Deleterious effects of a combination therapy using fluoroquinolones and tetracyclines for the treatment of Japanese spotted fever: a retrospective cohort study based on a Japanese hospital database.

OBJECTIVES: Tetracyclines are the standard treatment for rickettsiosis, including Japanese spotted fever (JSF), a tick-borne rickettsiosis caused by Rickettsia japonica. While some specialists in Japan advocate combining fluoroquinolones with tetracyclines for treating JSF, the negative aspects of combination therapy have not been thoroughly evaluated. Whether fluoroquinolones should be combined with tetracyclines for JSF treatment is controversial. The study aimed to evaluate the disadvantages of fluoroquinolones combined with tetracyclines for JSF treatment. METHODS: This retrospective cohort study was conducted using a Japanese database comprising claims data from April 2008 to December 2020. The combination therapy group (tetracyclines and fluoroquinolones) was compared with the monotherapy group (tetracycline only) regarding mortality and the incidence of complications. RESULTS: A total of 797 patients were enrolled: 525 received combination therapy, and 272 received monotherapy. The adjusted odds ratio (OR) for mortality was 2.30 [95% confidence interval (CI): 0.28-18.77] in the combination therapy group with respect to the monotherapy group. According to the subgroup analysis, patients undergoing combination therapy with ciprofloxacin experienced higher mortality rates compared with those receiving monotherapy (adjusted OR = 25.98, 95% CI = 1.71-393.75). Additionally, 27.7% of the combination therapy group received NSAIDs concurrently with fluoroquinolones. The combination therapy with NSAIDs group was significantly more likely to experience convulsions than the monotherapy without NSAIDs group (adjusted OR: 5.44, 95% CI: 1.13-26.30). CONCLUSIONS: This study found no evidence that combination therapy improves mortality outcomes and instead uncovered its deleterious effects. These findings facilitate a fair assessment of combination therapy that includes consideration of its disadvantages.

Spotted fever rickettsia-induced microvascular endothelial barrier dysfunction is delayed by the calcium channel blocker benidipine.

The tick-borne bacterium Rickettsia parkeri is an obligate intracellular pathogen that belongs to spotted fever group rickettsia (SFGR). The SFG pathogens are characterized by their ability to infect and rapidly proliferate inside host vascular endothelial cells that eventually result in impairment of vascular endothelium barrier functions. Benidipine, a wide range dihydropyridine calcium channel blocker, is used to prevent and treat cardiovascular diseases. In this study, we tested whether benidipine has protective effects against rickettsia-induced microvascular endothelial cell barrier dysfunction in vitro. We utilized an in vitro vascular model consisting of transformed human brain microvascular endothelial cells (tHBMECs) and continuously monitored transendothelial electric resistance (TEER) across the cell monolayer. We found that during the late stages of infection when we observed TEER decrease and when there was a gradual increase of the cytoplasmic [Ca2+], benidipine prevented these rickettsia-induced effects. In contrast, nifedipine, another cardiovascular dihydropyridine channel blocker specific for L-type Ca2+ channels, did not prevent R. parkeri-induced drop of TEER. Additionally, neither drug was bactericidal. These data suggest that growth of R. parkeri inside endothelial cells is associated with impairment of endothelial cell monolayer integrity due to Ca2+ flooding through specific, benidipine-sensitive T- or N/Q-type Ca2+ channels but not through nifedipine-sensitive L-type Ca2+ channels. Further study will be required to discern the exact nature of the Ca2+ channels and Ca2+ transporting system(s) involved, any contributions of the pathogen toward this process, as well as the suitability of benidipine and new dihydropyridine derivatives as complimentary therapeutic drugs against Rickettsia-induced vascular failure.

The clinical course of 239 cases of Japanese spotted fever in Ise Red Cross Hospital, 2006-2019.

