A Dissertation on
A RANDOMIZED STUDY TO COMPARE THE EFFICACY OF SINGLE DOSE ORAL AZITHROMYCIN VERSUS INJECTION BENZATHINE PENICILLIN G IN THE TREATMENT OF EARLY
SYPHILIS IN A TERTIARY CARE HOSPITAL IN SOUTH INDIA
This dissertation submitted to
THE TAMILNADU DR. M.G.R MEDICAL UNIVERSITY In Partial Fulfilment of the university rules and
regulations for award of the Degree of
DOCTOR OF MEDICINE
DERMATOLOGY, VENEREOLOGY AND LEPROSY BRANCH – XX
Reg. No. : 201830054
GOVERNMENT STANLEY MEDICAL COLLEGE & HOSPITAL CHENNAI – 600001
MAY-2021
CERTIFICATE BY THE INSTITUTE
This is to certify that this dissertation entitled “A RANDOMIZED STUDY TO COMPARE THE EFFICACY OF SINGLE DOSE ORAL AZITHROMYCIN VERSUS INJECTION BENZATHINE PENICILLIN G IN THE TREATMENT OF EARLY SYPHILIS IN A TERTIARY CARE HOSPITAL IN SOUTH INDIA” is a bonafide work done by Dr. GURU. R, post graduate student of the Department of Dermatology, Venereology and Leprosy, Government Stanley Medical College and Hospital, Chennai – 600001 during the academic year 2018 – 2021 for the partial fulfilment of university rules and regulation for the award of M.D DEGREE IN DERMATOLOGY, VENEREOLOGY AND LEPROSY (BRANCH - XX). This work has not been submitted previously for the award of any degree.
Dr. PARIMALAMKUMAR Dr. P.BALAJI
M.D., D.D., Dip.N.B., M.S., FRCS., Ph.D., FCLS.,
Professor and Head of Department, Dean,
Department of DVL, Govt. Stanley Medical College Govt. Stanley Medical College & Hospital, Chennai-600 001.
Chennai- 600 001.
DR. K.P SARADHA, MD (DVL)., DCh., Associate Professor,
Department of DVL,
Govt. Stanley Medical College & Hospital, Chennai-600 001.
CERTIFICATE BY THE HEAD OF THE DEPARTMENT
This is to certify that this dissertation entitled
“A RANDOMIZED STUDY TO COMPARE THE EFFICACY OF SINGLE DOSE ORAL AZITHROMYCIN VERSUS INJECTION BENZATHINE PENICILLIN G IN THE TREATMENT OF EARLY SYPHILIS IN A TERTIARY CARE HOSPITAL IN SOUTH INDIA”is a bonafide work done by
Dr. GURU. R,post graduate student of the Department of Dermatology,
Venereology and Leprosy, Government Stanley Medical College andHospital, Chennai – 600001 during the academic year 2018 – 2021 for the partial fulfilment of university rules and regulation for the award of
M.D DEGREE in DERMATOLOGY, VENEREOLOGY AND LEPROSY (BRANCH - XX). This work hasnot been submitted previously for the award of any degree.
Dr. PARIMALAMKUMAR M.D., D.D., Dip.N.B.,
Professor and Head of Department, Department of DVL,
Govt. Stanley Medical College & Hospital, Chennai-600001.
CERTIFICATE BY GUIDE
This is to certify that this dissertation entitled
“A RANDOMIZED STUDY TO COMPARE THE EFFICACY OF SINGLE DOSE ORAL AZITHROMYCIN VERSUS INJECTION BENZATHINE PENICILLIN G IN THE TREATMENT OF EARLY SYPHILIS IN A TERTIARY CARE HOSPITAL IN SOUTH INDIA” is a bonafide workdone by
Dr. GURU. R,postgraduate student of the
DEPARTMENT OF DERMATOLOGY, VENEREOLOGY AND LEPROSY,Government Stanley Medical College and Hospital, Chennai – 600001 during the academic year 2018 – 2021 for the partial fulfilment of university rules and regulation for the award of
M.D DEGREE in DERMATOLOGY, VENEREOLOGY AND LEPROSY (BRANCH - XX).This work has
not been submitted previously for the award of any degree.Dr. K.P SARADHA, MD (DVL), DCh., Associate Professor,
Department of DVL,
Govt. Stanley Medical College & Hospital, Chennai - 600 001.
PLAGIARISM CERTIFICATE
This is to certify that this dissertation work entitled
“A RANDOMIZED STUDY TO COMPARE THE EFFICACY OF SINGLE DOSE ORAL AZITHROMYCIN VERSUS INJECTION BENZATHINE PENICILLIN G IN THE TREATMENT OF EARLY SYPHILIS IN A TERTIARY CARE HOSPITAL IN SOUTH INDIA” of the candidate Dr. GURU. R with Registration Number 201830054 for the award of M.D DEGREE IN DERMATOLOGY, VENEREOLOGY AND LEPROSY (BRANCH - XX). I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains pages from introduction to conclusion and the result shows 7 percentage of plagiarism in the dissertation.
DR. K.P SARADHA, MD (DVL), DCh., Associate Professor,
Department of DVL,
Govt. Stanley Medical College & Hospital, Chennai-600 001.
DECLARATION BY THE CANDIDATE
I Dr. GURU. R solemnly declare that the dissertation titled
“A RANDOMIZED STUDY TO COMPARE THE EFFICACY OF SINGLE DOSE ORAL AZITHROMYCIN VERSUS INJECTION BENZATHINE PENICILLIN G IN THE TREATMENT OF EARLY SYPHILIS IN A TERTIARY CARE HOSPITAL IN SOUTH INDIA” is a bonafide work done by me at the Department of Dermatology, Venereology and Leprosy, Government Stanley Medical College and Hospital during 2018 – 2021 under the guidance of my guide, Dr. K.P SARADHA, MD(DVL), DCh., Associate Professor, and under the supervision of my HOD, Prof. Dr. PARIMALAM KUMAR, M.D., D.D., Dip., N.B.
The dissertation is submitted to THE TAMILNADU Dr M.G.R.
MEDICAL UNIVERSITY towards the partial fulfillment of requirement for the award of M.D DEGREE IN DERMATOLOGY, VENEREOLOGY AND LEPROSY (BRANCH - XX).
Date :
Place: Chennai.
Dr. GURU. RACKNOWLEDGEMENT
Language with all elaborations seems to be having limitations especially when it comes to expression of feelings it is not possible to convey all emotions in words. It would take pages to acknowledge everyone who in one way or another has provided me with assistance, but certain individuals deserve citation for their individual help.
I would like to express my heartfelt thanks to Dr. BALAJI. P. M.S., FRCS., Ph.D., FCLS., Dean, Government Stanley Medical College and Hospital for bestowing me the permission and privilege of presenting this study and for enabling me to avail the institutional facilities.
I fall short of words to express my deep sense of gratitude to my esteemed and reverend teacher, Prof. Dr. PARIMALAM KUMAR, M.D., D.D., Dip.N.B., Professor and Head of Department of Dermatology and Leprosy for her invaluable guidance and motivation.
