Rickettsia typhi (Murine typhus)
Authors: Max Maurin, M.D., Ph.D., Didier Raoult, M.D., Ph.D.
Microbiology
Rickettsia species are gram negative, strictly intracellular bacilli that multiply within the cytosol of endothelial cells. Rickettsia typhi (formerly R. mooseri), a typhus group rickettsia, is the etiologic agent of murine or endemic typhus.
Epidemiology
Rickettsia typhi is transmitted primarily by the rat flea, Xenopsylla cheopis, although lice and mites are also potential vectors. Commensal rodents (mainly Rattus norvegicus, and Rattus rattus) are considered the main reservoir of bacteria, but other vertebrate hosts may serve as reservoir including house mice, shrews, opossums, skunks, and cats. Rat and rat fleas do not suffer from R. typhi infection, and the latter remain infected life-long. Murine typhus is of worldwide distribution, but occurs primarily in ports and coastal towns where commensal rodents are prevalent. Recent serosurveys and case reports of murine typhus indicate that the disease is still prevalent in all continents, including in Europe (8, 17, 24, 30, 39), Asia (11, 42, 51, 55, 63, 74, 76), especially South-East Asia (3, 5, 21, 41, 43), Africa (2, 12, 33, 38, 44), North America (9, 14, 27, 34, 45, 69), Central and South America (1, 56, 75), New Zealand (20, 48), and in Australia (4, 7, 19, 26). Not surprisingly, murine typhus is frequently diagnosed in travelers returning from endemic areas (53, 64, 67).
Clinical Manifestations
The clinical manifestations of murine typhus are similar to those of epidemic typhus, although the former is usually less severe. The incubation period is usually more prolonged than that of epidemic typhus. Prodromal symptoms include headache, arthralgia and ill feeling, with or without a low grade fever. Onset is characterized by persistent headache, a high grade fever, and a cutaneous rash predominating on the trunk. The rash is usually less apparent than in epidemic typhus, and occasionally absent. Complications remain rare in murine typhus which is considered a benign disease since complete recovery occurs spontaneously in almost all cases. However, severe diseases have been occasionally reported, including ophthalmic complications (28) and severe pneumonia (52, 66), especially in the elderly (65) and in transplanted patients (42).
Laboratory Diagnosis
Diagnosis of rickettsial diseases remains based upon serology (10, 32). An antibody response is usually detected only after 10 days from the onset of systemic symptoms, and antibody titers reach a peak after 3 to 4 weeks or later if an antibiotic therapy has been administered. Thus an appropriate antibiotic therapy should be administered upon suspicion of a rickettsial infection, without waiting for diagnostic confirmation using specific serological tests. Although, murine typhus is usually a mild disease, delay in appropriate antibiotic therapy is the main factor for poor prognosis in patients involved with rickettsial diseases. Before rickettsial antigens were available for diagnosis, the Weil-Felix test was based on the observation that antibodies from patients recovering from rickettsial infections were able to agglutinate antigens from different Proteus vulgaris strains (OX-K, OX-2, OX-19). Sera from patients involved with murine typhus displayed cross reacting antibodies against Proteus vulgaris OX-19. More recent serological tests use R. typhi grown in cell culture as antigen (32). Techniques which have been used include complement fixation tests, microagglutination assays, indirect fluorescent antibody (IFA) tests, and ELISA. IFA remains the current reference, allowing determination of IgG and IgM. Using the IFA test, a single IgG antibody titer of > 128, an IgM titer of > 32, or fourfold increase in antibody titers between acute phase and convalescent phase sera are considered diagnostic. However, serology often does not allow accurate determination of the Rickettsia species involved. Adsorption assays and western blot may help in such a differentiation. Culture of Rickettsia spp. from clinical samples (mainly blood) requires cell culture systems and a level-3 equipped laboratory, and thus is only available in reference laboratories. Sensitivity is low, especially when an appropriate antibiotic therapy has been administered before collecting clinical samples. Direct amplification of rickettsial DNA using PCR or real-time PCR methods may be obtained from blood (buffy coat) or rarely from other clinical samples (18, 46). This technique may be especially useful early in the course of a rickettsial disease, before an antibody response is detected.
