Postantibiotic Effect
Question 1. Write a short note on the post-antibiotic effect
Answer:
Postantibiotic Effect Notes:
Some antibiotics continue to suppress bacterial multiplication even after their plasma concentration falls below the MIC known as the postantibiotic effect (PAE), for example, Aminoglycosides, carbapenems, and chloramphenicol against gram-negative bacteria.
Read And Learn More: Pharmacology Question And Answers
The exact mechanism of development of PAE is not known but may be due to:
- Persistence of the drug in the periplasmic space or at the binding site.
- The time is needed for suppressed enzymes in the microbes to be resynthesized, e.g. DNA gyrase.
- Aminoglycosides and quinolones exhibit concentration-dependent killing and also have a PAE.
- Thus, an entire day’s dose of gentamicin may be given as a single dose—this allows good bactericidal activity because the entire dose is given in one injection and also has the convenience of single daily injections.
Combination Of Antimicrobials
The use of a combination of antimicrobials may have synergistic, antagonistic, or indifferent effects.
Combination of a bacteriostatic + bactericidal drug → not useful because bacteriostatic drugs inhibit the multiplication of bacteria and thereby antagonize the effects of bactericidal drugs (as bactericidal drugs act on actively multiplying bacteria).
A combination of antimicrobial agents is needed in some specific situations as below:
1. To obtain synergism: A combination of antibiotics to attain synergism is recommended:
- Bacterial endocarditis: Penicillin + streptomycin/gentamicin is synergistic.
- Pseudomonas infections: Carbenicillin + gentamicin
- Pneumocystis jiroveci pneumonia: Trimethoprim + sulfamethoxazole
- β-lactamase producing organisms like H. influenzae: Amoxicillin + clavulanic acid
- Tuberculosis: INH + rifampicin.
2. Treatment of mixed infections:
- Intra-abdominal infections, brain abscesses, and genitourinary infections are often mixed infections with gram-positive and gram-negative aerobic and anaerobic organisms.
- Two or more antimicrobials can be used depending on the culture and sensitivity report.
3. Initial treatment of severe infections:
- Drugs covering both gram-positive and gram-negative pathogens are used initially till the culture report is available, for example, Penicillin + aminoglycoside; cephalosporin + aminoglycoside.
- If anaerobes are likely to be present, metronidazole may be added.
- Samples for culture should be taken before starting the antibiotics.
4. To prevent the emergence of resistance: As in the treatment of tuberculosis and leprosy.
5. To reduce the adverse effects:
- Lower doses are needed when a combination is used and this may reduce the incidence and severity of adverse effects.
- For example, Amphotericin B + flucytosine in cryptococcal meningitis.
Disadvantages Of Antimicrobial Combinations:
- Risk of toxicity from each agent—may get added up, especially if toxicity is overlapping, for example, Many antitubercular drugs are hepatotoxic.
- Toxicity of one drug may be enhanced by another, for example, Vancomycin + aminoglycosides → more severe renal toxicity
- Selection of resistant strains: The few resistant mutants that remain may multiply unchecked.
- The emergence of organisms resistant to multiple drugs.
- The increased cost of therapy.
Chemoprophylaxis
Chemoprophylaxis is the use of antimicrobial agents to prevent infection. This is recommended in the following situations
1. To protect healthy persons:
- Penicillin G for prevention of gonorrhea or syphilis postexposure prophylaxis.
- For preventing meningococcal infection in healthy children during an epidemic, rifampicin or sulfonamides may be used.
- Malaria in healthy individuals visiting an endemic area—chemoprophylaxis with chloroquine or pyrimethamine + sulfadoxine.
2. To prevent infection in high-risk patients:
- In neutropenic patients, like patients on anticancer drugs, immunosuppressive agents, and patients with AIDS → penicillin/fluoroquinolones/cotrimoxazole may reduce the incidence of bacterial infection.
- In valvular heart disease patients, even minor procedures like dental extraction, tonsillectomy or endoscopies may result in bacterial endocarditis (damage to mucosa results in bacteremia). Penicillin is used for prophylaxis.
