CEPHALOSPORINS

 1 INTRODUCTION:-

The term antibiotic was derived from the name ‘antibiosis’ which means “against life”. Initially, antibiotics were considered organic substance, which is produced by the single organism and have toxic activity against other microbes. So according to this conception, the antibiotic was described as a substance acquired by biological sources.

 Cephalosporin compounds were first time taken from the Cephalosprium acremonium culture by an Italian scientist named Giuseppe Brotzu. Cephalosporin C is the naturally occurring agent from which other cephalosporins are derived by making some modifications in their structures. Cephalosporins and penicillins are linked with each other in sense of their structures and functions because both have a common beta-lactam ring. This ring plays an important role to stop the cell-wall synthesis of bacteria, in this way they perform their bactericidal activity. Parental cephalosporins are used frequently in hospital therapy because of their broad-spectrum activity against various pathogens. 

 2 CLASSIFICATION OF CEPHALOSPORINS:-

Cephalosporins are classified into 5 generations based on their discovery and anti-microbial activities. 

 1ST generation cephalosporins:-They have activity against gram +ve bacteria (for example:-streptococcus and staphylococcus) and have a little bit of activity against gram –ve bacteria.

2nd generation cephalosporins:-They have remarkable activity against gram –bacteria as compared to 1st generation cephalosporin drugs. And they are less active against gram +ve bacteria when making a comparison with 1st generation bacteria.

3rd generation cephalsporins:-They is also known as broad-spectrum antibiotics, they have excellent activity against gram +ve and gram –ve bacteria, but they ideally work against gram –ve bacteria.

4th generation cephalosporins:-They are extended-spectrum antibiotics but have resistance against beta-lactamase enzymes.

5th generation cephalosporins:-These cephalosporins have wonderful activity against MRSA (methicillin-resistant staphylococcus aureus).

3 MECHANISM OF ACTION:-

All cephalosporins interfere with the bacterial cell wall synthesis step which makes the membrane less stable against osmotic pressure due to which bacteria become die therefore they are known as bactericidal, so for this purpose, cephalosporins bind with the transpeptidase enzyme which is also known as penicillin-binding proteins which are essential for the synthesis of the cell wall of bacteria and bacterial cell wall helps to survive the bacteria in unfavourable conditions. Cephalosporins are only active against the growing organism that manufactures a peptidoglycan cell wall. Therefore they are inactive against those organisms which do not contain peptidoglycan in their cell walls structure like viruses, fungi and protozoa. In addition, the differences in PBPs can change the activity of cephalosporins which opposes Enterobacteriaceae and pseudomonas aeruginosa. Cephalosporins make more post-antibiotic effect (the reduction of bacterial growth after a short sensitivity towards microbes) in gram +ve bacteria but they produce a negligible effect in gram –ve bacteria.

 4 MECHANISMS OF RESISTANCE:-

Bacteria are also able to develop different mechanisms to prevent the lethal activity of cephalosporins against them. Like alteration of PBPs, production of beta-lactamase enzyme and change in cell wall permeability of gram –ve bacteria. Every strain of bacteria has different kinds of PBPs and gram –bacteria have more types of PBPs than the gram -ve bacteria. Initially, first-generation cephalosporins are resistant to staphylococcal penicillinases. Cefazolin is not that responsible to be hydrolyzed by the varieties of penicillinase as compared to other cephalosporins. 2nd and 3rd-generation cephalosporins are well developed/strong to prevent the hydrolysis by the common lactamase enzymes of gram–bacteria. The limiting use of these antibiotics can prevent resistance and inactivation of these drugs towards bacteria.

5 PHARMACOKINETICS:-

Pharmacokinetic properties and anti-bacterial spectrum of cephalosporins are affected by the two side chains at positions 3 and 7.

• Oral cephalosporins:-

Commonly, oral cephalosporins absorb rapidly like cefaclor cefadroxil, cephradine and cephalexin are rapidly and fully absorbed, but some cephalosporins like cefixime and cefuroxime are absorbed into the minimum extent. These all above compounds get their therapeutic effect mainly in bones, synovial fluids and pleural fluids. All oral cephalosporins are excreted via urine except cefixime which is excreted by the non-renal route.

