City College of San Francisco Microbiology 12

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The Spirochetes

NOTE: INFORMATION ON THIS PAGE IS INTENDED FOR EDUCATIONAL USE ONLY. FOR MEDICAL ADVICE YOU SHOULD CONSULT WITH A PHYSICIAN.

Taxonomy

• DOMAIN BACTERIA
• KINGDOM EUBACTERIA
• SUPERPHYLUM GRACILICUTES
• Order Spirochaetales (from Greek spira=coiled and chaete=hair)

Spirochetes are gram negative, helical bacteria possessing an internal flagellum known as an axial filament. The filament lies between a membranous outer sheath and the cell wall. The organisms move by a corkscrew-type motion which is thought to aid in penetration of fluids and tissues. All spirochetes divide by binary fission, producing two shorter cells from an elongated one.

Representative organisms and disease(s):

• Treponema pallidum & Syphilis
• Borrelia burgdorferi and Lyme Disease

Syphilis

Background

Syphilis is a sexually-transmitted disease (STD ) caused by the spirochete, Treponema pallidum. The genus and species names reflect Greek and Latin word roots meaning "faintly colored turning thread." For many years the origins of the disease have been controversial. Two main schools of thought exist on this issue. The New World (Columbian) Theory proposes that syphilis was endemic in what is now known as Haiti and was brought back to the old world by Columbus' crew following his second voyage in 1493. The Old World (Pre-Columbian)Theory proposes that syphilis had been present in the old world prior to Columbus' voyage and that the disease had been either unrecognized or confused with other diseases such as leprosy. Hudson and others believe that the disease originated in Central Africa, manifested as an infection called yaws. Yaws, transmitted by direct skin contact, produces deep, ulcerative lesions of the skin, underlying tissues and bone. As people moved northward to cooler, drier climes they tended to wear more clothes which made direct transmission of the treponeme difficult. It is thought that the treponeme adapted to be transmitted (most likely) by oral contact and produced a destructive disease called bejel. Yaws-like and/or bejel-like diseases were probably brought to Europe by travelers and slave traders. The treponeme gradually evolved a venereal mode of transmission and many characteristics of present day syphilis. Origins notwithstanding, a major pandemic of syphilis appeared in all parts of Europe in the 1490's including regions as far north as Scotland. During this period syphilis was an acute disease and was often fatal in the secondary stage. Today the treponeme produces a much slower, chronic form of the disease. Studies of the disease have been hampered by the fact that to date, no pathogenic treponemes have been cultured on laboratory media.

For centuries the causative agent of syphilis remained elusive. The period 1905 -1910 saw three critical breakthroughs as far as the clinical management of the disease was concerned:

• 1905: The discovery of T. pallidum by Schaudinn and Hoffmann in Berlin.
• 1906: The development of serologic tests for syphilis. Notably, the Wassermann test, which allowed the detection and treatment of millions of previously undiagnosed individuals.
• 1910. The development of arsenical compounds to treat syphilis, namely Salvarsan (compound 606), developed by Paul Ehrlich. Prior to the use of salvarsan, effective but highly toxic mercury treatment had been used!

Other interesting developments in the treatment of syphilis included the use of "fever-therapy" by the Viennese psychiatrist, Wagner-Jauregg. Starting around 1917, he demonstrated that infecting syphilitics with malaria and allowing up to 12 fever episodes would help produce remissions of syphilis. Malaria therapy was later replaced by the Kettering electronic cabinet in the U.S. with comparable results.

Without doubt, the biggest impact on the treatment of syphilis was the discovery of penicillin by Fleming in 1928. Penicillin remains a major drug of choice for the disease.

Transmission

Syphilis is most often spread via vaginal or anal intercourse as well as oral-genital and oral-anal contact. Transmission usually occurs when there is contact between open lesions on an infected partner and mucus membranes or skin breaks on the receptive partner. The risk of acquiring syphilis from a single exposure with an infected partner is quite high (estimated at one in three). Ulcerative STDS like syphilis also increase the risk of HIV transmission, if present. Treponemes can be transmitted in saliva at certain stages of infection. Donated blood does not have to be screened for treponemes as the bacteria are easily killed by refrigeration.

