Tigecycline for Severe Rickettsioses: Gained Experience Needing a Slight Grain of Salt.

Dear Editor:

We read with interest the article by Mastroianni and colleagues titled “Does Tigecycline Have a Place in Therapy for Rickettsial Infection of the Central Nervous System [1].” In this report, the authors describe their experience using tigecycline to treat those with neurologic manifestations of spotted fever group (SFG) rickettsiosis in Italy. In their series of 5 patients, they report a favorable response to the use of high dose tigecycline (200 mg loading dose followed by 100 mg administered twice daily). Tigecycline, a relatively unproven antibiotic for clinical rickettsioses, has in vitro activity against several tested rickettsiae [23] and appears effective in an animal model for lethal Rocky Mountain spotted fever (RMSF) [3]. Although doxycycline is the agent of choice, manifestations such as nausea/vomiting or concern for impaired absorption associated with critical illness, may preclude its oral use. Unfortunately, as highlighted by this article, the parenteral formulation is not always available in some regions [13]. Sharing clinical therapeutic experience through publication of observational studies is of importance when controlled trials are not feasible, so the case series by Mastroianni et al. [1] may be very helpful to clinicians faced with severe manifestations of SFG rickettsioses without the availability of intravenous doxycycline.

It is important to note that these cases described by Mastroianni et al. [1] do not represent RMSF though. RMSF is caused by Rickettsia rickettsii, an organism strictly endemic to the Americas [4]. Rather, the authors are most likely describing illness caused by Rickettsia conorii (Mediterranean spotted fever [MSF]). Like RMSF, manifestations of MSF can be severe with neurologic signs and symptoms [5]. Other SFG rickettsiae are also distributed in Italy (e.g., Rickettsia massiliae and Rickettsia monacensis) and have been documented to cause illness, albeit generally not as severe as MSF [46]. In addition to R. rickettsii being absent from Italy, it is generally not associated with formation of an inoculation eschar, a finding often found in those with MSF [7], as documented in 2 of the patients described in this series [1].

The 5 patients described were all laboratory confirmed via 4-fold increase in antibody titer from paired sera (reportedly separated by 2 weeks), but antibodies stimulated by a SFG rickettsial species will react against antigen derived from other SFG rickettsiae [4]. Without cumbersome cross absorption techniques performed on reactive sera or through use of molecular methods, a species-specific diagnosis is not obtainable through standard serologic methods (i.e., indirect immunofluorescence assay or enzyme-linked immunosorbent assay) [8]. Thus, the regional epidemiology becomes very important when interpreting serologic results. MSF can be quite severe, but the case fatality rate in the antibiotic era is generally lower than that of RMSF (2.5% vs. 4.0 – 8.0%, respectively) [7]. Thus, the optimism for tigecycline’s clinical effectiveness in RMSF must be tempered due to the lack of clinical data with this entity. Despite this point, the experience shared in this series [1] and others (tigecycline has been successfully used in a severe case of Rickettsia australis [9] and Rickettsia typhi infection [10]) is valuable for clinicians when intravenous doxycycline is unavailable.