• Parental cephalosporins:-

These parents can be given via intravenous or intramuscular route. They are largely propagated to the tissues and fluid, including bones, cerebrospinal fluids, pleural fluids and cerebrospinal fluid. 1st or 2nd generation cephalosporins and ceftriaxone, ceftazidime, ceftizoxime, cefotaxime, and cefuroxime can get their therapeutic activity in the CSF even the meningitis is there. Cephalosporins can pass through the placenta and excrete out in small amounts by breast milk. Ceftizoxime, cefuroxime, ceftazidime and cefazolin are metabolized slowly. Cefotaxime, cephapirin and cephalothin are converted to a diacetyl metabolite by metabolism. Parental cephalosporins are water-soluble and polar therefore they are mostly excreted out in the urine in unchanged form. Approximately 40% of ceftriaxone is excreted out via bile whereas cefoperazone up to 70% excrete out via bile.

6 ADVERSE REACTIONS:-

Commonly, cephalosporins produce minor adverse reactions. Skin rash along with arthritis and fever (serum sickness-like syndrome), are reported during the cefaclor therapy but they are uncommon. Renal diseases are observed during the use of cephalosporins along with the increase in blood nitrogen urea and serum creatinine levels. Cephalosporins were first time found as a substance of nephrotoxicity in 1965. Cefazolin and cefamandole produce necrosis of proximal tubule in subjects and it shows that they are less nephrotoxic with rabbits. Cephalosporins are also responsible to increase nephrotoxicity which is caused by the aminoglycosides. It was seen during the cephalothin therapy, so different tests are held in which it has been confirmed that penicillins give protection against aminoglycosides induced nephrotoxicity while cephalosporins assist to increase aminoglycosides induced nephrotoxicity. GIT complications like nausea, vomiting and diarrhoea are also found in oral therapy. Tally & associated gave the conclusion that cefixime produces diarrhoea in 13.4% of patients during therapy while changing the bowel habits in 12.8% of people. During the ceftriaxone therapy, cholecystitis occurs due to the billary deposits which are frequently observed but maybe it occurs due to the formation of calcium salt precipitates of ceftriaxone in the gall bladder.

7 CLINICAL USES:-

• Oral cephalosporins:-
Cephradine, cephalexin, cefadroxil and cefaclor are used for the treatment of acute and chronic upper and lower respiratory tract infections, which are caused by the streptococcus pyrogens, streptococcus pneumonia, staphylococcus aureus, H. influenza and klebsiella. Erythromycin/sulfamethoxazole and amoxicillin / clavulanic acid both are effective and cheap as compared to oral cephalosporins when they are used for the treatment of ampicillin-resistant strain of B. catarhalis & Haemophilus influenza. For UTI therapy, cefuroxime is also used and also shows its activity against various organisms which cause otitis media. Cefuroxime and probenecid combination is useful as a single daily dose for the treatment of rectal, urethral and endocervical gonorrhoea. Cefixime therapy causes the GIT problems but when it is compared with amoxicillin it is more potent against Haemophilus influenza, B. catarhalis and middle ear infections but it has potency like amoxicillin in case of urinary tract infection treatment in adults.
• 1st generation parental cephalosporins:-
These cephalosporins are provided in pre and post-operative situations to maintain the hygienic conditions in contaminated procedures like C- section, cholecystectomy and vaginal hysterectomy etc. They are also broadly used in people subjected to clean surgeries, for example:-cardiovascular procedures and arthroplasty etc.
• 2nd generation parental cephalosporins:-
Cefoxitin has more potency against B. fragile species and various gram +ve and –ve bacteria. It is used to treat intra-abdominal and pelvic infections. Cefoxitin is repeatedly used as a preventive agent for those patients who have done colorectal or pelvic surgery. Cefoxitin is also very useful and helpful in the form of combination with clindamycin and aminoglycosides. Cefotetan is responsible for the treatment of gynaecological infection, lower respiratory tract, obstetric, serious UTI, intra– abdominal and skin and soft tissue infections which are caused by the bacteria. 
• 3rd generation parental cephalosporins:-
Commonly cefotaxime is prescribed to treat meningitis which is caused by the gram–bacilli. It has more potency against S. pneumonia, Neisseria meningitis and H. influenza. Sometimes it is given to treat meningitis in young children and infants. Cefotaxime and ceftizoxime both are responsible to treat complicated gram–bacillary infections such as serious UTI, gynecologic, bone, intra-abdominal and lower RTI infections. Ceftriaxone has supreme activity against the Neisseria gonorrhoea in which tetracycline N. gonorrhoea is also included. It is also frequently used in experimental monotherapy against many infections. 3rd generation agents are properly used to treat salmonellosis which is induced by ampicillin and chloramphenicol-resistant bacteria. Ceftazidime has activity against hospital-acquired gram–bacteria.
• 4th generation parental cephalosporin:-
According to some experiments it has been revealed about the good activity of cefepime and cefpirome against complicated and uncomplicated UTIs, gynaecological and upper and lower respiratory tract infections. Patients with ventilator-associated pneumonia can be treated with the 4th generation cephalosporins. Cefepime 2g BID dose has great efficiency to treat hospital-acquired pneumonia.
• 5th generation parental cephalosporins:-
It is an advanced generation of cephalosporins, which is used to treat the methicillin-resistant staphylococcus aureus strain (MRSA) and also streptococcus species otherwise they have similar activity like 3rd generation cephalosporins but it has not that much activity against pseudomonas aeruginosa.

