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Comparative Study of Efficacy of Ciprofloxacin and Ceftriaxone in Typhoid Fever
Authors Dr. M. Usha Rani1, Dr. Ch. Jhansivani2 1Assistant Professor of Pharmacology, Guntur Medical College, Guntur, Andhra Pradesh, India 2Asst.Professor, Dept. of Pharmacology Email: [email protected] ABSTRACT Typhoid fever is an acute systemic disease. It is caused by Salmonella typhi. The disease is unique to humans. In 1880, Ebreth first isolated the causative organism. The disease has worldwide in distribution and endemic in Tropical Countries. Between 15 and 35 years of age incidence of disease is more. Typhoid had been prevalent in many parts of India and is resistant to chloramphenical, ampicillin, co-trimaxazole. The use of quinolones in children has been prevalent. The Ciprofloxacin used in children are not free from adverse effects. The resistant cases requires Cephalosporins. Currently the III generation cephalosporins like ceftriaxone and cefotaxime are used in multi drug resistant typhoid fever. These drugs are bactericidal and are very effective. The aim of the present study is to compare the efficacy Ciprofloxacin and Ceftriaxone in treatment of Typhoid fever. Patients who attended the department of Medicine with fever were selected. They were divided into two groups. 25 patients were treated with ceftriaxone under Group – I and another 25 patients were treated with Ciprofloxacin under Group – II. The results of both groups were recorded. There were significant differences observed among patients in the two groups with regard to age, sex, duration of fever before admission and clinical findings. The mean number of days for patients to become afebrile was significantly lowered in those receiving ceftriaxone (P < 0.001) than in those receiving Ciprofloxacin. Ceftriaxone in the treatment of typhoid fever was proved safe and effective in the present study Key Words: Cephalosporins, Ceftriaxone, Ciprofloxacin, Typhoid fever, quinolones.
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INTRODUCTION Medical Service Officer in three graduated doses. Typhoid fever is an acute systemic disease Later Pfeiffer and Kelle injected living organisms. resulting from infection with Salmonella typhi. In 1896 - Widal introduced the serological means The disease is unique to humans. The causative of diagnosis of the disease. organism was first isolated by Ebreth in 1880. The disease has worldwide in distribution. The peak AETIOLOGY incidence of the disease is between the age of 15 Typhoid fever is caused by Salmonella typhi. It is and 35 years. It is rare in infants, especially below a gram negative rod shaped organism about 3 the age of 2 years. It is not commonly seen after micron in length and 0.5 micron in breadth. It has 50 years. Males are more affected than females18. got flagella and is actively motile. Since 1990 a multidrug resistant variety of Typhoid had been prevalent in many parts of India. The use of Quinolones in children has been prevalent. Ciprofloxacin used in children are not free from adverse effects. The resistant cases have a higher morbidity and require Cephalosporins.
Currently the III generation cephalosporins like Diagram of Salmonella Showing Peritrichous ceftriaxone and cefotaxime are used in multi drug flagella resistant typhoid fever. These drugs are more safe, Its optimum growth in seen at blood temperature. bactericidal, less toxic, no toxicity on joints and It is killed by boiling water and when exposed to a cartilages. It can be used safely in children. temperature of 600centigrade for 15 minutes.