Words would not be certainly enough to express my gratitude to my guide Dr. K.P. SARADHA MD (DVL)., DCH., Associate professor of the Department of DVL, who has made countless efforts in shaping this study .
Words will not suffice the gratitude I owe to my beloved co-guide Dr. SYED IQBAL, M.D (DVL)., Assistant professor, Department of DVL, for
his guidance and endless patience in moulding of the study.
I would like to express my sincere thanks and heartfelt gratitude to Prof, Dr. V. ANANDAN M.D (Derm), who has been a guiding light with his constant encouragement throughout my Post Graduation course.
I would like to express my sincere and heartfelt thanks to Dr. N. SARAVANAN (DVL), Associate professor of the Department of DVL, for his guidance and encouragement.
I express my deep sense of gratitude to Prof. Dr. S. ARUN KUMAR M.D., and Prof. Dr. M. MANIMEGALAI MD.,DD.,DNB, former Professors, Department of DVL, for their constant support and motivation.
I would like to express my sincere thanks and gratitude to Dr. KAYALVIZHI, M.D (DVL) and Dr. ANITHA CHRISTY, M.D (DVL),
Dr. SARANKUMAR, M.D (DVL) Assistant professors, Department of DVL for their help and suggestions.
I wish to thank my teachers DR. SOWMIYA, M.D (DVL), Dr. NITHYAGAYATHRI DEVI M.D (DVL), Dr. MOHANASUNDARI, M.D
(DVL), Dr. V. SENTHIL KUMAR D.V, DNB (DERM), Dr. MANISURYAKUMAR, M.D (DVL), Dr. SARASWATHI, M.D (DVL),
Dr. N.S. JAYANTHI M.D (DVL), Dr. ANBULAKSHMI. J. DDVL. Assistant Professors Department of DVL, for their valuable guidance, timely advice throughout my study. I am grateful for their valuable advices and encouragement throughout my post graduate course.
I am thankful to my colleagues Dr. Arunkumar. M, Dr. Aveni Koza, Dr. Balakumaran. C, Dr. Jagan. R, Dr. Madhanchand. M, Dr. Pravinkumar. S, Dr. Sakthivadivu. S, Dr. Tamilselvi. V, Dr. Vikram. V.
Huddar for their support throughout the study.
I am also extremely thankful to my seniors, juniors and my wife Er TAMILARASI. S.R. & family members who always supported me
throughout my career. Their love, support and guidance enabled me to reach this stage of life. This work is dedicated to them.
I extended my thanks to Dr Abishek. J. (Department of Community Medicine) who always supported me throughout my study.
I owe a lot of thanks to my patients who cooperated with me throughout my work. Finally it is endowment of spiritualism and remembrance of almighty for all that I achieved.
CONTENTS
S.NO TITLE PAGE.NO
1 INTRODUCTION 1
2. REVIEW OF LITERATURE 3
3. AIMS & OBJECTIVES 45
4. MATERIALS & METHODS 46
5. OBSERVATION & RESULTS
6. DISCUSSION 76
7. SUMMARY 80
8. CONCLUSION 83
9. BIBLIOGRAPHY 84
10. ANNEXURES
i) PROFORMA
ii) CONSENT FORM iii) MASTER CHART
ABBREVIATIONS
CSF - Cerebro Spinal Fluid
HIV - Human Immuno Defficiency Virus
IgG - Immunoglobulin G
IgM - Immunoglobulin M
INJ - Injection
IVDA - Intra Venous Drug Abuse
mRNA - Messenger RNA
RPR - Rapid Plasma Reagin
STD - Sexually Transmitted Disease
TAB - Tablet
TPHA - Treponema Pallidum Hemagglutination Assay
TPI - Treponema Pallidum Immobilization
TP - Treponema Pallidum
TROMP - Treponema Pallidum Rare Outer Membrane Protein TRUST - Toludine Red Unheated Serum Test
VDRL - Venereal Disease Research Laboratory
INTRODUCTION
Syphilis is an infectious disease caused by Spirochaete Treponema pallidum. The disease is transmitted mainly by sexual contact. Treponema pallidum may infect any organ causing an infinite number of clinical presentations. The World Health Organization has estimated that there are 12 million new cases of syphilis globally every year, with 90% occurring in developing countries.1 Despite dramatic decrease of syphilis cases since the onset of the antibiotic era, syphilis remains a relatively common disease and a major public health problem that contributes to substantial morbidity and mortality. Syphilis also contributes to biological amplification of the risk for acquisition of human immunodeficiency virus (HIV) infection, 2-4 for nearly 160 years, the mainstay of syphilis treatment has been penicillin. Due to the lack of an effective vaccine against syphilis, treatment relies completely on antibiotics.
The current recommended therapy for the treatment of early syphilis is a single dose of injection Benzathine Penicillin G 2.4 million IU, 5 widely preferred because of its low cost and absence of problems related to poor adherence. But as with most parenteral therapies, it has the disadvantages of relatively high prevalence of anaphylactic reactions and pain associated with large-volume, deep, intramuscular injections. Most of these disadvantages can be overcome with the introduction of an effective and well tolerated oral drug.
A promising candidate is the macrolide antibiotic, Tablet Azithromycin 2gm
oral stat which has a long half-life and proven efficacy against other sexually transmitted organisms like Chlamydia trachomatis, 6 Neisseria gonorrhoeae,7 Hemophilus ducreyi.8
Injection Benzathine Penicillin G 2.4 million IU exerts a bactericidal action against penicillin-susceptible microorganisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell-wall peptidoglycan, rendering the cell wall osmotically unstable. Tablet Azithromycin 2gm oral stat prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. Azithromycin has also been used in a pilot study to treat early syphilis in North America, as well as in a large randomized controlled trial in Africa.9-10
We compared cure rates for patients of early syphilis treated with a single dose of tablet azithromycin (2.0 g administered orally) with cure rates for those treated with injection benzathine penicillin G (2.4 million units administered intramuscularly).
REVIEW OF LITERATURE
“He who knows syphilis, knows medicine”
Sir William Osler DEFINITION
Syphilis was defined by Stokes, as an infectious disease; due to Treponema pallidum; of great chronicity; systemic from the outset; capable of involving practically every structure of the body in its course; distinguished by florid manifestations on the one hand and years of complete asymptomatic latency on the other hand; able to simulate many diseases in the field of medicine and surgery; transmissible to off-spring in man; transmissible to certain laboratory animals and treatable to the point of presumptive cure.11
HISTORY OF SYPHILIS
There are two theories regarding the origin of syphilis. One, the Unitarian theory, according to which the disease originated in the tropics as a primitive treponemal disease and later spread to more temperate climates affecting more advanced communities where transmission by sexual contact became the usual mode of spread.
The other theory is the Columbian theory, according to which the disease was brought to Europe with the return of Columbus in 1493 after his discovery of America where the disease was existing in American Indians.
From Europe the disease spread to India and Far East through Portuguese sailors.
The disease acquired its name from a poem “Syphilis sive morbus gallicus” written in 1530 by an Italian Pathologist Girolamo Fracastoro about an infected mythical shepherd named Syphilis afflicted with the French disease as punishment for cursing the gods.