8 CONCLUSIONS:-

Cephalosporins are an extremely useful and diverse group of antibiotics. Because of their remarkable and effective bactericidal actions, they treat many infections which are caused by various dangerous bacteria. In ambulatory antibiotic therapy, 3rd generation cephalosporins are used as 1st line drugs. Cephalosporins should be preferred over other antibiotics because of their low tendency to favour the emergence of resistant mutant example:-quinolones favour the emergence of mutant strains and aminoglycosides increases the chances of ototoxicity and nephrotoxicity. Cephalosporins are classified or divided into five generations according to their spectrum as the generation goes towards a higher one, the activity against gram –bacteria increases and activity against gram +ve bacteria decreases except for 1st and 4th generation cephalosporins both have similar activity against gram +ve bacteria. Rather than learn about all cephalosporins, it will be convenient for the health care providers to become familiar only with the frequently used cephalosporins among the oral and parental cephalosporins like ceftazidime and cefepime both have anti-pseudomonal activity, cefoxitin has activity against anaerobic bacteria, enterococci and MRSA is treated with 5th generation of the cephalosporins and no any oral cephalosporin is effective against pneumococci, it is highly resistant to penicillin.

CONTRACEPTION AND ITS METHODS

DEFINITION OF CONTRACEPTION:-

Contraception is also known as birth control. It is designed to obstruct the pregnancy by causing the interruption with the normal physiological processes of ovulation, fertilization & implantation.

METHODS OF CONTRACEPTION:-

There are several methods of contraception such as,

1. Barrier methods (diaphragms, cervical cap, condom and sponge)

2. Short acting hormonal method (mini pills, injection, pills, vaginal ring and patch)

3. Long acting reversible contraceptive method (contraceptive implants and intrauterine devices)

4. Male and female Sterilization (male vasectomy and female tubal occlusion or ligation)

5. Natural rhythm methods (avoiding sexual intercourse)

                    BARRIER METHODS:-

·        CONDOM:-It is the only type of contraception which protects against lots of sexually transmitted diseases and also prevents the pregnancy. It acts like a physical barrier by preventing the sexual fluids to pass between the peoples during the sexual intercourse.

·        DIAPHRAGM:-It is a small and soft silicon dome structure, which is used to stop the entrance of sperm in the uterus by placing it inside the vagina.

·        CERVICAL CAP:-It is the deep silicon cup which is placed inside the vagina and fits over the cervix tightly. It is also used to prevent the entrance of sperm within the uterus. This cup is reusable.

       

·        SPONGE:-It is a soft, small and disk shaped structure, it contains spermicide by killing or blocking the sperms and prevent the entry of sperm within the uterus.

      ii.            SHORT ACTING HORMONAL METHODS:-

       MINI PILL:-It is one of the all birth control pills. It contains only progestin hormone and it works by thinning the uteral lining, thickens the cervical mucus and also suppresses the ovulation.

·        PILLS:-These contraceptive pills mostly are the “combination pills” (means containing mixture of both estrogen and progesterone hormones). These pills are used to prevent ovulation, thicken the mucous and also used to thinning the uterus wall.

·        INJECTION:-It is a shot which contains hormones, either a combination of progestin and estrogen or only a progestin alone.

·        PATCH:-It is also the form of contraception and it contains both progestin and estrogen hormones. It is applied on the skin and works similarly like the contraceptive pills.

·        VAGINAL RING:-It is a circular, flexible device which is placed inside the vagina, where it releases hormones and these hormones through vaginal wall move into the bloodstream. These hormones are useful to prevent pregnancy.

    iii.            LONG ACTING REVERSIBLE CONTRACEPTIVE METHODS:-

·        CONTRACEPTIVE IMPLANTS:-It is a small, flexible and plastic rod which is placed under the skin of upper arm, where it slowly releases appropriate amount of progesterone hormone to prevent pregnancy.