HISTORICAL ASPECT OF TYPHOID OCCURRENCE FEVER The organism S.typhi is found in the blood, This disease was named by Louis in 1829. The Peyer’s patches lymphoid follicles of the small word typhoid is derived from 'typhoide' which intestine, faeces, mesenteric glands, lymph nodes, means 'disturbed mental condition' which is often spleen, liver, gall bladder, kidney and urine. present in this condition. Typhoid is an ancient
disease and has been described by 'Hippocrates' in MODE OF SPREAD his book 'Epidemic'. The infection spreads through infected food or In 1880 Eberth obtained the causative organism drink. It is transmitted by the faeco oral route. The Salmonella typosus, from the mesenteric gland. food may be contaminated from the following. Wright in 1896, was the first to introduce
prophylactic vaccination against typhoid. He
injected heat-killed organisms to an Indian
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I. Carriers continues to raise but pulse shows a relative Patients who continue to shed bacilli in faeces for bradycardia7. There is enlargement of liver. The 3 weeks to 3 months. spleen enlarges towards the end of the week8. II.Flies: Rose spots appear on the 7th or 8th day. They occur Flies are important agents in the spread of more commonly on the trunk, but they also are infection by contaminating the articles of food. seen in other parts rarely. They are rose coloured, III.Fomites : slightly raised and fade on pressure. Contract with articles used by the patient also aid The Second Week in spread of infection. The temperature is raised and continuous. The IV.Water born : patient becomes toxic there is mental apathy and Contaminated water is an important source for he may become delirious. The relative bradycardia causing large epidemics. disappears towards the end of the week. The Clinical Features of Typhoid Fever mouth and lips become dry and cracked and sticky The clinical features of typhoid fever are mucus covers the mouth and tongue. The patient classically described by dividing the whole course now develop diarrhoea and the typical peas cup of the disease into four weeks. stools may be seen. There is abdominal distension The First Week and spleen becomes larger. The incubation period is usually 14 days, but may The Third Week range from 5 - 20 days, and appears to be related In cases which recovered the temperature fall by to the dose of the infection. The disease is gradual about the fifteenth day. Toxaemia diminishes and in onset with malaise, loss of appetite and appetite returns to normal. In unfavourable cases, headache. The headache is usually in the frontal the symptoms become more severe and the patient region. There is sore throat and the patient may becomes profoundly toxic, the lapses into a stage have symptoms pertaining to respiratory system of ‘Coma Vigil’ in which he is semi conscious, by way of nasal catarrh and cough. During: the dehydrated, unaware of the surrounding and first three days the patient is ambulatory but from tremulous. Hence third week is the danger period third day on wards the symptoms become more for these unfavourable cases. severe. The temperature raises to step ladder The third week is also the period of the most fashion. The evening raise being greater by 0.5 to serious complications, intestinal hemorrahage and 10 F6. perforation of the bowel. There is abdominal discomfort and slight The fourth Week distension. At this stage constipation is more The severe case runs a downhill course and dies. common than diarrhoea and there may be Uncomplicated cases after about 10 days of vomiting. The tongue is dry and coated centrally. cessation of therapy, the attack is milder and less There are signs of bronchitis. The temperature severe, complications are uncommon.
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Typhoid Fever in Children and sigmoid. The perforation is usually single, In children the disease may show more variable rarely multiple, perforation is hearalded by severe forms. It may be acute in onset, with vomitings, abdominal pain, starting in the right iliac fossa and couvulsions and high fever. Diarrhoea may be spreading to the whole of the abdomen. There is present on the first day. fall of temperature even to subnormal level and Some may show bronchopneumonia or lobar signs and symptoms of peripheral failure. pneumonia. Meningism is often present. In some Liver and Gall bladder it may be very mild and pass off with vague Acute cholecystitis may occur in the first week, symptoms. Haemorrhage and perforation are rare when diagnosis becomes difficult. Rarely acute as the Payer’s patches are not developed. cholangitis, jaundice, perforation of gall bladder Typhoid Fever in the Aged and liver abscess may take place. It is rare after the age of 40 years. Fever is slight Spleen but complications like hypostatic pneumonia and In rare cases spleenic abscess and spontaneous heart failure are common. Mortality is also high. rupture of the spleen have been reported. In cases that recover convalescence is prolonged. Respiratory System Typhoid Fever in Pregnancy Bronchopneumonia and lobar pneumonia may Abortion or premature delivery occurs in 60% of occur in the second or third week. Fibrinous cases. pleurisy or pleural effusion may be seen. Rare complications are empyema, lung abscess, COMPLICATIONS infarction and spontaneous pneumothorax. Gastrointestinal Tract Cardiovasuclar System Superficial ulcers develop towards the end of first In severe cases acute myocardial failure or week on the