Fritz Schaudinn and Erich Hoffmann in 1905 discovered the spiral organism in serum from patient of secondary syphilis. They reported that syphilis was caused by a spirochaete. This work was quickly confirmed when Karl Landsteiner introduced the dark field method for the detection of organism in 1906.
Initially, the treatment of syphilis included less efficient methods that were accompanied by pain and multiple adverse reactions.12 Taking into consideration that the disease was associated with the discovery of the American continent, numerous treatments included plants brought from the New World, such as the guaiac tree (lat. Guaiacum Officinale), known also as sasafras or willow (Salix), which led to the widest recognition at the time.
These plants acted as purgative agents, lead to sudoration, diarrhoea and the increase in urinary debt and were believed to be “blood cleansers”.13
One of the main supporters of the guaiac tree utilisation in the treatment of syphilis, and in the same time an ardupus opponent of mercury treatment, was Ulrich von Hutten (1488-1523), a former priest who described in a detail the manifestations of the disease as well the symptoms of mercury intoxication, based on his own experience as a sufferer from the disease.14-15 From the guaiac tree a decoction was made, the resulted potion was boiled and the patient was
assumed to consume the mixture daily for 30 days. Before drinking the potion, the patient was covered in blankets in order to induce perspiration, and a mild purgative was also administered. [Paracelus (1493-1541) was one of the first supporters of the mercury treatment. Mercury was used in Arabic medicine in the treatment of several dermatomes as well as leprosy, and succeeded to gain rapidly an important place in medical field at that time. Mercury is a potent diuretic that also leads to excessive salivation when administered in toxic doses.
At the time, is considered that the “virus” was eliminated from the body through sweat, salivation and dieresis.16
There were several methods of administering mercury. Thus, in a mixture with grease, mercury was administered topically, leading to ulcerations. Barbarossa pill, named after the Turk admiral who gave the pill to his soldiers and was affected by the malady, contained a mixture of mercury and perfume essence and fruit flavours. Mercurous chloride (calomel, Hg2Cl2) was a white salt able to be administered orally, topically or by injections. The metallic form of mercury was administered also under the form of therapeutic fumigation. Patients seemed to find the adverse reactions of the treatment acceptable, however, the treatment lead to systemic intoxication (hidrargyrism) and pneumonia.
Bismuth salts were introduced in syphilis treatments in 1884. These compounds were less toxic than mercury, in the same time bearing a stronger bactericidal effect that the former, consequently, becoming the cardinal heavy metal employed in syphilis treatment.
German scientist Paul Ehrlich (1854-1915) received Nobel Prize in Physiology and Medicine in 1908 for his discovery of arsphenamine (Salvarsan). The scientist discovered the compound that acted like an antibiotic by accident, while working on finding a cure for Trypanosoma brucei.
Ehrlich’s desire was to discover a “magical bullet”- a drug able to specifically bind to a bacterium and kill it, without affecting human cells. Salvarsan was also denominated as “Compound 606”, as it was discovered after 606 failed experiments.17
The safer novel drug that superseded the more toxic and less water- soluble salvarsan as a treatment for syphilis was Neosalvarsan, also an arsenic compound. Both Salvarsan and Neosalvarsan were replaced in the treatment of syphilis by Penicillin, after 1940. Observing that fever lead to symptomatic improvement of neurosyphilis, various methods of fever induction have been experimented with turpentine, tuberculine, mercury and even Salmonella typhi.
In 1917, the Austrian physician Julis Wagner-Jauregg (1857-1940) includes malaria in the treatment of syphilis. Malaria induced fever paroxysms able to be controlled, as quinine had already been discovered. Jauregg injected patients suffering from malaria with blood presenting Plasmodium vivax. The patients exhibited fever paroxysms lasting for approximately 6 hours and core temperature returning to normal values; quinine was injected after 3-4 cycles on a 2 day period, in order to treat malaria. In 1927 Jauregg received Nobel Prize for Physiology and Medicine for his discovery.18
In 1928, Alexander Fleming (1881-1955) discovered penicilin and from 1943, it became the main treatment of syphilis.Nowadays, worldwide, prevention and treatment programs control syphilis spreading.
EPIDEMIOLOGY
Syphilis occurs all over the world without any restriction of socio economic status. The factors that operate and interact in acquisition and spread of the disease are complex in nature. Sexual promiscuity and prostitution are the twin factors. The population explosion, migration of people from rural to urban areas, disproportionate male to female ratio in urban and pilgrim centres, the mushrooming growth of slums in the cities and towns leading to overcrowding with lower socioeconomic status, decline in moral values, lack of personal and sexual hygiene, all account for the spread of disease. The social stigma attached to a sexually transmitted disease leads to its concealment and aids its spread.
In India, prostitution is still an important cause for the spread of STDs.
Economic factors play a considerable role in prostitution particularly among the underprivileged.
A country’s socioeconomic structure and its functioning determine the prevalence of syphilis in a community. In India, as well as in other developing countries, poor reporting systems make it difficult to obtain the exact incidence and prevalence of syphilis. The reported incidence of early syphilis among STD patients in India is 3.9%.
As per serological surveys prevalence ranges from 2.66 to 26.6%.
Syphilis is more common in males than in females. It has been observed that majority of males continue to be sexually active even after acquiring the infection.19
MICROBIOLOGY
The morphological characteristics of T.pallidum can be studied microscopically. T.pallidum is a close –coiled,slender,regular spiral organism varying in length from 6 to 15 μ m and consisting of from 8 to 24 coils; its width is seldom more than 0.25 μm. The movements of T.pallidum, as seen by Dark Ground examination, may be divided into those of locomotion and those of change of shape. Locomotion consists of rotation and propulsion, the speed of the corkscrew movement of rotation varying with the viscosity of the surrounding medium. Propulsion is slow and regular rather than spasmodic;
when examined with the 2mm oil-immersion objective of the microscope the organism stays within the field of vision for considerable time. Movements of change of shape are angulation, buckling, undulation, coil compression and expansion, and looping; of these ,angulation, in which the organism bends on itself at an acute or obtuse angle, is most typical. In buckling, as when a coil spring is compressed at each end, cenral coils resist the movement and spring out of line. In coil expansion the organism increases in length. Occasionally, looping in the form of a U may be seen.
CLASSIFICATION AND ANTIGENIC TYPES
Classification of the pathogenic treponemes is based primarily upon the clinical manifestations of the respective diseases they cause. Treponema pallidum subsp pallidum causes venereal syphilis; T pallidum subsp pertenue causes yaws; T pallidum subsp endemicum causes endemic syphilis; and T carateum causes pinta. Venereal syphilis is transmitted by sexual contact; the other diseases are transmitted by close non venereal contact.
ELECTRON MICROSCOPE
The cytoplasm of treponemes is surrounded by trilaminar cytoplasmic membrane, enclosed by a cell wall containing peptidoglycan which gives cell rigidity and shape. External to this is lipid rich outer membrane layer, through which only a few antigenic proteins protrude (TROMP) from each end of cell.