Pathogenesis
R. typhi is inoculated to humans through the skin via the bite of the rat flea. Endothelial cells are the primary target cells for rickettsiae, leading to a generalized vasculitis. The diversity of the rickettsial microvascular injuries in the infected patient explains the wide spectrum of clinical manifestations and life threatening complications that may be encountered.
SUSCEPTIBILITY IN VITRO AND IN VIVO
According to their obligate intracellular life-style, susceptibility of rickettsiae to antibiotics cannot be assessed in conventional microbiological tests. Three types of experimental models have been developed to test the antibiotic susceptibility of rickettsiae, including animal models, the embryonated egg model, and cell culture models. Animal models and the embryonated egg model were the first described, however, antibiotic doses used in these models were much higher than those usually used in humans, and therefore it is difficult to extrapolate data to the clinical situation. In vitro infected cell models have been more recently elaborated. They allow more convenient investigation of the antibiotic susceptibility of rickettsiae, and extracellular antibiotic concentrations used in these models may be compared to antibiotic concentrations obtained in human sera.
Single Drug
Animal Models: In mice infected with murine typhus rickettsiae (6), chlortetracycline, and to a lesser extent chloramphenicol were effective, with increased survival ratio as compared to untreated infected mice. Penicillin G was not effective (73).
Embryonated Egg Model: In the embryonated egg model, rickettsiae were injected into the yolk sac of the eggs. This resulted in death of the embryo usually within a few days following infection. Antibiotics were administered by the same route and usually in the same time than rickettsial inoculation. Antibiotic activity was deduced from the difference in mean survival time (DMST) of infected embryos receiving antibiotics as compared to infected untreated controls. A rickettsiostatic effect of antibiotics allowed the embryos to survive up to the last day of experiments, usually 14 days. The rickettsiacidal activity of antibiotics was assessed from subculture of yolk sacs from surviving eggs at 14 days post infection. Direct smear examination prepared from infected tissues and stained with the Gimenez technique were also informative regarding the action of antibiotics. Such model, however, did not allow direct evaluation of the growth rate of rickettsiae.
Using the embryonated egg model, Penicillin G, streptomycin, and gentamicin were not effective (25, 58, 70) (Table 1). PABA (para-aminobenzoic acid) displayed only moderate activity (22, 47, 58). Chloromycetin allowed a DMST > 2.5 days at concentrations > 250 µg/egg (57). Oxytetracycline (Terramycin), chlortetracycline (Aureomycin), doxycycline, erythromycin, and rifampin were found to be effective against R. typhi (40, 60, 61).
Cell Culture Models: The primary target cells for rickettsiae are endothelial cells. However a number of eukaryotic cell lines can be infected with rickettsiae in vitro, including fibroblasts, macrophages, primary chick embryo cells, and human endothelial cells. The plaque formation in infected cell cultures was first used for numeration of viable rickettsiae (35, 36, 68, 71), and then adapted to determine their in vitro antibiotic susceptibility (35, 37, 72). The plaque assay system is currently the recommended technique allowing evaluation of both the bacteriostatic and the bactericidal activity of antibiotics. Cell monolayers (usually Vero cells) grown in tissue culture Petri dishes are acutely infected by rocking incubation with a rickettsial inoculum. Infected cells are then overlaid with Eagle MEM with 2% fetal calf serum and 0.5 % agar. Antibiotics are added at different concentrations at the same time, whereas no antibiotics are added in drug-free controls. Petri dishes are incubated 4 days at 37°C in a 5% CO2 atmosphere. Cell monolayers are then stained with neutral red dye, allowing visualization of the plaques. The MICs are defined as the lowest antibiotic concentration allowing complete inhibition of plaque formation, as compared to a drug-free growth control. A disk assay was proposed as a convenient modification of the plaque assay. In this model antibiotic disks are placed on the surface of the agar overlay. The diameter of the plaque formation inhibition zone around the antibiotic disk represents a measure of the anti-rickettsial activity of the antibiotic.
