clin Infect Dis, 2019. 68(5): p. 738-747.

Gikas, A., et al., Comparison of the effectiveness of five different regimens on infection with Rickettsia Typhi: Therapeutic data from 87 cases. Am J Trop Med Hyg, 2004. 70.

Bella, F., et al., Randomized Trial of Doxycycline versus Josamycin for Mediterranean Spotted Fever. Antimicrob Agents Chemother, 1990. 34(5): p. 937-938.

Anton, E., et al., Randomized Trial of Clarithromycin for Mediterranean Spotted Fever. Antimicrob Agents Chemother, 2015. 60(3): p. 1642-5.

Cascio, A., et al., Clarithromycin Versus Azithromycin in the Treatment of Mediterranean Spotted Fever in Children: A Randomized Controlled Trial. Clinical Infectious Diseases. 15: p. 154-8.

Cross, R., et al., Revisiting doxycycline in pregnancy and early childhood--time to rebuild its reputation? Expert Opin Drug Saf, 2016. 15(3): p. 367-82.

Gaillard, T., et al., Has doxycycline, in combination with anti-malarial drugs, a role to play in intermittent preventive treatment of Plasmodium falciparum malaria infection in pregnant women in Africa? Malar J, 2018. 17(1): p. 469.

Volovitz, B., et al., Absence of Tooth Staining With Doxycycline in Young Children. Clinical Pediatrics, 2007. 46(2): p. 121-126.