- In patients with contaminated or exposed wounds as in road traffic accidents.
- Catheterization of the urinary tract—norfloxacin is used.
- In burns, to prevent colonization by bacteria.
3. In close contact: When infectious (open) cases of leprosy or tuberculosis are in close contact.
Surgical prophylaxis: Prevention of surgical wound infection is vital to limit morbidity and for the success of the surgery.
Selection of the antibiotic for surgical prophylaxis:
- Antibiotics should be effective against most likely microorganisms that could infect the surgical wound.
- Toxicity should be low and the antibiotic should be inexpensive.
- Antibiotics must achieve adequate concentration well above the MIC at the site of infection and must be present before incisions and throughout the procedure. If the antibiotic is short-acting, a dose may be repeated for long surgical procedures.
- Cefazolin 1 g injected IV at the induction of anesthesia (or 60 minutes prior to incision) is the agent of choice for most clean procedures. In cesarean section, the antibiotic is injected after umbilical cord clamping.
- Duration: Should be for the shortest period and in most cases as a single dose.
Superinfection:
- Superinfection/suprainfection is the appearance of a new infection resulting from the use of antimicrobials.
- The use of antibacterials alters the normal microbial flora of the intestinal, respiratory, and genitourinary tracts.
The normal flora contributes to host defense mechanisms as follows:
- When the normal flora is destroyed by antibacterials, there can be dangerous infections due to various organisms, especially the normal commensals which become pathogenic.
- The broader the antibacterial spectrum of a drug, the more the chances of superinfection because the alteration of the normal flora is greater.
Common causative microorganisms, manifestations, and treatment of superinfection:
1. Sites involved: Gastrointestinal, respiratory, and genitourinary tracts.
2. Superinfection is likely to occur in the following situations:
- Use of broad-spectrum antibiotics
- Immunocompromised patients
- Diabetes mellitus
- AIDS patients.
Measures To Prevent Superinfection:
- Narrow spectrum and specific antibiotics should be used.
- Antibiotics are to be used only when absolutely necessary.
- Appropriate drug to be used for the right duration with prolonged antibiotic use.
Misuse of antibiotics: Antibiotics are one of the most overused or misused drugs. Faultypractices like
- The use of antibacterials in viral infections which are self-limiting
- Using too low doses or unnecessarily prolonged treatment
- Using antibiotics in all fever cases—are all irrational and can do more harm than benefit.
- Since most of the vulnerable sites in the microorganisms have already been targeted by various antibiotics, we are left with very few or no targets for the development of antibiotics in the future.
- Hence, it is absolutely necessary that we do not encourage the development of resistance by microbes due to inappropriate use of the available antimicrobials.
Antibiotics in pregnancy:
- As far as possible, antibiotics are to be avoided in pregnancy. Very few of them have been known to be safe in pregnancy like penicillins and some cephalosporins.
- Many of them including tetracyclines, chloramphenicol, sulfonamides, and aminoglycosides should be avoided in pregnancy.
Probiotics:
- Probiotics are products containing live, nonpathogenic microorganisms administered orally to alter the intestinal microflora for health benefits. Lactobacillus, Bifido bacterium,
- Streptococcus salivarius, some enterococci, and Saccharomyces boulardii are some of the presently tried probiotics. Vibact 500 mg cap 1 BD.
SuperinfectionMechanism of action may be:
- Production of bacteriocins
- Compete with pathogens for nutrients
- Block binding of pathogens
Superinfection Uses: Probiotics are tried in the following
- Acute infantile diarrhea—due to rotavirus
- Antibiotic-associated diarrhea
- Irritable bowel syndrome
- Inflammatory bowel disease
- Lactose intolerance.
Prebiotics:
Prebiotics are nondigestible substances that stimulate the growth of intestinal flora and thereby prevent the colonization by pathogenic bacteria, for example, Lactulose, and inulin.
Sulfonamides
- Sulfonamides were the first effective antibacterial agents to be used systemically in man.
- They were introduced by Domagk in 1935 but currently, their role in therapeutics is limited because of their toxicity, development of resistance, and availability of safer drugs.