anterior pillars of the fauces, soft peripheral circulatory failure are common palate and the pharyngeal wall. Intestinal complications. haemorrhage occurs during third or fourth week. Central Nervous System It is rare in children below the age of 12 years. Meningism is of common occurrence in children The haemorrhage may be single or repeated. right from the onset or sometimes late in the Repeated small haemorrhages are more dangerous course of the disease. There are signs of than a single large bout. meningeal irritation along with muscular Perforation of the bowel is the next dreadful twitchings and occasionally convulsions. complication of typhoid. It occurs in 2-4% of Complete recovery occurs in the course of an year cases, usually in the third week. Like or two. haemorrhage, this is also rare in children. The Ear: Temporary deafness occurs commonly in the sites of perforation in order of frequency are lower course of the disease. part of ilium, caecum, appendix, colon, jejunum
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Clinical Diagnosis Third generation cephalosporins are now In the past the question of diagnosis of typhoid considered as the first line drug against multi drug fever was left to the laboratory. But in Garron's resistant typhoid fever. opinion the great majority of cases can be Ceftriaxone: It is a III generation cephalosporin, diagnosed clinically. The following clinical bactericidal, it prevents relapse and carrier state. criteria should be applied. Mechanism of action same as penicillin a) Pyrexia of remittent type defervescence seen after 4-5 days. It can be safely b) Low pulse-temperature ratio used in children. It is the effective and safe drug in c) Characteristic toxaemia the treatment of typhoid fever. d) Splenic enlargement Ciprofloxacin e) Eruption of rose-spots. Fluoroquinalones are quinolone antimicrobials Treatment having one or more fluorine substitutions. In 1.Ciprofloxacin 1990s compounds with additional fluoro and other There have been a shift in the preference of drugs substitutions have been developed. from chloramphenicol to fluroquinolones Chemistry especially ciprofloxacin. The fluoroquinalones 2 – quinolones contain a carboxylic acid moiety in are contraindicated in children because of its toxic the 3 position of the basic ring structure. The effect on growing cartilage24. Changing trends in newer fluoroquinolones also contain a fluorine the antibiotic sensitivity pattern of S. typhi has substitution at position 6 and many of these been noticed recently. compounds contain a piperazine moiety at 2.Cephalosporins position 7.
Mechanism of Action23 ADVERSE EFFECTS Potent inhibitor of nucleic acid synthesis. It blocks Gastrointestinal: Nausea, vomiting, bad taste bacterial DNA synthesis by inhibiting DNA anorexia. gyrase preventing the relaxation of super coiled Central Nervous System: Dizziness, restlessness, DNA which in required for normal transcription anxiety and insomnia, convulsions. and replication. Skin : hypersensitivity, photosensitivity swelling of lips, urticaria tendonitis and tendon rupture few cases have been reported.
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Bone: Arthralgias and joint swelling have 1. Bind to specific penicillin binding developed in children receiving fluroquinolones. proteins. That serves as drug receptors on bacteria. Therefore these drugs are not recommended in the 2. Inhibition of cell wall synthesis by prepubertal children. blocking transpeptidation of peptidoglycan. Dosage: A dose of 500 – 750 mg b.d. for 10 days 3. Activation of autolytic enzymes in the cell is recommended. Patients unable to take ovally wall. are treated with 200 mg I.V. b.d in the beginning. Adverse Effects On an average fever subsidesin 4-5 days. Prevents Side effects are local reactions including pain, carrier state due to cidal action. It is also used in induration and tenderness at injection site. treating carriers (750 mg b.d for 4-8 weeks). Side effects are: Rash, hypoprothrombanaemia and bleeding. CEPHALOSPORINS Dosage and administration Cephalosporins are semi synthetic antiobiotics Preparation : 250 mg, 500 mg, 1 g vials are derived from ‘Cephalosporin-C’ obtained from a available. fungus cephalospirium acremonium. The first Dose : 4 gms i.v. once a day for 2 days followed source of cephalosporins, was isolated on 1948 by by 2gms per day till 2 days after fever subsides. Brotzu. These are chemically related the Place of Ceftriaxone in typhoid fever pencillins. The nucleus consists of a Beta-lactum Studies had been done. Typhoid fever responded ring fused to dihydrothiazine ring (7 amino very well and less side effects were noticed. It is cephalosporamic acid). By addition of different safe in children and adults. side chains at position 7 of beta lactum ring (altering spectrum of activity) and position 3 of MATERIALS AND METHODS dihydro thiazine ring affecting pharmacokinetics, The study was under taken in Typhoid fever a large number of semisynthetic compounds have patients attending Department of Medicine for the been produced. duration of 6 months. Selection Criteria of the Patient s Patients were selected as per the exclusion and 1 R -C-NH inclusion criteria. 1 || 7 6 2 Inclusion Criteria 0 5 3 || N 4 R Patients aged between 15-40 years male 0 2 COO and female were selected with history of continuous fever for more than 5 days CEPHEM NUCLEUS duration with nausea, vomiting, abdominal All cephalosporins are bactericidal and have same discomfort. mechanism of action as penicillin.