There is 3 - 4 endoflagella which wind around axis of cell but do not protrude outside, remain within outer membrane layer. The highly immunogenic portions of organism are lipoprotein anchored predominantly to periplasmic leaflet of cytoplasmic membrane and protoplasmic cylinder.21
CULTIVATION
Pathogenic T.P. does not grow in artificial media. Virulent T.P. strains are maintained for decade by serial testicular passage in rabbits (Nichol Strain).
This is used for diagnostic and research purpose. The isolate of non - pathogenic T.P (Reiter Strain) is used as antigen in group specific treponemal test for diagnosis of syphilis. The Reiter strain grow well on thioglycollate medium containing serum.
RESISTANCE
Treponema pallidum is very delicate, inactivated by drying or at the temperature of 41 - 42ºC in one hour which is the basis for fever therapy which was practiced earlier to cure syphilis. It is killed in 1 - 3 days at 0 - 4ºC. It is Inactivated by contact with soap, arsenic, mercury, bismuth and common antiseptic agents.
PATHOGENESIS
The complex host microbe interactions that characterize the varied clinical course of syphilis are poorly understood. The outer membrane of Treponema pallidum is a phospholipid bilayer through which only a few antigenic proteins protrude and the major membrane immunogens are subsurface proteolipids. These structural features, along with a slow doubling time of 30- 33 hours, result in a delay in host immune response since the principal immunogens are largely inaccessible as long as the spirochetes remain intact.
This feature undoubtedly plays a role in the organism’s ability to persist despite an apparently vigorous host immune response and the development of cross reacting non specific non treponemal antibodies. The immune response fails to clear the infection in many instances because an effective Th1 (cellular) response is downregulated in difference to an ineffective Th2 (humoral) response. In immunologically dysfunctional persons (eg. those infected with HIV) aggressive and/or persistent chronic infections are more likely.
Spirochetemia can occur throughout the course of Treponema pallidum infection including asymptomatic stages of incubation and latent syphilis.22
CLASSIFICATION
CONGENITAL ACQUIRED
1.Early EARLY SYPHILIS (Infectious)
2.Late 1. Primary
3. Stigmata 2. Secondary
3. Early latent
4. Relapse and Reinfection
LATE SYPHILIS
(Non infectious) 1. Late latent 2.Tertiary syphilis -BENIGN TERTIARY (16%)
-CARDIOVASCULAR (10.4%)
PRIMARY SYPHILIS
It is characterized by a chancre which develops after an incubation period of 9-90 days (mean 21 days) following infection and is usually accompanied by regional lymphadenitis.
It presents as a single, indurated, painless ulcer with sharply defined border. The floor consists of dull red clean looking granulation tissue and is covered by a yellowish slough or a greyish scab. A painless non - inflammatory, discrete enlargement of the adjacent lymph nodes usually bilateral develops after the appearance of the lesion.
Two third of cases on healing leave thin atrophic invisible scar. Extra genital chancre occurs on anorectal, oral cavity, breast, hands, fingers, nails etc.
Condom chancre - chancre occuring at hilt of shaft of penis.
Chancre redux - recurrence of primary sore at the site of original lesion
Pseudo chancre redux - Gumma occuring at the site of primary sore
Follman's balanitis - Inflammatory reaction of glans in primary syphilis.
The primary lesions will heal even without treatment within three to ten weeks and may go unnoticed by the patient.
SECONDARY SYPHILIS
The lesions of secondary syphilis usually occur six to eight weeks after the appearance of primary lesions. The lesions are generalized, affecting the skin and mucous membranes.
Characteristically, these eruptions are non vesicular, non pruritic, widespread and bilaterally symmetrically distributed.23
TYPES OF CUTANEOUS LESIONS IN SECONDARY SYPHILIS
Macular Syphilide.
Papular Syphilide (Annular, Corymbose, Papulosquamous, Lichenoid and Lenticular).
Papulo squamous Syphilide.
Pustular Syphilide.24
MACULAR SYPHILIDE
Appearing at about 8 weeks, the eruption may be pinkish, coppery red, round or oval in shape distributed chiefly over shoulders, chest, back, abdomen and flexor surfaces of upper arms. It disappears in few days or evolves into a papular rash.
PAPULAR SYPHILIDE
Maculopapular rash is most characteristic which appears 3 months post infection. They present as dull red, non scaly lesion distributed over trunk, extremities, face and genitals. Lichenoid, nodular and acneiform lesions also occur.
ANNULAR SYPHILIDE
Annular syphilide is seen mostly in black patients. It consists of annular lesions on the face, anogenital area, axillae, palms, and soles.
Lenticular syphilide manifests as pinhead to lentil or bean-sized papules on face and genitalia.
LICHENOID SYPHLIDE
Lichenoid syphilis is characterized by maculopapular lesions with a lichenoid (violaceous) hue. It had been described frequently in the pre- penicillin era. A recent increase in its incidence may be attributable to the HIV epidemic
CORYMBIFORM
Characterized by a central plaque and surrounding smaller satellite papules
CORONA VENERIS
Linear arrangement of papules along the forehead below hairline.
BUSCHKE OLLENDORF SIGN
Deep dermal tenderness can be elicited over the rash present over bony prominence by pressing the papule directly with a small blunt object like a pin head.
CONDYLOMA LATA
Large fleshy, greyish white, moist, flat topped and broad based papule and plaque distributed over intertriginous areas like peri anal area, between thigh and scrotum, vulva and perineal regions. It is loaded with treponemes and is highly infectious.
HAIR INVOLVEMENT IN SECONDARY LESIONS MAY PRESENT AS
1. Follicular papular lesions on scalp.25 2. Diffuse alopecia
3. Irregular patches of non scarring hair loss on occipital and parietal regions of scalp (moth eaten alopecia).
NAILS
Nail involvement may lead to britttle nails, pitting, onycholysis or shedding.
Nail fold involvement will lead to paronychia.
PAPULO SQUAMOUS SYPHILIDE:
1. Papular eruption in which scaling is prominent and papules coalesce to form plaque.
2. Presence of scaly plaque may resemble the clinical picture of psoriasis.
LUES MALIGNA
1. Malignant syphilis is more prevalent in immunosuppresed individuals.
2. Characterised by prodrome of fever, headache, muscular pain followed by papulo pustular eruption.
3. The eruption soon become necrotic resulting in sharply marginated ulcer with thick rupioid crust.
4. Mucous membrane may be involved and hepatitis may occur.26
MUCOSAL PATCH
Greyish white patch in which surface gets eroded forming a sharply defined superficial erosion surrounded by a dull red area. Confluence of the lesions form irregular serpiginous erosions called as ‘SNAIL TRACK ULCERS’ seen in oral and genital mucosa.
LATENT SYPHILIS
The latent period of syphilis follows the secondary stage. By definition latent syphilis is that stage of syphilis where there are no clinical signs or symptoms of the disease; the spinal fluid has been examined and its negative, but the serological tests for syphilis are reactive. This latent period is divided into early and late. Early means that the disease has been present for less than two years and late for more than two years.27
LATE SYPHILIS
In this stage of syphilis, the following clinical features are encountered.
1. Late latent syphilis.
2. Late benign (Gumma including visceral syphilis).
3. Systemic syphilis, (ie) cardiovascular syphilis and neurosyphilis.
The optic neuritis and optic atrophy are considered as special late entity.
