Antibiotics: Treatment, Sensitivity and Resistance

TREATMENT OF SCRUB TYPHUS

Scrub typhus can be treated with antibiotics, most commonly doxycycline.  Chloramphenicol (chloromycetin) was the original antibiotic found to be effective against scrub typhus, but is now used as an alternative to doxycycline.  Current recommendations on antibiotic treatment are given below.  The first trial treatment of scrub typhus in a population was done in Malaysia in 1948, by a collaborative team consisting of members of a Research Unit of the U.S. Army (shown in the photo below) associated with the Department of Virus and Rickettsial Diseases, Army Medical School, Washington, D.C., and members of the Institute for Medical Research, Kuala Lumpur.

 

 

The collaborative effort resulted in a successful drug trial in Malaysia as reported in The Journal of the Royal Army Medical Corps (Vol 92, No. 2: p. 101-105; 1949). The success of the team was celebrated in an editorial cartoon in the Malay Mail Reporter.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

RECOMMENDATIONS CONCERNING ANTIBIOTIC TREATMENT

Details on the treatment of scrub typhus have been reviewed by Kelly 1999.   Recommendations from this paper are presented in the figure below.

The Centers for Disease Control and Prevention recommends that Scrub typhus should be treated with the antibiotic doxycycline.  Doxycycline can be used in persons of any age.  CDC suggests that antibiotics are most effective if given soon after symptoms begin.  However, some questions have been raised about the timing of treatment, however.   Doxycycline acts as a bacteriostatic agent.  Early treatment or prophylactic treatment has been observed in some situations to result in recrudescence of infection, possibly because of failure to allow full immunological response to infections (Twartz et al 1982).

 

THE POTENTIAL FOR ANTIBIOTIC RESISTANCE

Suspicion of the presence of drug resistant scrub typhus was first raised in the early 1990’s by observations made on patients in northern Thailand at the local provincial hospital (Dr. Charoen Chouriyagune) and by Dr. George Watt from the Armed Forces Research Institute of Medical Sciences, Bangkok (Watt et al., 1996).  They observed patents who were very ill (including 15% who died) in spite of treatment with oral doxycycline or intravenous chloramphenicol.  Given the severity of the disease and treatment failures there was some doubt about the identity of the disease, but serological tests confirmed the diagnosis as  scrub typhus.  Later, isolation of the pathogen removed any question that disease was caused by Orientia tsutsugamushi and also provided materials that genetically demonstrated  the uniqueness of the strains  (Dr. Gregory Dasch, Naval Medical Research Institute Bethesda, MD).  These findings prompted a series of clinical studies evaluating alternate antibiotic treatments including azithromycin and rifampin, in vivo mouse-based sensitivity testing and in vitro cell culture-based trials.

There still appears to be some doubt about the existence of resistance in spite of published clinical, in vitro and in vivo confirmatory data.  It is not apparent how selection for such resistance could occur since the vector mite feeds but once on a vertebrate during the mite’s life-cycle, and laboratory-based attempts to infect mite lines from infected rodents have generally (but not always) failed.  Thus the mite appears to be both the reservoir and the host leaving rodents or humans as dead-end hosts.   It is possible that, if true antibiotic resistance exists in Orientia, it may not be a product of selective pressure. It may have been present in the population throughout the evolutionary history of Orientia.  In this case resistance was detected only relatively recently when clinicians, now armed with better diagnostic tools such as the PCR,  began to recognize and investigate such cases in depth.  Recent data suggesting some sort of non-selective pressure-induced resistance mechanism in Orientia such as homologous recombination may be in play (Sonthayanon, 2010).  Alternately, there is recent evidence garnered from ancient permafrost sediments that have identified genes coding tetracycline resistance in other bacteria that could not have been subjected to selective pressure from human manufactured antibiotics (D’Costa, 2011).  Resistance may have been present all along, possibly due to natural selective pressures.

For additional information, see our recent review on this topic: Kelly, Fuerst and Richards, 2017. The Historical Case for and the Future Study of Antibiotic Resistant Scrub Typhus. Tropical Medicine and Infectious Disease. 2017, 2, 63

 

THE RELEVANCE OF REINFECTION AND/OR PERSISTENCE TO THE ISSUE OF ANTIBIOTIC RESISTANCE

(coming soon – June 2018)

 

GENOMES AND ANTIBIOTIC RESISTANCE

One approach to searching for the basis of antibiotic resistance in Orientia would be to examine the genome sequences that are now becoming increasingly available for study.  Searching for sequences that have homology with genes known to facilitate antibiotic resistance in other organisms is one approach that can be used.  A number of genes have been identified.  Information on these genes is given in a separate page on antibiotic resistance genes.

 

Other potential genes of interest also exist in the genomes.  Many antibiotics work by inhibiting interactions between ribosomal RNAs and ribosomal proteins.  In Rickettsia, differences in drug susceptibility between the typhus and spotted fever group of species appear to be  related to genetic changes in the large subunit rRNA (23S rRNA) gene, together with changes at a ribosomal protein (L22) (Rolain and Raoult, 2005a).   

Other potential genetic sources of antibiotic resistance in members of Rickettsia have been identified (Rolain and Raoult, 2005b), and we can assume that a careful comparison of well curated genome sequence from various isolates of O. tsutsugamushi will yield additional insights.

 

 HORIZONTAL TRANSFER OF RESISTANCE

An alternative approach to searching for the existence of specific resistance genes is to analyze genomes from putative drug resistant isolates,  and compare them with genome sequences from drug sensitive strains to search for genetic differences between sensitive and resistant genomes.  Recombination is suspected to occur much more frequently in Orientia than in other members of the rickettsiales, indicating that horizontal transfer of genes is a real possibility.  There is the possibility that isolates may acquire resistance through horizontal transfer from other isolates or from other bacteria.  Comparison of the genomes searching for altered or missing/added sequences may allow the identification of potential unique target genes or sites for further study.

One problem with this sequence based approach for the study of scrub typhus is that Orientia genes/genomes show substantial variability within the genus.  To successfully identify a gene or site that contributes to resistance, comparisons must be made between “resistant” isolates and “susceptible” isolates that are very similar genetically to putative resistant strains.   However, substantial variation exists in the genes of Orientia, making it difficult to identify which differences are relevant.  Further, structural changes in the genome and gene order are more difficult to identify in Orientia genomes than in the genomes of most bacteria (because of the high percentage of the Orientia genome that is composed of repetitive elements).   One supplementary approach may be possible, if putative resistant isolates show genetic differences from other isolates.  In this case a search for aspects of the sequences of resistant isolates which show unusual similarity (compared to genomes of resistant strains in other taxa) might provide possible target sequences for additional analysis.