Congenital syphilis occurs from transplacental transmission of spirochetes and may result in miscarriage or stillbirth. Neonates can suffer a variety of deformities, such as notched incisors, perforated hard plate and "snuffle-nose".

Symptoms and stages

The disease follows three stages if left untreated.

• Primary syphilis is characterized by an ulcerative lesion called a chancre at the site of spirochete entry (see image below). This appears about 3-4 weeks after infection. The chancre is usually hard and painless and occurs on the genitals but may be found on other body sites such as the lips, tongue, fingers and rectum. Chancres may not be detected in females if present on the cervix. The lesions typically clear after about a month without scarring. If untreated the disease will progress. Serologic tests are often negative when the chancre first appears but become reactive in the following 1-4 weeks.

• Secondary syphilis usually occurs several weeks to 6 months after the chancre has healed. This stage is typified by a skin rash of painless, reddish raised bumps that eventually rupture and ooze a discharge. Flu-like symptoms may occur at this time, such as mouth sores, fever, sore throat and fever. Symptoms may come and go over a period of several years during which the person is contagious. The spirochetes may also be transmitted by kissing. Eventually lesions heal and the person enters a latent stage during which there are no signs or symptoms of the disease. This period can last for several years to decades. The only way to detect syphilis at this point is through reactive serologic tests. Spirochetes continue to multiply and invade the circulatory system, CNS and bones.

• Tertiary syphilis occurs in at least 1/3 of those with untreated disease. Permanent damage to the cardiovascular (heart and major blood vessels) and nervous systems occur in this period which can result in death. Granulomatous lesions called gummas can cause massive destruction of nervous tissue and skin. Neurosyphilis can result in paralysis , or a deteriorating form of mental illness called general paresis. Prior to the antibiotic era, as many as 50% of patients in some mental asylums were thought to be suffering of neurologic manifestations of tertiary syphilis.

Diagnosis

In the primary stage, syphilis is diagnosed by examination of the chancre and dark field microscopic examination of fluid from a chancre to which specific antibody against T. pallidum is added. Serologic tests such as the VDRL (Venereal Disease Research Laboratory) test can be used if the disease reaches the secondary stage of infection. VDRL tests tend to have a high rate of false positives and must be followed by a confirmatory test, such as the fluorescent antibody test.

Treatment & Prevention

The disease is treatable with penicillin. Fortunately, the spirochetes have not evolved resistance to this antibiotic. Tetracycline and erythromycin are also effective. With increased availability of penicillin in the 40's and 50's the incidence of syphilis began to fall in the U.S. However, syphilis made a comeback in the 80's, most likely due to increased risky sexual behaviors coinciding with crack cocaine use. Syphilis declined again in the 1990's but vigilance is needed to keep this STD from another resurgence. As with any STD, an awareness of the disease and reducing risky sexual behaviors ( multiple partners and unprotected sex, etc.) are key to controlling the disease. There is no vaccine for syphilis and recovery after treatment does not confer immunity!

Lyme Disease

Background

Lyme disease is currently the most common tick-transmitted disease in the U.S. and was first recognized as the cause of a cluster of juvenile rheumatoid arthritis cases in Lyme, Connecticut in 1975. The causative agent of Lyme disease is the spirochete Borrelia burgdorferi.

The disease was known in Europe as early as 1883 under several other names and has been traced back 100 years in the U.S. Lyme disease is known to produce a confusing variety of symptoms and can make the illness difficult to diagnose. As its symptoms can mimic many other diseases, Lyme disease is often referred to as the "great imitator" or "great masquerader."

Transmission

Lyme disease has a complex pattern of transmission. Three tick species can transmit the disease. In the Northeastern U.S. the tick vector is Ixodes dammini (a.k.a. I. scapularis). Juvenile ticks become infected in the summer when they take a blood meal from a rodent reservoir, the white-footed mouse. As many as 25-50% of I. dammini ticks in the Northeast are infected with Borrelia burgdorferi. The infected larval tick lays dormant over the winter and undergoes further development in the following spring. The tick molts and becomes a nymph. Humans become accidental hosts of the tick if they enter into infested areas in the spring and summer months. Adult ticks normally feed on deer hosts in the fall months.