LATE BENIGN SYPHILIS
The essential lesion of late benign syphilis is gumma. Gummas are probably the result of hypersensitivity reactions of treponemal infection. The most common sites are skin, bone and liver, but nearly any organ may be involved.
Skin lesions may be solitary or multiple.They are destructive and chronic. They tend to heal centrally and extend peripherally. Skin lesions may present as nodular lesions, psoriasiform lesions or subcutaneous gumma and heal with tissue paper scarring.
Bone lesions are usually marked by periosteitis with new bone formation, or by gummatous osteitis with bone destruction. Deep seated boring pain at the site is the commonest symptom. The most common sites are cranial bones, the tibia and the clavicle.
CARDIOVASCULAR SYPHILIS
Cardiovascular syphilis is usually caused by medial necrosis of aorta, with aortic dilatation which may extend into valve commissures. The clinical signs of cardiovascular syphilis are those of aortic insufficiency or saccular aneurysm of the thoracic aorta. When fully developed, these conditions are not difficult to detect. Careful clinical evaluation of hypertension, arteriosclerosis and previous rheumatic heart disease is essential. Saccular aneurysm of the thoracic aorta is primafacie evidence of cardiovascular syphilis. Aortic insufficiency with no other valvular lesions in a person of middle age, with a
reactive serological test should be considered as cardiovascular syphilis, until proven otherwise. VDRL titre are usually low in cardiovascular syphilis.27 CENTRAL NERVOUS SYSTEM SYPHILIS 28-29
After acquiring the infection, spirochetes frequently invade the meninges earlier within 3 - 18 months of infection, eventhough neurosyphilis is considered as a late manifestation.CNS involvement is classified by Merrit et al. as
1. Asymptomatic Neuro Syphilis:
Characterized by CSF abnormalities (ie) positive CSF VDRL, increased cell count, occasionally increased protein without symptoms or signs of neurological involvement.
2. Meningeal Syphilis :
Onset is usually less than 1 year after acquiring infection which involve either brain or spinal cord and presents with headache, nausea, vomiting, neck stiffness, cranial nerve involvement, seizures and changes in mental status.
Those presenting with uveitis or iritis frequently have meningeal syphilis.
3. Meningovascular syphilis :
Occurs 5 to 10 years after infection. The disease reflects diffuse inflammation of pia and arachnoid together with evidence of focal or widespread arterial involvement. Common presentation is Stroke syndrome involving middle cerebral artery often manifesting as subacute encephalitic syndrome.
4. Parenchymatous syphilis a. General paresis of insane
Occurs 15 - 20 years after infection which reflects widespread late parenchymal damage; including abnormalities of personality , hyperactive reflexes, Argyll-Robertson pupil, Altered sensorium and reduction in recent memory and speech.
b.Tabes dorsalis
The disease occurs due to demyelination of posterior column, dorsal rootand dorsal root ganglia. Usually occurs 25 - 30 years after infection and Symptoms include ataxic wide based gait, paresthesia, bladder disturbances, impotence, areflexia and loss of position, deep pain and temperature sensation., Charcot Joint (Trophic Joint degeneration), perforating ulceration of feet and a small irregular Argyll robertson pupil reacting to accommodation and not to light.
DIAGNOSIS:
BEDSIDE INVESTIGATIONS DARK FIELD MICROSCOPY
In a dark field microscope only light rays hitting the organism or particles at an oblique angle, enter the microscope objective and so the organism appears as a bright object which exhibits cork screw movement on a dark background. The main component of a dark field microscope is the dark field condenser.30
SPECIMEN COLLECTION -ULCER
With gloved hands clean the ulcer is cleaned using a gauze piece soaked in normal saline. The ulcer is let dry and held between thumb and index finger which Allows serous fluid to come out from the ulcer. The serous fluid is transferred to clean sterile glass slide and covered by cover slip .a drop of oil is added on the condenser of dark field microscope and the slide is examined immediately.
LYMPH NODE
Lymph nodes commonly affected are inguinal, axillary, cervical, epitrochlear and femoral lymph nodes. The skin over the enlarged lymph node is infitrated with 1% lidocaine for local anesthesia. The overlying skin is stretched and the lymph node is held firmly. With a disposable syringe, 0.2 mL of sterile normal saline is injected into the lymph node. The lymph node is massaged gently and fluid is aspirated and expressed on a glass slide.31
Amniotic fluid obtained by amniocentesis can also be examined by dark field microscopy for treponemes in pregnant women suspected to have early syphilis.32
GRAM STAIN - To look for gram negative organisms.
TZANCK SMEAR - To look for herpes virus.
TISSUE SMEAR - To look for donovanosis.
SEROLOGICAL TEST FOR SYPHILIS 33
NON TREPONEMAL TESTS TREPONEMAL TESTS Complement fixation
tests(Wasserman reaction) Flocculation test
-Rapid plasma reagin (RPR)
-Venereal Disease Research Laboratory(VDRL)
-Toluidine Red Unheated Serum Test(TRUST)
Treponema pallidum immobilization assay(TPI) Fluorescent treponemal antibody absorption (FTA-AbS) test.
Treponema pallidum
haemagglutination assay(TPHA) Treponema pallidum passive particle agglutination
assay(TPPA) Enzyme immune assay(EIA) Western
Blot(WB) and Pseudoblots Automated Chemiluminescence platforms Chromatographic point of care (POC)tests
Microsphere Immunoassay.33
VENEREAL DISEASE RESEARCH LABORATORY TEST 34-35
Mechanism: This detects both immunoglobulin IgG and IgM (Ab against cardiolipin) formed by the host in response to lipoidal material released by damaged host cells early in infection and lipid from the cell surfaces of the treponeme itself.
Seroconversion occurs from 21 days of exposure till about up to 6 weeks after infection.
Variants of Venereal Disease Research Laboratory test
RPR test: Results are available within 5 min Conventional RPR card test, Automated RPR test
Uses cardiolipin Ag with carbon Immunoassay technique using latex Particle to detect regain Ab Particles coated with lecithin and cardiolipin
Toludine red unheated serum test
Unheated serum reagin test
Reagin screen test
Automated reagin test.
INTERPRETATION
Qualitative test for screening syphilis
Results are reported as nonreactive, reactive, and weakly reactive IN REACTIVE NTT:
A fourfold increase in titer indicates infection, reinfection, or treatment failure
A fourfold decrease in titer indicates effective therapy.
QUANTITATIVE VDRL:
The VDRL test can be quantitated by examining serial dilutions of serum and can be used to follow the course of illness, including the response to therapy
Patients with early syphilis who have been treated with appropriate doses and preparations of benzathine penicillin should be evaluated clinically and serologically, using NTT, after 3 months to assess the results of therapy
A second evaluation should be performed after 6 months and, if indicated by the results at this point, again after 12 months to reassess the condition of the patient and detect possible reinfection.
When a nontreponemal serologic test shows persistent reactivity with no signs of decline of titer at 6 months even after adequate therapy or if it fails to show a fourfold decrease of initial high titer within 1 year, it is considered a seroresistance or serofast state.
ADVANTAGES
Inexpensive and simple Suitable for mass screening
The baseline titer can be used to follow-up the treatment response.