R. typhi strain Wilmington (ATCC VR-144) was used in most of in vitro antibiotic susceptibility experiments (Table 1). In early experiments, using the plaque assay technique, authors have shown that chloramphenicol (MIC=1.0 µg/ml), tetracycline (MIC=0.1 µg/ml), chlortetracycline (MIC=1.0 µg/ml), and erythromycin (MIC=1.0 µg/ml) were bacteriostatic against R. typhi (6). In contrast, penicillin G, methicillin, ampicillin, oxacillin and cephalotin were not, which concurred with the poor activity of beta-lactam compounds against rickettsial infections observed in vivo. The other antibiotics tested in this study were not bacteriostatic, including aminoglycosides (kanamycin, streptomycin, neomycin), novobiocin, lincomycin, viomycin, cycloserine, bacitracin, polymyxin B, sulfisoxazole, and sulfadiazine (6). Chloramphenicol was active against R. typhi grown in human macrophages (15). Nalidixic acid produced only partial inhibition of plaque formation by R. typhi (35), whereas the fluoroquinolone compounds were moderately active. In a more recent investigation (50), R. typhi was shown to be highly susceptible to doxycycline and rifampin (MIC of 0.125 and 0.25 µg/ml, respectively). Thiamphenicol and erythromycin were rickettsiostatic at concentrations of 2 and 0.5 µg/ml, respectively. Activity of josamycin and clarithromycin was comparable to that of erythromycin. The fluoroquinolones pefloxacin, ofloxacin and ciprofloxacin inhibited rickettsial growth at 1 µg/ml of extracellular concentration. The new ketolide compound, telithromycin displayed an MIC of 0.5µg/ml (49).
ANTIMICROBIAL THERAPY
Drug of Choice
The conventional antibiotic regimen for typhus group rickettsiosis is a 7 to 14 day oral course of doxycycline 200 mg daily (Table 2). Recently, Gikas et al. (16) compared the efficacy of doxycycline, ciprofloxacin and chloramphenicol in 55 patients suffering from murine typhus. The mean time to defervescence was 2.89 days for doxycycline, 4.23 days for ciprofloxacin and 4.0 days for chloramphenicol. Tetracyclines are classically contraindicated in children less than 8 years old because of the possibility of tooth discoloration (59). They are also contraindicated during pregnancy, because they may be toxic to the fetus, including bone toxicity and discoloration of deciduous teeth when given after the 16th week of gestation (59), and they have been reported to cause serious hepatotoxicity, often with pancreatitis, in pregnant women (23). These antibiotics may also induce gastric intolerance and photosensitization as general side effects (59). However, a single dose of 100-200mg doxycycline has been reported to be as effective as the conventional therapy for murine typhus (31). The single dose doxycycline regimen may represent the current best alternative in children less than 8 years old, both because it's the most effective alternative and it's well tolerated.
Monotherapy or Combination Therapy
Antibiotic combinations have not been tested in vitro against R. typhi. The combinations of doxycycline plus ciprofloxacin or plus chloramphenicol in 32 murine typhus patients were no more effective than doxycycline alone (16). Combination therapy is not indicated in common clinical presentations of epidemic typhus. Early administration of doxycycline before definite diagnosis is made is more critical.
Special Situations
In severely diseased patients, doxycycline should be administered first by the intravenous route at 200 mg daily, and a total of 14 days therapy should be considered. There is no clinical indication that other drugs should be more effective than tetracyclines, even in patients with neurological complications.
Alternative Therapy
Chloramphenicol and fluoroquinolones (e.g. ciprofloxacin) may be considered potential alternatives to treat patients with murine typhus (16) (Table 2). Chloramphenicol has often been administered in children as an alternative to tetracyclines (14, 30, 69). However, this antibiotic presents the potential risk of aplastic anemia, and is also contraindicated in pregnant women. Furthermore, relapses of murine typhus have been reported in Israel after treatment with this drug (54). Among 72 patients suffering murine typhus, 9 (i.e. 12.5 %) relapsed 3-8 days after completion of chloramphenicol therapy (2-3 g daily, 6-14 days). Five of the patients who relapsed became afebrile spontaneously, whereas the 4 remaining were successfully treated with tetracycline. Chloramphenicol represent an interesting alternative, when antibiotic therapy should be administered by parenterally, and doxycycline cannot be used. There are some reports of successful therapy of murine typhus using ciprofloxacin (8, 13, 16, 53, 62), and more recently moxifloxacin (53). Fluoroquinolones are highly active against rickettsiae in vitro and present the advantage to be also active in the treatment of enteric fever. Fluoroquinolones are however also contraindicated in the child and the pregnant woman. Although R. typhi is susceptible to newer macrolide compounds (azithromycin and clarithromycin) in vitro, clinical data with macrolides are sparce (29).