Sulfonamides Classification:
- Short-acting: Sulfisoxazole, sulfadiazine
- Intermediate-acting: Sulfamethoxazole
- Long-acting: Sulfamethoxypyridazine, sulfadoxine
- Poorly absorbed: Sulfasalazine
- Topical: Sulfacetamide, mafenide, silver sulfadiazine
- Chemistry: Sulfonamides are structural analogs of p-aminobenzoic acid (PABA).
Antibacterial spectrum: Sulfonamides inhibit many gram-positive and some gram-negative bacteria
- Streptococci – H. influenzae – H. ducreyi – Meningococci
- Nocardia – E. coli – Salmonella – Pneumococci
- Shigella – Proteus – V. cholerae
- Staphylococci (few strains) – Gonococci
They are also effective against chlamydiae, P. falciparum and Toxoplasma gondii.
Sulfonamides Mechanism of action:
- Folic acid is essential for the synthesis of nucleic acids. Bacteria synthesize their own folic acid from PABA with the help of the enzyme folic acid synthetase.
- Sulfonamides are structurally similar to PABA and competitively inhibit the enzyme folic acid synthetase.
- This results in folic acid deficiency and thereby inhibition of bacterial growth as well as injury to the bacterial cell. Sulfonamides are bacteriostatic.
- Human cells are not affected because they require preformed folic acid supplied from the diet and cannot synthesize folic acid by themselves.
- In the presence of pus, blood, and tissue breakdown products, sulfonamides is ineffective because they are rich in PABA.
Resistance: Bacteria acquire resistance to sulfonamides by overproduction of PABA and using alternative metabolic pathways for folic acid synthesis.
Sulfonamides Pharmacokinetics:
- Sulfonamides (except sulfasalazine) are well-absorbed, extensively bound to plasma proteins, and well-distributed to all tissues, body fluids, and CSF.
- They are metabolized in the liver by acetylation and glucuronidation and excreted through the kidney. The dose of sulfonamides should be reduced in renal failure.
Preparations and Dose:
- Sulfadiazine: 0.5–2 g BD
- Silver sulfadiazine, cream 1%
- Sulfasalazine: 0.5–1 g BD
- Sulfamethoxazole: 0.5–1 g BD
- Sulfacetamide: 10, 20, 30%eye drops, 6% eye ointment.
Sulfonamides Adverse Effects:
- Renal irritation, haematuria, albuminuria, and crystalluria: Due to precipitation of the drug in acidic urine. Nephrosis and allergic nephritis can also occur.
- Allergic reactions:
- Sulfonamides can produce a range of hypersensitivity reactions like rashes, fever, anaphylactoid reactions, urticaria, photosensitivity, and rarely, StevensJohnson syndrome (SJS) and exfoliative dermatitis. SJS can be fatal and should be watched for.
- Nephritis may also be of allergic etiology.
- Anorexia: Anorexia, Nausea, Stomatitis, Abdominal pain, Conjunctivitis, and Arthritis can occur.
- Hemolytic anemia: Hemolytic anemia and decreased granulocyte and thrombocyte count in patients with G6PD deficiency.
- Kernicterus: Sulfonamides displace bilirubin from the plasma protein binding sites which crosses the BBB and may cause kernicterus in the newborn. Hence, sulfonamides are contraindicated in pregnancy and in infants.
Sulfonamides Uses:
Because of the development of resistance and availability of better antimicrobials that are more effective and less toxic, sulfonamides are mostly given in combination with other drugs like trimethoprim and pyrimethamine.
- Urinary tract infections (UTI): Uncomplicated acute UTI in areas where resistance is not high—sulfisoxazole (1 g QID) or sulfamethoxazole (1 g TDS).
- Nocardiosis: High doses of sulfonamides as alternatives.
- Toxoplasmosis: Sulfadoxine with pyrimethamine treatment of choice in T. gondii infection. They block sequential steps in folate synthesis and are synergistic. Sulfadoxine 4 g/day with pyrimethamine bolus dose of 75 mg followed by 25 mg daily continued for 4–6 weeks. Such doses require leucovorin rescue (10 mg folinic acid daily) to prevent severe folic acid deficiency.