LIMITATIONS
Reduced sensitivity in primary syphilis and late latent syphilis
False-positive results due to technical error and variations in normal population, due to antiphospholipid autoantibodies (biologic false positivity)
False-negative results: In VDRL test, the optimal ratio of the antigen antibody yields an insoluble precipitate that is visible, thus rendering the test positive. The zone of equivalence defines this optimal ratio.
TREPONEMA PALLIDUM HAEMAGGLUTINATION ASSAY (TPHA):
FLUORESCENT TREPONEMAL ANTIBODY ABSORPTION (FTA-Abs) TEST:
EXAMINATION OF THE CEREBROSPINAL FLUID IN NEUROSYPHILIS
The CSF is a sensitive indicator of presence of active neurosyphilitic infection.
The CSF abnormalities consists of
1. Cell count : More than 5 lymphocytes.
2. Total proteins : A total protein of more than 40mgs%.
.
3. CSF VDRL : A reactive CSF VDRL is practically always an indication of central nervous system syphilis,
but not necessarily of its activity. False positive reactions in the cerebro
spinal fluid are rare.
4. Increase in gammaglobulin (IgG) - Usually with oligoclonal banding.(28-29)
The glucose content is usually normal. In general, the cell count may be expected to return first to normal followed by the protein and finally the serological test. Early forms of neurosyphilis (meningeal and meningo vascular) and ocular syphilis (uveitis) were more common in patients who were inadequately treated for early syphilis than in untreated patients. Partial therapy clears most treponemes from the peripheral sites of infection,with organisms remaining in the eye and the central nervous system. These organisms were then able to multiply unhampered by the immune system, leading to ocular and neurologic disease.
TREATMENT OF PRIMARY, SECONDARY AND EARLY LATENT SYPHILIS (36-37)
RECOMMENDED REGIMEN
- Inj. Benzathine penicillin G 2.4million units intramuscular single dose (1.2 million units deep IM in each buttock) given after testing intradermal.
sensitivity for penicillin (or)
-Inj.Procaine benzyl penicillin 600000 IU daily I.M for 10 days (or) -cap doxycycline 100mg BD for 14 days
All the patients who have syphilis should be tested for HIV infection. If it is negative, a repeat test should be done after 3 months, especially in areas where the HIV prevalence is high. Patients with early syphilis who have features suggestive of meningitis or uveitis should be evaluated for neurosyphilis.
FOLLOW UP
EVERY MONTH - FIRST 3 MONTHS.
EVERY 3 MONTH - NEXT 6 MONTHS.
EVERY 6 MONTHS - NEXT 1 YEAR.
There should be fourfold decrease in the non treponemal (VDRL) titre within 6 months. Patients who have persistent symptoms or recurrence of symptoms, or failure of titre to decline fourfold within 6 months should be re- evaluated for reinfection, treatment failure, HIV infection or unrecognized CNS infection. All such patients should undergo a thorough neurological evaluation including CSF analysis and HIV testing.
When they are retreated, they should preferably be given 3 weekly doses of Inj. Benzathine penicillin G 2.4million units, unless CSF examination indicates the presence of neurosyphilis.
TREATMENT OF LATE LATENT SYPHILIS
All the patients who have latent syphilis should be evaluated for tertiary syphilis. CSF analysis is clearly indicated if any one of the following criteria is present.
- CNS or eye changes.
- Evidence of active tertiary syphilis.
- HIV infection.
- Treatment failure.
- Non treponemal titre>1.32.
If the CSF analysis shows features of neurosyphilis then the patient should be treated for the same.
Late latent syphilis should be treated with 3 weekly doses of Inj.
Benzathine Penicillin G 2.4 million units IM after test dose or Inj. Procaine benzyl penicillin G 1.2 million units IM daily for 20 days.
DOSES IN CHILDREN
Three weekly injection of Benzathine Penicillin G at a dose of 50,000 units per kg body weight upto an adult dose of 2.4million units IM.
FOLLOW-UP
EVERY MONTH - FIRST 3 MONTHS. EVERY 3
MONTH - NEXT 6 MONTHS.
EVERY 6 MONTHS - NEXT 1 YEAR.
EVERY YEAR - NEXT 3 YEARS.
After treatment, the patient should be re-evaluated for neuro syphilis if any of the following criteria is present.
- Fourfold increase in the titre of VDRL.
- An initially high VDRL titre(>1.32) failing to decline at least fourfold within
12-24 months of therapy.
- The patient developing signs and symptoms of tertiary syphilis.
PENICILLINS
The penicillins shares chemistry, mechanism of action, pharmacology, and immunologic characteristics with those of cephalosporins, monobactams, carbapenems, and βlactamase inhibitors. All are β-lactam compounds, so named because of their unique four-membered lactam ring.38
CHEMISTRY
All penicillins have the basic structure shown in Figure 4. A thiazolidine ring(A) is attached to a β-lactam ring (B) that carries a secondary amino group (RNH–). Substituents (R; examples shown in Figure 1) can be attached to the amino group. Structural integrity of the 6-aminopenicillanic acid nucleus (rings
A plus B) is essential for the biologic activity of these compounds. Hydrolysis of the βlactam ring by bacterial βlactamases yields penicilloic acid, which lacks antibacterial activity.38
Figure 1Basic structure of penicillin
CLASSIFICATION
Substituents of the 6-aminopenicillanic acid moiety determine the essential pharmacologic and antibacterial properties of the resulting molecules.
Penicillins can be assigned to one of three groups (below). Within each of these groups are compounds that are relatively stable to gastric acid and suitable for oral administration, eg, penicillin V, dicloxacillin, and amoxicillin.
1. Penicillins (Eg, Penicillin G)
These have greatest activity against gram-positive organisms, gram- negative cocci, and non–β-lactamase producing anaerobes. However, they have little activity against gram-negative rods, and they are susceptible to hydrolysis by βlactamases.
2. Antistaphylococcal Penicillins (Eg, Nafcillin)
These penicillins are resistant to staphylococcal βlactamases. They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and gram-negative cocci and rods.
3. Extended-Spectrum Penicillins (Ampicillin and the Antipseudomonal Penicillins)
These drugs retain the antibacterial spectrum of penicillin and have improved activity against gram-negative organisms. Like penicillin, however, they are relatively susceptible to hydrolysis by β lactamases.
PENICILLIN UNITS AND FORMULATIONS
The activity of penicillin G was originally defined in units. Crystalline sodium penicillin G contains approximately 1600 units per mg (1 unit = 0.6 mcg; 1 million units of penicillin = 0.6g). Semisynthetic penicillins are prescribed by weight rather than units. The minimum inhibitory concentration (MIC) of penicillin (or any other antimicrobial) is usually given in mcg/mL. Most penicillins are dispensed as the sodium or potassium salt of the free acid. Potassium penicillin G contains about 1.7 mEq of K+ per million units of penicillin (2.8 mEq/g).
Nafcillin contains Na+, 2.8 mEq/g. Procaine salts and benzathine salts of penicillin G provide repository forms for intramuscular injection. In dry crystalline form, penicillin salts are stable for years at 4°C. Solutions lose their activity rapidly (eg, 24 hours at 20°C) and must be prepared fresh for administration.