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On examination raised body temperature, After selection patients were divided into two toxic look, coated tongue, hepatomegaly, groups. splenomegaly were selected. Group – I-- 25 patientswere treated with Exclusion Criteria Ceftriaxone parenterally 4gms iv once a day for 2 X-ray chest was taken to rule out days followed by 2gms/day till 2 days after fever tuberculosis and other long diseases. subsides and results were recorded. Blood picture was taken to exclude Group - II -- 25 patients were treated with malaria and fever due to other diseases. Ciprofloxacin 500-750mg b.d. for 10 days. Typhoid cases complicated with Patients unable to take orally are treated and perforation, peritonitis, meningitis, and 200mg iv/bd and results were noted. encephalitis were excluded from the study.
RESULTS PATIENTS DEMOGRAPHIC DATA In group-I-- The male, female ratio was 3:2. In group-II-- The male, female ratio was 3:2.
Table – I Demographic date of patients Age and Sex distribution and duration of illness Duration of Sex Age in Years illness in days Drug Range N M F MeanSD MeanSD between Ceftriaxone-I 25 15 10 12-40 24.168.31 9.760.96 Ciprofloxacin-II 25 15 10 12-40 27.086.73 11.280.97
P0.05 P < 0.001 N = Number of patients M = Male F = Female The duration of illness in Group I was mean 9.76 with diarrhoea, 20/25 (80%) were with days and in Group II the duration was mean splenomegaly and 10/25(40%) presented with 11.28. The onset was insidious in all two groups. hepatomegaly. Clinical Presentation In Group - II all 25 patients were admitted with In Group - I All patients were presented with fever fever more than 1020F temperature headache in more than 1020 F at the time of admission 16/25 14/25(56%), abdominal discomfort and tenderness (64%) of patients had headache, 22/25 (88%) in 15/25 (56%), vomiting 16/25 (64%), diarrhoea were presented with abdominal discomfort and 4/25 (16%), splenomegaly 10/25 (40%) and tenderness. 13/25(52) had vomiting, 6/25(24%) hepatomegaly 12/25(48%) were present.
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Table – II Clinical presentation signs and symptoms
Fever Abdo-minal Head-ache Vomiting Diarrohea Spleno- Hepato- Drug >1020F (%) dis-comfort (%) (%) (%) megaly (%) megaly (%) (%) Ceftriaxone-I 100 64 88 52 24 80 40 Ciprofloxacin- 100 56 60 64 16 40 48 II P0.05 P0.05 P0.05 P0.05 P0.05 P0.05
There were no significant differences observed The mean number of days for regression of among patients in the two groups with regard to splenomegaly was significantly lowered in those age, sex, duration of fever before admission and receiving ceftriaxone (P < 0.001) than in those clinical findings. (Table-I). receiving ciprofloxacin (Table-III). Days required for disappearance of signs and There is significant difference (P < 0.001) in the symptoms means of number of days for disappearance of The mean number of days for patients to become abdominal discomfort and tenderness in those afebrile was significantly lowered in those patients receiving ceftriaxone than ciprofloxacin receiving ceftriaxone (P < 0.001) than in those (Table III). receiving ciprofloxacin (Table – III).