- Trachoma, inclusion conjunctivitis, lymphogranuloma venereum, and chancroid: Sulfonamides are alternatives to tetracyclines.
- Malaria: Sulfadoxine—pyrimethamine with artemesinin in malaria.
- Prophylactic use: In patients allergic to penicillins, sulfonamides are used for prophylaxis of streptococcal pharyngitis in rheumatic fever.
- Topical: Sulfacetamide eye drops in bacterial conjunctivitis—readily penetrate into aqueous humor. Mafenide and silver sulfadiazine (preferred) ointments—used in burns to prevent infection.
- Ulcerative colitis: Sulfasalazine is useful in ulcerative colitis and rheumatoid arthritis.
Cotrimoxazole
The combination of trimethoprim and sulfamethoxazole is cotrimoxazole.
Antibacterial spectrum:
- Cotrimoxazole is effective against several gram-positive and gram-negative organisms like Staph. aureus, streptococci, meningococci, C. diphtheriae, E. coli,
- Proteus, H. influenzae, Salmonella, Shigella, and Pneumocystis jiroveci.
Cotrimoxazole Mechanism of Action:
- Sulfonamides inhibit the conversion of PABA to dihydrofolate (DHF) acid and trimethoprim inhibits dihydrofolate reductase (DHFR) and thus prevents the reduction of DHF to tetrahydrofolate (THF) acid.
- The two drugs thus block sequential steps in folic acid synthesis and the combination is synergistic. Given alone, both trimethoprim and sulfonamides are bacteriostatic but the combination is bactericidal.
- Trimethoprim is highly selective for bacterial DHFR compared to human enzymes.
- The ratio of ‘trimethoprim: sulfamethoxazole’ used is 1:5 to attain the right plasma concentration. The optimal peak plasma concentration of the combination is in the ratio 1:20,m (trimethoprim: sulfamethoxazole).
- Resistance: The development of resistance to the combination is slower than to individual drugs given alone. Resistance by mutation or by acquisition of a plasmid coding for an altered DHFR.
Cotrimoxazole Pharmacokinetics:
- Both trimethoprim and sulfamethoxazole have similar t½. Given orally and in serious infection IV. Both are well absorbed from the gut and widely distributed in the body.
- Trimethoprim has good distribution into the tissues including prostatic and vaginal fluids.
- Because of its basic nature, trimethoprim concentrates in acidic fluids. Both drugs are excreted by the kidneys → in renal failure reduce the dose.
Cotrimoxazole Adverse Effects:
- Nausea, vomiting, headache, glossitis, stomatitis, and skin rashes are common.
- In patients with folate deficiency, cotrimoxazole may precipitate megaloblastic anemia.
- Hematological reactions like anemia and granulocytopenia are rare.
- AIDS patients are more prone to adverse effects of cotrimoxazole.
- Patients with renal disease may develop uremia.
- Contraindicated in pregnancy as they are antifolate drugs—could be teratogenic.
Cotrimoxazole Preparations:
Trimethoprim-Sulfamethoxazole
80 mg – 400 mg
160 mg – 800 mg double strength (DS)
Cotrimoxazole Uses:
- Urinary tract infections:
- Uncomplicated acute UTI: Cotrimoxazole 7–10 days (DS, twice a day)-both Trimethoprim and Sulfamethoxazole attain good concentration in the urine.
- Chronic and recurrent UTI: Small doses for prophylaxis (1 tab thrice a week).
- Bacterial prostatitis: Trimethoprim attains a high concentration in prostatic fluid. Cotrimoxazole DS twice daily.
- Respiratory tract infections: Upper and lower respiratory infections including bronchitis, sinusitis, and otitis media respond.
- Bacterial gastroenteritis: Due to Shigella and E. coli.
- Typhoid: As an alternative to fluoroquinolones.