MECHANISM OF ACTION
Penicillins, like all β-lactam antibiotics, inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis.
The cell wall is a rigid outer layer unique to bacterial species. It completely surrounds the cytoplasmic membrane (Figure 2), maintains cell shape and integrity, and prevents cell lysis from high osmotic pressure.
Figure 2 Penicillin mechanism of action Penicillin-binding protein (PBP, an enzyme) removes the terminal alanine in the process of forming a cross-link with a nearby peptide.
Cross-links give the cell wall its structural rigidity. β-Lactam antibiotics, structural analogs of the natural D-Ala-D- Ala substrate, covalently bind to the active site of PBPs. This inhibits the transpeptidation reaction (Fig 3), halting peptidoglycan synthesis, and the cell dies.
Figure 3 Transpeptidation reaction
The exact mechanism of cell death is not completely understood, but autolysins and disruption of cell wall morphogenesis are involved. Β-Lactam antibiotics only kill bacterial cells thar are either in their active growth phase or which synthesise their cell walls.
ANTIMICROBIAL ACTIVITY 39
The antimicrobial spectra of penicillin G (benzylpenicillin) and penicillin V (the phenoxymethyl derivative) are very similar for aerobic gram- positive microorganisms. Penicillin G is 5–10 times more active against Neisseriaspp and certain anaerobes.
Most streptococci (but not enterococci) are very susceptible to the drug.
However, penicillin resistant viridans streptococci and S. pneumonia are increasingly seen. Penicillin-resistant pneumococci also are resistant to third- generation cephalosporins and are especially common in children. More than 90% of staphylococcal isolates are now resistant to penicillin G, as are most strains of S. epidermidis and many strains of gonococci. With rare exceptions, meningococci are quite sensitive to penicillin G.
Most anaerobic microorganisms, including Clostridium spp, are highly sensitive. Bacteroidesfragilisis are generally resistant to penicillins and cephalosporins by virtue of expressing a broadspectrum cephalosporinase.
Actinomyces israelii, Streptobacillus moniliformis, Pasteurella multocida, and L. Monocytogenes are inhibited by penicillin G. Most species of Leptospira are moderately susceptible to the drug. Treponema pallidum is exquisitely
sensitive. Borrelia burgdorferi, the organism responsible for Lyme disease, also is susceptible.
ABSORPTION
With Oral Administration, about one-third of an oral dose of penicillin G is absorbed from the GI tract under favorable conditions. Gastric juice at pH 2 rapidly destroys the antibiotic. Absorption is rapid, and maximal concentrations in blood are attained within 1 hour. Ingestion of food may interfere with GI absorption. Thus, oral penicillin G should be administered at least 30 minutes before or 2 hours after a meal, and oral therapy should be used only for infections in which clinical experience has proven its efficacy. The difference of penicillin V in comparison with penicillin G is that it is better absorbed from the GI tract, yielding plasma concentrations two to five times greater than those provided by penicillin G.
Parenteral administration of Penicillin G:
After intramuscular injection, peak concentrations in plasma are reached within 15–30 minutes. This value declines rapidly (t1/2of 30 minutes).
Repository preparations of penicillin G increase the duration of its effect. Such compounds include penicillin G procaine(WYCILLIN, others) and penicillin G benzathine (BICILLIN L-A, PERMAPEN), which produce relatively low but persistent levels of penicillin in the blood.
Penicillin G procaine suspension combines procaine with penicillin in equimolar ratios; a dose of 300,000 units contains ~120 mg procaine, which
exerts local anesthetic effects when injected. If the patient is believed to be hypersensitive to procaine, a test dose of 0.1 mL of 1% solution of procaine should be injected first.
Penicillin G benzathine suspension is the aqueous suspension of the salt obtained by combining 1 mol of an ammonium base and 2 mol of penicillin G;
this provides a very slow release. The persistence of penicillin in the blood after an intramuscular dose reduces cost, need for repeated injections, and local trauma. The average duration of demonstrable antimicrobial activity in the plasma is 26 days.
DISTRIBUTION
Penicillin G is distributed widely, but the concentration differs in various fluids and tissues. Its apparent volume of distribution is ~0.35 L/kg.
Approximately 60% of penicillin G in plasma is reversibly bound to albumin.
Significant amounts appear in liver, bile, kidney, semen, joint fluid, and lymph.
Cerebrospinal Fluid
Penicillin does not readily enter the CSF but penetrates more easily with meningeal inflammation.
EXCRETION
Normally, penicillin G is eliminated rapidly from the body, mainly by the kidney. Approximately 60–90% of an intramuscular dose of penicillin G in aqueous solution is eliminated in the urine, largely within the first hour after
injection. The remainder is metabolized to penicilloic acid. The t½ for elimination of penicillin G is ~30 minutes in normal adults. Approximately 10% of the drug is eliminated by glomerular filtration and 90% by tubular secretion Clearance values are considerably lower in neonates and infants because of incomplete development of renal function; thus, penicillin persists in the blood for several times as long in premature infants as in children and adults.
After renal function is fully established in young children, renal excretion is considerably more rapid than in adults. Anuria increases the t1/2 of penicillin G to ~10 hours. The dose of the drug must be readjusted during dialysis and the period of progressive recovery of renal function.
PENICILLIN IN SYPHILIS:
MAHONEY, ARNOLD and HARRIS were the first to use Penicillin for treating Syphilis in experimental animals and man in the year 1943. Since 1943, Benzathine penicillin has remained the drug of choice for all forms of syphilis. remains main stay of effective and simplified treatment. A serum level of penicillin >0.018mg/L or 0.03 IU/mL is considered as bactericidal for treponemes. Hence, a level of penicillin maintained for 7-10 days is curative for syphilis. Of the various penicillins, Benzathine penicillin is preferred as it has a persistent low but treponemicidal blood level for 18-25 days
DOSAGE :
Inj. Benzathine Penicillin 2.4 million units deep IM single dose (1.2 MU deep IM in each buttock)
For children: 50,000 units/ kg IM up to the adult dose of 2.4 million units in a single doe.
Treatment to be given after testing intradermal sensitivity for Penicillin.
Alternatively, Inj. Procaine penicillin G 600,000 IU daily IM for 10 days.
In case of neurosyphilis , instead of Benzathine Penicillin (as it doesn’t cross the blood brain barrier) , Inj.Aqueous crystalline penicillin G 18-24 million units/day is administered as3-4 million units IV every 4 hours or as continuous infusion for 10 to 14 days or alternatively, Procaine penicillin G2.4million units IM daily along with probenecid 500mg orally QID can be given for 10 - 14days .
JARISCH - HERXHEIMER REACTION:
It is an acute febrile reaction to killed treponemes and their liberated toxins which occurs within the first 24 hrs after the initiation of any therapy for syphilis.
Incidence is higher in early syphilis because of the higher bacterial load.