·        INTRA-UTERINE DEVICE (IUD):-It is a small sized object, which is placed inside the uterus. It is of 2 types, copper IUD (contains copper) and hormonal IUD (contains hormone progesterone). It prevents fertilization and implantation.

    iv.            MALE AND FEMALE STERILIZATION:-

·        MALE VASECTOMY:-Vasectomy is a type of male contraception, which occurs by blocking or cutting the tubes (vas deferens) that carry sperm.

·        TUBAL LIGATION:-It is also known as tubal sterilization. It occurs in female. In this type of contraception, fallopian tubes are tied, cut or blocked to prevent pregnancy permanently.

ORAL CONTRACEPTIVE DRUGS:-

In oral contraceptive drugs, estrogen and progestin hormones are used.

Estrogen medications are the ‘Ethinylestradiol-30micrograms’ and ‘Mestranol-50micrograms’.

Progesterone medications are the ‘Norethindrone-1mg’, ‘Norethindrone acetate-5mg’, ‘Norgestimate-0.180mg’, ‘Desogestrel-150micrograms’ , ‘Norgestrel-0.5mg’ and ‘Levonorgestrel-150 micrograms’.

Different types of oral contraceptive pills are found:-

·        Combined pills

·        Progestin only pills

·        Postcoital (Emergency) pills.

1.      COMBINED PILLS:-These contraceptive combined pills, containing both synthetic (men made) estrogen and progestin hormones. These pills are more effective in temporary contraception.

There are different types of combined contraceptive pills exist.

·        Monophasic pills

·        Biphasic pills

·        Triphasic pills

a)      MONOPHASIC PILLS:-These pills contain fixed amount of estrogen and progestin hormones in each hormonally active pill which is given throughout the cycle.

For example:-Brevicon (ethinylestradiol and norethindrone)

                        Previfem (ethinylestradiol and norgestimate)

DOSING SCHEDULE:-Monophasic pills are available in both 21 days pill pack and 28 days pill pack. In both conditions, these pills have same amount of hormones (estrogen and progestin) for 21 days.

·        If women taking 21 day formulation so she would take active hormones for 21 days and followed by 1 week in which she will not take any pill.

·        If women taking 28 day formulation so she would also take the active hormones for 21 days ₊  placebo pills for 7 days.

USES:-

1.      These pills are used to prevent pregnancy.

2.       Used by some other women who have polycystic ovary syndrome (PCOS) so these pills regulate their menstrual cycles.

3.      Also helpful in improving the symptoms of menstrual cycles, like lightening of bleeding, reducing pain and cramps and easing the premenstrual syndrome (PMS).

ADVERSE EFFECTS:-Adverse effects of monophasic pills are;

1.      Bleeding or spotting between the periods.

2.      Depression / mood changes.

3.      Possible weight gain

4.      Breast tenderness

5.      Nausea

These monophasic pills can also cause some serious and dangerous medical conditions like;

1.      Severe abdominal or chest pain.

2.      Swelling or pain in the legs.

3.      Severe headache

4.      Blurred vision

These symptoms could be the signal of blood clot presence due to which heart attack or stroke can occur.

b)      BIPHASIC PILLS:-These pills have fixed amount of estrogen but progestin amount varies according to the phases of menstrual cycle.

For example:-Amethia Lo (ethinylestradiol and levonorgestrel extended – cycle)

                        Azurette (ethinylestradiol and desogestrol)

                        Lo Seasonique (ethinylestradiol and levonorgestrel)

DOSING SCHEDULE:-If any woman is using biphasic 21 day schedule, so she would take one strength (color) pills for 7 or 10 days (first phase). After that in (second phase) she would take medicines of other strength (color) for next 11 or 14 days. So in this woman has taken 21 tablets. But for biphasic 28 days schedule, she would also take extra 7 inactive tablets (3^rd color).

USES:-Due to increase in the biphasic pills doses over the cycle reduces the occurrence of bleeding and spotting and also the occurrence of amenorrhea which is associated with the utilization of low dosed monophasic combined drug.

ADVERSE EFFECTS:-Biphasic contraceptive pills are less effective as compared to monophasic contraceptive pills in pregnancy prevention. These biphasic pills cause more side effects and poorly control the cycle and also have less continuation rates.

   

c)      TRIPHASIC PILLS:-The amount of estrogen may be constant or variable but the quantity of progestin increases equally in 3 phases.

For examples:-TriNessa (ethinylestradiol and norgestimate)

                        Enpresse (ethinylestradiol and levonorgestrel)

                        Caziant (ethinylestradiol and desogestrel)

DOSING SCHEDULE:-If any woman is using triphasic 21 days schedule, so she would take one strength (color) pills for 5, 6 or 7 days (first phase). After that in (second phase) she would take medicines of second strength (color) for next 5, 7 or 9 days. And then in (3^rd phase) she would take 3^rd strength (color) pills for next 5, 7, 9 or 10 days. So in this way woman has taken 21 tablets. But for triphasic 28 days schedule, she would also take extra 7 inactive tablets (4^th color).