INTRODUCTION: Although the mortality rates associated with Japanese spotted fever (JSF) are unknown, advances in testing technology have led to an increase in JSF-induced mortality reported in clinical practice. Up-to-date clinical information is essential for accurate diagnosis and prompt treatment of JSF. METHODS: This retrospective descriptive study included patients with JSF who were treated at the Ise Red Cross Hospital between 2006 and 2019. Diagnostic criteria included positive results of molecular-based tests during the acute phase and/or increased serum-specific antibody titers. This study was performed based on the clinical findings, clinical course, treatment, and prognosis in confirmed cases of JSF. RESULTS: We investigated 239 patients with a confirmed diagnosis of JSF (48.1% men, mean age 69.2 years). Notably, 237 patients received tetracycline antibiotics, and eight patients died (one patient was misdiagnosed and died without adequate treatment). Four of the remaining patients had a multi-organ failure at the time of admission. However, among the 155 consecutive patients who received effective antibiotic therapy after 2012, we observed two deaths; one patient died of hemorrhage secondary to non-steroidal anti-inflammatory drug-induced duodenal ulcer. CONCLUSIONS: Our study showed a case fatality rate of 3.3%, which indicates that JSF is a severe illness. Although a few cases of the fulminant disease are reported, early initiation of therapy was shown to improve JSF-induced mortality by approximately 1%. Prompt initiation of antibiotic therapy (even in the absence of genetic test results) is warranted in cases of suspected JSF.

Massive Tick Bites Causing Spotted Fever Rickettsial Infection: A Hazard in a Tea Plantation, Sri Lanka.

Tea plantations in Sri Lanka cover the central hills of the island, where spotted fever group (SFG) rickettsial infection is common. In most cases, the history of tick bite is obscure and eschars are not present. A 45-y-old female experienced massive tick bites while working in her tea plantation. She developed fever 2 d after exposure, but the diagnosis of SFG infection was not considered until a skin rash appeared on the eighth day. She had a very high titer of antirickettsial antibodies detected by immunofluorescence assay and responded to doxycycline. Here, we highlight the high risk of exposure to ticks and tick bites within tea estates and its causal relationship to SFG infection, which is increasing in Sri Lanka. Active case detection, notification, surveillance, and community awareness are imperative. Possible preventative measures for tick bites have to be introduced. There is a need to explore the effectiveness of local remedies currently in use.

In vitro evaluation of minimum inhibitory concentration of several antibacterial agents against Rickettsia japonica using a plaque reduction assay system.

The study was conducted to determine the minimum inhibitory concentrations (MICs) of several antibacterial agents against Rickettsia japonica, which causes Japanese spotted fever. A plaque reduction assay as an in vitro culture method was conducted to determine the MICs of antibacterial agents (4 types of tetracyclines: tetracycline, doxycycline, minocycline, and tigecycline; 3 types of quinolones: ciprofloxacin, ofloxacin, and levofloxacin; and 2 types of macrolides: azithromycin and clarythromycin) against R. japonica. R. japonica was sensitive to the antibacterial agents tested with MICs similar to those against other spotted fever rickettsia determined in previously described plaque reduction assays.

HLA-B27 spondyloarthritis and spotted fever rickettsiosis: case-based review.

Rickettsia rickettsii, a tick borne disease, is the pathogen responsible for inducing Rocky Mountain Spotted Fever (RMSF), an illness that can progress to fulminant multiorgan failure and death. We present a case where R. rickettsii, acquired on a camping trip, precipitated a flare of peripheral arthritis and episcleritis in an HLA-B27 positive patient. Although Yersinia, Salmonella, Mycobacteria, Chlamydia, Shigella, Campylobacter, and Brucella have been previously associated with HLA-B27 spondyloarthritis, this unusual case demonstrates that obligate intracellular rickettsial organisms, and specifically, R. rickettsii, can also induce flares of HLA-B27 spondyloarthritis. Rickettsial infections in general can rapidly become fatal in both healthy and immunosuppressed patients, and thus, prompt diagnosis and therapy are required.