Symptoms and signs include intensification of rash, peripheral vasoconstriction followed by vasodilation, leucocytosis, leucopenia, eosinophilia
It is treated with antipyretics, fluidsand a short course of steroids (prednisolone 30-40 mg for two to three days prior to injection with gradual tapering) which is given from 48 hrs prior to treatment
PROCAINE REACTION (HOIGNE SYNDROME):
Inadvertent injection of crystals of Procaine Penicillin intravenously leads to micro embolism in brain causing acute psychotic episode , severe anxiety, agitation , vertigo, hallucinations.
DESENSITISATION OF PENICILLIN:
Desensitisation should be done orally over 4 hours starting with small doses with doubling the dose every 15 minutes.
OTHER ADVERSE REACTIONS
Penicillin G has been associated with impaired hemostasis due to defective platelet aggregation. Most common among the irritative responses to penicillin are pain and sterile inflammation at sites of intramuscular injection, phlebitis or thrombophlebitis. May lead to severe hyperkalemia and seizures in persons with renal dysfunction.
ALTERNATIVE REGIMEN FOR PENICILLIN ALLERGIC PATIENTS - Cap. Doxycycline 100mg BD orally for 2weeks (or)
- Tab. Erythromycin 500mg QID orally for 2weeks.
- Tab Azithromycin 2gm stat
The efficiency of these regimens are not well documented. Hence frequent follow up of the patients receiving these therapies is essential. The effectiveness of these therapies in HIV infected patients has not been studied.
AZITHROMYCIN :
Azithromycin is a semi-synthetic macrolide antibiotic structurally related to erythromycin having activity against both gram positive and gram negative bacteria (both aerobic and anaerobic).40
CHEMICAL NAME:
2R,3S,4R,5R,8R,10R,11R,13S,14R)-11-[(2S,3R,4S,6R)-4-
dimethylamino-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy- 13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-
3,5,6,8,10,12,14- heptamethyl-1-oxa-6-azacyclopentadecan-15-one.
STRUCTURE:
Figure 4 Shows Structure of Azithromycin Empirical formula : C38H72N2O12
Molecular weight : 748.984 Melting point : 126-1270C
Physical form : white or almost white powder
Solubility : Practically insoluble in water, freely soluble in anhydrous ethanol and methylene chloride.
PHARMACOKINETICS
Azithromycin is acid-stable and thus oral drug is readily absorbed with its absorption being greater on an empty stomach. Time to peak concentration in adults is 2.1 to 3.2 hours for oral dosage forms and 1 to 2 hours for intravenous (IV) forms. Due to the high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of azithromycin are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma. This is due to ion trapping and the high lipid solubility of the drug.
Following a single 500 mg dose, plasma concentrations of azithromycin is declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and a terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.41
Biliary excretion of azithromycin, predominantly unchanged, is the major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.
PHARMACOLOGY
Mechanism of action: Azithromycin interferes with the protein synthesis of bacteria by binding to the 50S subunit of the bacterial ribosome thereby inhibiting translation of mRNA. Nucleic acid synthesis is not affected.
Dosage and Route of administration: Azithromycin is commonly administered in tablet or oral suspension. It is also available for intravenous injection and in a 1% ophthalmic solution. Tablets come in 250 mg and 500 mg doses. Oral suspension comes in 100 mg/teaspoon and 200 mg/teaspoon strengths.
Adverse reactions: Most common side effects are gastrointestinal; diarrhea (5%), nausea (3%), abdominal pain (3%) and vomiting. Less than 1% of patients stop taking the drug due to side effects. Serious allergic reactions, nervousness, dermatologic reactions, and fatalities have been reported but are extremely rare.
TREATMENT OF TERTIARY SYPHILIS (GUMMA AND CARDIOVASCULAR SYPHILIS)
Three weekly doses of Inj. Benzathine Penicillin G 2.4 million units deep i.m after test dose. 42
TREATMENT OF NEUROSYPHILIS42
Patients with neurosyphilis or syphilitic eye disease in the form of neuroretinitis, optic neuritis, uveitis or any other cranial nerve palsies should have CSF examination done and be treated with Aqueous crystalline penicillin G 18-24 million units per day which is administered as 3-4million units IV every 4hours or continuous infusion for 10to 14 days.
Benzathine penicillin G has no role in the treatment of neurosyphilis as it does not cross the blood barrier in sufficient quantity.
FOLLOW UP
CSF should be re-examined every 6 months until it becomes normal.
CSF cell count should become normal by 6 months and CSF VDRL and protein levels by 2 years. If not , patient should be retreated.
MANAGEMENT OF PARTNERS
The sex partners should be evaluated clinically and serologically and treated according to the following recommendations.
1. Persons who are exposed within the 90 days preceding the diagnosis of primary, secondary or early latent syphilis even if sex partner IS seronegative and should be treated with epidose of Inj. Benzathine penicillin 2.4 million units deep i.m after test dose (single dose).
2. Persons who were exposed >90 days before the diagnosis of primary, secondary or early latent syphilis should be treated presumptively if serologic test results are not available immediately and if the opportunity for follow up is uncertain.
3. For purpose of partner notification and presumptive treatment of exposed sex partners, patients with syphilis of unknown duration who have high non treponemal serological test titre (>1.32) can be assumed to have early syphilis. However serologic titre should not be used to differentiate early from late latent syphilis for the purpose of determining treatment.
4. Long term sex partners of patients who have latent syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of the evaluation findings.42
BACKGROUND :
In a study done by kiddugavu et al, 43 the mean age of patients in males was 35.5 years and 39.3 years in female patients,whereas in a study done by Gabriele Riedner,et al,44 the average age of participants was 27.0 years.
In a study done by Heidi E Hutton et al., no direct influence of Alcoholism & Smoking was demonstrated in the cure rate of STI.45
Almost 100% of the study population showed positive reports in a study done by Edward w Hook et al. 1 But no statistically significant relation could be found between the dark field examination positivity and outcome of treatment response in both the groups.
In a study done by Edward w Hook et al1 where 26% belonged to primary stage and 74% to the secondary stage.
In the study done by Gabriele Riedner et al where among the 24 of 25 participants with confirmed primary syphilis examined one or two weeks after treatment, ulcers had resolved in 15 (62.5 percent) and were in the process of healing in 9 (37.5 percent). There was also no significant difference found in the healing rates between the groups.44
Cutaneous lesion was found in 80% of penicillin group and 76.7% of Azithromycin group, which also showed no correlation in the outcome of the study and has no statistical significicance.
In a study done by Edward w Hook et al,74.6% of the patients treated with oral Azithromycin showed 4 fold decrease from their base line RPR at 3 months and 77.6% of them showed the same results at 6 months of examination. In that study ,in turn,75.7% of the patients treated with azithromycin showed 4 fold decrease of their RPR titres at 3 months and 78.5%
of them at 6 months.1
AIMS AND OBJECTIVES
AIMTo compare the efficacy of single dose 2gm oral azithromycin versus injection Benzathine Penicillin G 2.4 MU in the treatment of early syphilis.
To establish an effective, safe and an oral alternative drug that can overcome the disadvantages associated with parenteral therapy in the treatment of early syphilis.
OBJECTIVES
To compare the efficacy of single dose 2gm oral azithromycin versus injection Benzathine Penicillin G 2.4 MU in the treatment of early syphilis.
To compare clinical and serological cure rate of both drugs in the treatment of early syphilis.