USES:-

·        These triphasic pills are useful in the prevention of pregnancy.

·        It decreases the chances of ovarian cyst development and also helps in the regulation of menstrual cycle.

·        It also improves acne problems.

ADVERSE EFFECTS:-These pills can develop different breast problems, dysmenorrhea, water retention & premenstrual syndrome along with irritability. And also causes headache and nervousness.

2.      PROGESTIN PILL ONLY:-This pill contains progestin only without estrogen and also known as minipill.

For example:-Micronor (norethindrone-0.35mg)

                        Norgest (norgestrel-0.075mg)

DOSING SCHEDULE:-Take one pill daily without any gap.

USES:-These pills are good for those women who cannot take estrogen due to health issues or other reasons. And also decrease the dysmenorrheal, menstrual blood loss and premenstrual syndrome symptoms.

ADVERSE EFFECTS:-These pills can also cause some side effects like, acne, mood changes, breast enlargement and tenderness, headache and vomiting.

3.      EMERGENCY CONTRACEPTIVE PILLS:-These pills are also known as “The Morning After Pill”. These are more effective and safe pills, after unprotected sex.

For example:-Postinor-1 (levonorgestrel-0.75mg)

                        EllaOne (ulipristal acetate-30mg)

DOSING SCHEDULE:-Take 2 doses of levonorgestrel-0.75mg in every 12 hours within 72 hours of unprotected sexual intercourse. OR take single dose of ulipristal acetate-30mg, within 72 hours after intercourse.

USES:-

·        These pills are used to prevent the unwanted pregnancy.

·        Reduce the blood loss and prevent anemia.

·        Prevent endometrial and ovarian carcinomas.

ADVERSE EFFECTS:-

·        Gall stones

·        Headache

·        Nausea and vomiting

·        Genital carcinoma

·        Weight gain

INJECTABLE CONTRACEPTIVE DRUGS:-

DMPA (Depot Medroxyprogesterone Acetate) is the contraceptive injection and it is similar to the progesterone hormone that is produced by the ovaries within the body.

Depo-provera is the brand name of DMPA.

DOSING SCHEDULE:-Contraceptive injection can be injected into the muscles of upper arm or buttock. It is mostly given first five days of menstrual cycle.

USES:-

It inhibits the ovulation.

·        It decreases the risk of ovarian and endometrial carcinomas.

·        It does not contain estrogen so can be taken by those women who cannot take estrogen.

·        It is also safe and effective for breastfeeding mothers.

ADVERSE EFFECTS:-

·        It causes rapid and irregular menstrual bleeding.

·        Amenorrhea

·        Spotting

·        Depression

·        Weight gain

TOPICAL CONTRACEPTIVE PATCH:-

The contraceptive patch is applied on the clean area of upper arm, shoulder, abdomen or buttock. It is less effective on 90kgs woman.

For example:-Ortho Evra (norelgestromin/ethinylestradiol)

DOSING SCHEDULE:-The (Ortho Evra) patch is applied each week for 3 weeks (21 days). But on the 4^th week, patch is not applied, during this time withdrawal bleeding is expected.

USES:-

·        This patch can easily use to prevent the pregnancy.

·        It also improves the acne problems.

·        Making the periods lighter and regular.

·        And relieve the menstrual cramps.

ADVERSE EFFECTS:-

·        Breast pain

·        Nausea, vomiting

·        Menstrual cramps

·        Headaches

·        Skin irritation

·        Spotting

·        And can cause blood clotting problems.

CONTRACEPTIVE IMPLANTS:-

It is the long-term contraception option for the women. It is small, matchstick like rod which is implanted under the skin of upper arm. It releases low and accurate dose to prevent the pregnancy.

For example:-Nexplanon (etonogestrel implant).

DOSING SCHEDULE:-This contraceptive implant is implanted between the 1^st day (menstrual bleeding) and 5^th day (menstrual cycle), even if the woman is still bleeding.

USES:-

·        It is the effective method to get the contraception.

·        It prevents pregnancy for 3 years.

·        If the implant is removed, fertility can be reversed.

·        It is good for that woman who cannot take estrogen.

ADVERSE EFFECTS:-

·        It causes weight gain, nausea, ovarian cyst and breast pain etc.

·        It does not provide protection against sexually transmitted diseases.

·        This technique is very costly.

·        Require a doctor for insertion.