Table – III Days required for disappearance of signs and symptoms Sl. No. Signs & Symptoms Ceftriaxone-I Ciprofloxacin-II 1. Afebrile 4.680.74 6.320.47 P<0.001 2. Abdominal Distension 3.220.42 4.330.48 P<0.001 3. Splenomegaly 4.200.41 5.120.61 P<0.001
Blood culture Blood samples were sent for culture from all 25 In Ciprofloxacin group 25 blood samples were patients in Ceftriaxone group, out of which only 8 sent in blood culture (S. Typhi) only 4 samples blood samples had shown growth of S.Typhi. The had shown growth of S. Typhoid. The blood blood culture was repeated after completion of culture was repeated after therapy and all four had therapy and found all 8 cases were sterile (Table – shown sterile. (Table – IV) IV).
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Table – IV Blood Culture No. of No. of samples +ve for After treatment Group samples sent Salmonella Typhi Salmonella Typhi Ceftriaxone-I 25 8 -ve Ciprofloxacin-II 25 4 -ve
Widal Test more than 1:160 dilutions. After therapy the Widal test was done in both groups (group I and widal test was repeated and find significantly group II) before starting the therapy. The widal reduced titre of less than 1:160 dilution (0 and H) test was positive for both ‘O’ and ‘H’ in titre of in both.
Table V Widal Test No. of samples +ve No. of samples After treatment Group for Salmonella sent O&H positive Typhi Cefriaxone-I 25 25 - Ciprofloxacin-II 25 25 11
Results of therapy Clinical cure: In ceftriaxone group the clinical cure was seen in 25/25 (100%). In ciprofloxacin group the clinical cure was seen in 14/25(56%). (table–vi)
Table – VI Clinical Response Group Ceftriaxone-I Ciprofloxacin-II 14 Clinical cure 25 P<0.001 11 Not responded to therapy 0 P<0.001 12 Adverse drug reactions 2 P<0.001
Adverse drug reactions: In ciprofloxacin group 12 patients had adverse The adverse effects were mild in ceftriaxone effects like loss of appetite in 8 patients, insomnia group, 2 patients had mild thrombophelbitis which in 3 patients and swelling of lips in 1 patient. was subsided within two days.
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DISCUSSION the follow up study period of four weeks. There Ceftriaxone in the treatment of typhoid fever was was significant reduction in the widal proved safe and effective in the present study. agglutination titre after therapy. Patients were recruited randomly as per our In the present study all most all patients had demographic data (Table-I) the mean age of shown the positive widal titre before treatment. ceftriaxone group was 24.6 years. The mean age The repeat widal test showed significant reduction of ciprofloxacin group was 27.08 years. in both ‘O’ and ‘H’ titre. Males are frequently affected than females in the Fluroquinolones have offered affordable oral ratio of 3:2 in both the groups. The fever was treatment option for adult patients. The safety of mostly of continuous type and gradual onset. In these agents in children is unsatisfactory, however ceftriaxone group the patients were responded and recent reports of Salmonella resistant to clinical cure was 25/25 (100%) cases. ciprofloxacin and its adverse effects further The days required for the reduction of temperature reinforce the need for alternative therapy. to normal was even and significant (P < 0.001) in In ciprofloxacin group the clinical cure was only ceftriaxone than ciprofloxacin group. There was 56% (14/25) and large number of patients showed significant difference in the number of days resistance to therapy (n=11) and adverse effects required in disappearance of abdominal (n=12). The days required for the temperature discomforts. (P < 0.001). There was significant differences was greater than ceftriaxone. The difference (P < 0.001) in the number of days mean of temperature differences was significant required in the regression of splenomegaly (P < 0.001). The days required for the regression between ceftriaxone and ciprofloxacin group. of splenomgaly was also showed significant There was no serious adverse affects in disfference (P < 0.001) with