In the western U.S. the tick vector for humans is Ixodes pacificus. Only 1-5% of I. pacificus ticks are infected with the spirochete, which is too small a fraction to comprise a sustained animal reservoir. The reservoir is the dusky-footed wood rat and the disease in the rat is maintained by Ixodes neotomae ticks. I neotomae ticks do not bite people, so both tick species are needed for humans to become infected.

Photo source: LymeNet. Within a fish hook are three stages of the black-legged tick, Ixodes scapularis, which can transmit Lyme disease. The largest tick in the hook is the adult female, below is a male and in front of the female are two small nymphal deer ticks. Nymphs are though to transmit most Lyme disease to people as they are most active in late spring and early summer. The dog tick on the right of the hook does not transmit Lyme disease.

Lyme Disease. Symptoms and Stages

If left untreated Lyme disease can follow three clinical stages with vary variable features.

The initial infection may accompanied by a spreading bull's eye rash called an ECM reaction (erythema chronicum migrans) four days to several weeks following the tick bite. The ECM only occurs in less than half of all cases and even when it does occur it may go unnoticed. After a tick bite, the spirochetes quickly disseminate in the blood and can be found in the CNS as soon as 12 hours later. This is why all infections need full dose antibiotic therapy with an agent that can penetrate all tissues and in concentrations that can kill the bacteria. A secondary stage follows weeks or months later whereby individuals may develop flu-like symptoms and fatigue. Cardiac arrhythmia's may develop along with arthritis and neurological signs. Third stage Lyme disease involves chronic arthritis and painful joint inflammation that can last for years.

Diagnosis

Lyme disease is still principally diagnosed based on symptoms and the entire clinical picture needs to be evaluated. Often other diseases have to be ruled out. No single test currently exists for a definitive diagnosis of Lyme Disease. A clinician must take into account tick exposure, rashes and evolution of symptoms in a previously asymptomatic person. If the ECM reaction is present, treatment should be started immediately without waiting for test results, as this is when success rates are highest. Serologic tests for antibodies do not become positive for several weeks after a tick bites and results are often inconsistent, especially in late stage Lyme.

Treatment

No one single antibiotic will work against all cases of Lyme disease and the medication and duration of treatment is very much individualized. The spirochete has a long generation time of 12-24 hours in vitro (possibly longer in vivo) and may undergo periods of dormancy, during which time antibiotics will be ineffective against the bacteria. For these reasons long treatment periods are necessary to maker sure the spirochetes are eradicated and to prevent relapses. Drug concentrations may have to be increased because of the deep tissue penetration by Borrelia burgdorferi. Four types of antibiotics are in general use for treatment of Lyme:

• Tetracyclines such as doxycyline
• Penicillins, usually amoxicillin given with probenecid
• Third generation cephalosporins such as ceftriaxone
• Erythromycin and other macrolides given with chloroquine or amantadine

Prevention

When in tick-infested habitats wear light colored clothing so you can spot ticks easily. Cover up exposed skin and use tick repellents containing 25% DEET. Tick repellents containing permethrin should be sprayed on clothes (not skin) and allowed to dry. Check clothes, skin, hair, and fur of pets for ticks. When removing ticks, use tweezers and pull the tick straight out. Do not irritate the tick with heat or chemicals. Be sure to remove the mouthparts from under the skin and take care not to crush the tick. Apply an antiseptic to the tick bite. Tape the tick onto a card and write the date and location of the bite.

In December 1998, the first Lyme Disease vaccine for human use was approved. Called LYMErix (manufactured by SmithKline Beecham), it is a recombinant vaccine which contains the outer surface lipoprotein (OspA) of the spirochete. When infected ticks bite vaccinated people, antibodies in the blood meal enter the tick gut and kill spirochetes before they have a chance to be transmitted. The vaccine is indicated for use in people 15 to 70 years of age. A complete vaccine series consists of three injections. The vaccine efficacy rates have been about 78% against definite Lyme disease. It is unclear how long protection lasts from the vaccine.

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