ENDPOINTS FOR MONITORING THERAPY
Successful therapy is associated with rapid defervescence and apyrexia usually 3 to 5 days following initiation of treatment (16). Antibiotic treatment should be continued at least 48 hours following apyrexia. Delay in obtaining apyrexia may be observed in patients with severe diseases, especially those with multi-organ involvement. Failure to respond promptly to the antibiotic therapy has never been associated with antibiotic resistance. It should raise the suspicion of an alternate diagnosis, especially in patients with atypical clinical presentation. There are no useful laboratory parameters of successful treatment.
VACCINES
There are no vaccines available.
PREVENTION
Prevention is directed toward the control of flea vectors and potential flea hosts. Since epidemic spread is associated with sources of flea infestation, cases of murine typhus should be reported to local public health authorities.
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Tables
Table 1. In vitro antibiotic susceptibility of R. typhi strain Wilmington (ATCC VR-144). The minimum antibiotic doses or MAD (mg/egg) allowing a DMST > 2.5 days in the embryonated egg model, and MICs (mg/L) obtained in cell culture models are presented.
| Antibiotics | Embryonated eggs MAD (mg/egg) |
Cell Cultures MICs (mg/L) |
References |
|---|---|---|---|
| Penicillin G | 100 |
(6) | |
| Methicillin | 500 |
(6) | |
| Oxacillin | >500 |
(6) | |
| Ampicillin | 500 |
(6) | |
| Amoxicillin | 128 |
(50) | |
| Cephalothin | >100 |
(6) | |
| Streptomycin | 10,000 |
>500 |
(6, 58) |
| Gentamicin | 500 |
16 |
(50, 70) |
| Kanamycin | 500 |
(6) | |
| Neomycin | >250 |
(6) | |
| Chloramphenicol | 1 |
(6) | |
| Chlortetracycline | 125 |
1 |
(6, 40) |
| Oxytetracycline | 50 30 |
(60, 61) | |
| Tetracycline | 0.1 |
(6) | |
| Doxcycline | 50 |
0.125 |
(50, 61 |
| Erythromycin | 50 40 |
1 0.5 |
(6, 40, 50, 61) |
| Lincomycin | 100 |
(6) | |
| Pristinamycin | 2 |
(50) | |
| Josamycin | 1 |
(50) | |
| Clarithromycin | 1 |
(50) | |
| Telithromycin | 0.5 |
(49) | |
| Ciprofloxacin | 1 |
(50) | |
| Ofloxacin | 1 |
(50) | |
| Pefloxacin | 1 |
(50) | |
| Sulfisoxazole | >200 |
(6) | |
| Sulfadiazine | >500 |
(6) | |
| Rifampin | 50 |
0.25 |
(50, 61) |
Table 2. Recommendations for antibiotic treatment of R. typhi infections.
| Condition | Antibiotic | Dose | Duration | References |
|---|---|---|---|---|
| endemic typhus in adult and in child > 8 years |
1. doxycycline | 100 mg b.i.d. p.o. (i.v. in case of severe disease) | 7-14 days | (16) |
| 2. doxycycline | 100-200 mg p.o. | single dose | (31) | |
| 3. chloramphenicol | 500mg every 6 hours | 7-14 days | (16) | |
child of less than 8 years old |
1. doxycycline | 100-200 mg p.o. | single dose | (14, 30, 69) |
| 2. chloramphenicol | 50mg/Kg/day in divided doses every 6 hours | 7-14 days | (14, 30, 69) |
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