ceftriaxone group. ceftriaxone group and noted only two patients complained of thrombophlebitis. SUMMARY AND CONCLUSION Ceftriaxone is a third generation cephalosporin Comparative study of 25 cases in each group of can be administered parenterally. It is safe in ceftriaxone and ciprofloxacin in the treatment of preschool children. It can be safely used in Typhoid fever was done. Ceftriaxone belongs to pediatric age group. The drug is well tolerated. -lactam group of drugs which are bactericidal, broad spectrum with less chance of development In the present study the clinical cure was 100% of resistance, with high therapeutic index and with Ceftriaxone parental therapy. The positive minimum adverse effects, taken for its cultures for salmonella typhi were turned sterile effectiveness in the treatment of typhoid fever. after the completion of therapy. The stool and Ciprofloxacin is used in the treatment of typhoid urine culture were negative. There were no fever. Its limitations in prepubertal children. relapses reported during the therapy and also after Because of its adverse effects on growing Dr. M. Usha Rani et al JMSCR Volume 3 Issue 2 February 2015 Page 4326
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cartilages central nervous system and 2. Gerald T. Keush – Salmonellosis, gastrointestinal system. Because of other factors Harrison’s Principles of Internal Medicine, we needed a more safer and effective drug. 14th edition, 1998 p.952. Group I – Ceftriaxone 25 cases were treated, 3. Henry F. Chambers; Antimicrobial Group II– Ciprofloxacin 25 cases were treated Agents; Good Man and Gillmans, the with ciprofloxacin . pharmacological basis of therapeutics 10th The common age group is 12-40 years. Males are edition, 2001, p.1249. affected more than females in the ratio of 3:2. All 4. J.D. Singh and J.D. Duguid – Salmonella of 25 patients are from lower socio-economic Mackie and Mc. Cartney, Practical group. Most of the patients are presented with Medical Microbiological, 13th edition continuous type of fever, abdominal discomfort, 1989, p. 457. tenderness and splenomegaly. Investigations are 5. K.D. Tripathi, M.D., - Broad spectrum sent before and after the starting of the specific antibiotics, Essentials of Medical therapy. Daily monitoring of temperature and Pharmacology, 5th edition 2003, p. 676. other basic signs and symptoms are recorded for 6. R. Anantha Narayan B.A., M.B;B.S, D.B. each group. The days required for the Ph.D. C.K. Jayaram Panikar, M.D. disappearance of signs and symptoms (1) Enterobacteriaceae III Salmonella: Text temperature differences; (2) abdominal discomfort Book of Microbiology, 4th edition 1990 p. and (3) splenomegaly are summariged in the 285. tables. 7. R. Anantha Narayan, B.A, M.B;B.S, D.B., The number of patients responded clinically and Ph.D. C.K. Jayaram Parikar M.D. not responded clinically are also explained. Enterobacteriaceae III Salmonella, Text The adverse effects in each group are also Book of Microbiology, 4th edition, 1990 – recorded and presented. p. 286. The present study has revealed that ceftriaxone 8. Threlfall E J, Ward L.R, Skinner JA, parental therapy is more effective with less Smith HR, Lacey S – Ciprofloxacin – adverse effects. resistant salmonella Typhi and treatment failure, Lancet 1999; 353:1590-1. BIBLIOGRAPHY 9. Umsanker S, wall RA, Berger J – A case 1. Edward. W. Hook Richard L. Gurrant, of Ciprofloxacin – resistant Typhoid fever. Salmonella infection, Harrison’s Principles CDR Rev. 1992; R 139-40. of Internal Medicine, 9th edition – 1980, p. 10. Washington C. Winn Jr. John M. Kissane, 642. Bacterial disease, Anderson’s Pathology, Vol: 1, 10th edition, 1996, p. 788.
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11. Willaim A, Petri, Jr., Antimicrobial 12. William A, Petri, Jr., Antimicrobial Agents; Goodman and Gillman's, the Agents, Goodman and Gillman's, The Pharmacological basis of therapeutics, 10th Pharmacological basis of therapeutics, 10th edition 2001, p. 1206. edition 2001, p.1182.
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