Rickettsia japonica Infections in Humans, Zhejiang Province, China, 2015.

We investigated 16 Japanese spotted fever cases that occurred in southeastern China during September-October 2015. Patients had fever, rash, eschar, and lymphadenopathy. We confirmed 9 diagnoses and obtained 2 isolates with high identity to Rickettsia japonica strain YH. R. japonica infection should be considered for febrile patients in China.

African Tick Bite Fever Treated Successfully With Rifampin in a Patient With Doxycycline Intolerance.

African tick bite fever is the most commonly encountered travel-associated rickettsiosis, occurring in as many as 5% of travelers returning from rural subequatorial Africa. This case report illustrates that rifampin represents an effective alternative to doxycycline for treatment of African tick bite fever in some selective situations.

Fever and Multiple Eschars After an African Safari: Report of Three Cases.

African tick-bite fever (ATBF), a tickborne disease endemic in rural areas of sub-Saharan Africa and the West Indies caused by Rickettsia africae, has been recognized as an emerging health problem in recent years. ATBF has been reported as the second most commonly documented etiology of fever, after malaria, in travelers who return ill from sub-Saharan Africa. Most cases reported in the literature occurred in middle-aged adults, so the incidence of ATBF in children is unclear. We report a cluster of three cases of ATBF that occurred in children ages 7 to 16 years after returning from a game-hunting safari in South Africa.

Queensland tick typhus in rural New South Wales.

We report five cases of Rickettsia australis infection from southern coastal New South Wales, Australia. All patients presented with a cutaneous eruption of erythematous papules and pustules and systemic features of malaise, headache, lymphadenopathy and myalgia. Acute kidney injury (AKI) was present in two of five cases and one of five cases had acute delirium. Improvement was only seen after treatment with doxycycline 100 mg b.i.d. Positive serology for R. australis was present in four of five cases and a positive polymerase chain reaction (PCR) was seen in one of five cases. Histology showed varying features, from neutrophilic vasculitis to Sweet's syndrome and lymphocytic vasculitis. Recent significant advances in the diagnosis of R. australis infection include an eschar swab or biopsy PCR and isolation of specific Rickettsia on serology. These investigations should be considered in the presence of any of the following features: eschar at site of a tick bite or lymphadenopathy and fever with an eruption of erythematous papules and pustules.

Evaluation of tetracycline and fluoroquinolone therapy against Japanese spotted fever: Analysis based on individual data from case reports and case series.

OBJECTIVES: Although approximately 40 years have passed since Japanese spotted fever (JSF) was first reported in Japan, its treatment has not yet been standardised. As in other rickettsial infections, tetracycline (TC) is the first-line treatment, but successful instances of fluoroquinolone (FQ) combination therapy in severe cases have been reported. However, the effectiveness of TC plus FQ combined treatment (TC+FQ) remains controversial. Therefore, the antipyretic effect of TC+FQ was evaluated in this study. METHODS: A comprehensive search of published JSF case reports was conducted to extract individual patient data. In cases where it was possible to extract temperature data, after homogenising patient characteristics, time-dependent changes in fever type from the date of the first visit was evaluated for the TC and TC+FQ groups. RESULTS: The primary search yielded 182 cases, with individual data evaluations resulting in a final analysis of 102 cases (84 in the TC group and 18 in the TC+FQ group) that included temperature data. The TC+FQ group had significantly lower body temperature compared with the TC group from Days 3 to 4. CONCLUSIONS: Although TC monotherapy for JSF can eventually result in defervescence, the duration of fever is longer compared with other rickettsial infections such as scrub typhus. The results suggest that the antipyretic effect of TC+FQ was more effective, with a potential shortening of the duration that patients suffer from febrile symptoms.

Emerging Spotted Fever Rickettsioses in the United States.

Spotted fever rickettsioses are important causes of emerging infectious disease in the United States and elsewhere. Rocky Mountain Spotted Fever, caused by R. rickettsii causes a febrile, acute illness in dogs. Because it circulates in peripheral blood in low copy number and because of the acute nature of the disease, dogs may test PCR and seronegative at the time of presentation. Therefore, therapy with doxycycline must be initiated and continued based on the clinician's index of suspicion. Combining PCR with serologic testing, repeat testing of the same pre-antimicrobial blood sample, and testing convalescent samples for seroconversion facilitates diagnosis. The prognosis can be excellent if appropriate antimicrobial therapy is begun in a timely fashion. It is well established that dogs are sentinels for infection in people in households and communities. Whether R. rickettsii causes illness in cats is not well established. The role of other spotted fever group rickettsia in causing illness in dogs and cats is being elucidated. Veterinarians should keep in mind that novel and well characterized species of SFG Rickettsia are important causes of emerging infectious disease. Veterinarians can play an important role in detecting, defining, and preventing illness in their canine patients and their human companions.

Acute infectious purpura fulminans: a case series from India.

Acute infectious purpura fulminans is a serious, potentially fatal condition. We present a case series of 11 patients from March 2005 to March 2017, whose clinical symptoms were fever (100%), confusion (63.6%) and headache (55%), and whose common laboratory abnormalities were thrombocytopenia (100%), elevated alkaline phosphatase (70%) and anaemia (63.6%). Three patients (27%) developed gangrene and two presented in shock. Only one grew Neisseria meningitidis in cerebrospinal fluid (CSF) culture and another confirmed by latex agglutination and polymerase chain reaction in CSF. Five others had serology confirmed spotted fever rickettsioses (SFG). All received broad spectrum antibiotics; in 9/11 patients, this included doxycycline or azithromycin. The mean hospital stay was 10.2 days and overall mortality was 18.2%.

Case report: A patient coinfected by Borrelia burgdorferi sensu lato and spotted fever group Rickettsiae in Urumqi, China.

RATIONALE: Both Borrelia burgdorferi sensu lato and spotted fever group Rickettsiae (SFGR) are pathogens carried by ticks. There is a possibility of co-infection with these tick-borne diseases. PATIENT CONCERNS: Male patient, 63 years-of-age, admitted to hospital with skin rash presenting for 1 week and fever with cough and expectoration for 3 days before admission. DIAGNOSES: We diagnosed that the patient was co-infected by B burgdorferi sl and SFGR using laboratory test results and the patient's clinical manifestations. INTERVENTIONS: The patient started therapy with oral minocycline, then levofloxacin by intravenous injection for SFGR. Meanwhile, he was treated with penicillin G sodium, cefoperazone sulbactam sodium and ceftriaxone by intravenous injection for B burgdorferi sl. OUTCOMES: After the patient was in stable condition, he was discharged from hospital. LESSONS: This case report highlights the possibility of co-infection by 2 tick-borne diseases in Urumqi, Xinjiang Uygur Autonomous Region, China. The antibiotic therapy should be based on the detection of pathogenic bacteria, and the different susceptibilities of co-infecting bacteria should be considered.

Case Report: Family Cluster of Japanese Spotted Fever.

Spotted fever group rickettsioses are transmitted by several types of arthropods (including ticks, chiggers, fleas, and lice) and are distributed worldwide. Japanese spotted fever (JSF) was discovered as an emerging rickettsiosis in 1984. The annual number of cases has increased 3-fold during the last decade. In Japan, JSF has been mainly reported in an area with warm climate that borders the Pacific Ocean. We describe a family/neighborhood cluster of three cases of JSF in an area of Japan that had previously not been considered endemic.

Case Report: Typhoid Fever and Spotted Fever Group Rickettsiosis Presenting Concomitantly in an Indian Immigrant.

We present a rare case of an Indian immigrant suffering from concomitant infection of Salmonella typhi and spotted fever group Rickettsia. We discuss the scarce reports of dual infections from the developing world and the related diagnostic challenges.