- Pneumocystis jiroveci infection: High doses for prophylaxis and (trimethoprim 20 mg/kg + sulfamethoxazole 100 mg/kg daily) treatment of Pneumocystis jiroveci pneumonia in neutropenic and AIDS patients. It also protects against infections with other gram-negative bacteria.
- Chancroid: Cotrimoxazole (DS, BD for 7 days) is the drug of choice.
- Melioidosis: It is caused by Burkholderia pseudomallei. An outbreak was reported recently in South India.
- Mild infection → Cotrimoxazole
- Severe infection → Ceftazidime/meropenem → 2 weeks
- Cotrimoxazole/doxycycline → For eradication
- Toxoplasmosis: As an alternative to pyrimethamine + sulfadiazine.
Quinolones And Chemotherapy Of Urinary Tract Infection
Quinolones are a group of synthetic antimicrobial agents and include nalidixic acid, oxalinic acid, and cinoxacin.
Urinary Tract Nalidixic Acid:
- Nalidixic acid is bactericidal against various gram-negative organisms like E. coli, Shigella,
- Enterobacter, Proteus and Klebsiella. Its mechanism of action is the same as that of fluoroquinolones by inhibition of DNA gyrase in the bacteria.
- Though nalidixic acid is well absorbed orally the plasma concentration of the drug is inadequate to produce systemic effects because it is too rapidly excreted.
- However, it attains high concentrations in the urine (see compare and contrast). Dose: 0.5–1 g 3–4 times a day.
Urinary Tract Adverse effects: Allergic reactions, hemolytic anemia, particularly in G6PD deficient individuals; myalgia and CNS effects like headache, drowsiness, and visual disturbances occur.
Urinary Tract Uses:
- UTI: Nalidixic acid is a urinary antiseptic used in uncomplicated UTIs due to E.coli, Shigella, and Proteus.
- Diarrhea: Useful in diarrhea due to Proteus, E. coli, and Shigella.
- Oxalinic acid and cinoxacin have properties and uses similar to nalidixic acid
Quinolone And Fluroquinolone:
Fluoroquinolones
The fluorinated quinolones have the following advantages over quinolones:
- A wider spectrum of activity
- Fewer side effects
- Lesser chances of resistance
- Attain therapeutic blood levels
- Have better tissue penetration.
The fluoroquinolones (FQs) include:
Fluoroquinolones Mechanism Of Action:
- Fluoroquinolones are bactericidal. They inhibit the bacterial enzymes DNA gyrase and topoisomerase IV which are required for DNA replication and transcription.
- During DNA replication, there is excessive positive supercoiling of the DNA.
- This is corrected by the enzyme DNA gyrase by continuously introducing negative supercoils and therefore, this enzyme is necessary for DNA replication.
- By inhibiting the enzyme DNA gyrase, fluoroquinolones inhibit DNA replication. Instead of DNA gyrase, human cells have topoisomerase II which functions as DNA gyrase.
- Topoisomerase II is also inhibited by FQs but only at 500–1,000 times higher concentrations. Hence, FQs are reasonably safe drugs.
Topoisomerase IV:
- Topoisomerase IV is essential for the separation of the daughter cells following replication. FQs also inhibit topoisomerase IV and block the separation of daughter cells.
- This activity of FQs is primarily responsible for inhibiting the gram-positive bacteria, while DNA gyrase inhibition suppresses gram-negative bacteria.
Bacteria with damaged DNA are formed which are destroyed by nuclease enzymes. Thus FQs are bactericidal.
Antibacterial Spectrum:
Some of the newer fluoroquinolones are effective against some anaerobic organisms and Streptococcus pneumoniae.
Fluoroquinolones Pharmacokinetics:
- FQs are well-absorbed and widely distributed. Food, antacids, and other cations interfere with their absorption → FQs should be taken 2 hours before or 4 hours after these. Pefloxacin and ofloxacin cross the BBB.
- All FQs are metabolized by hepatic microsomal enzymes and FQs are microsomal enzyme inhibitors—that can result in related drug interactions.
- These drugs are excreted by the kidneys and the dose should be reduced in renal failure except for moxifloxacin. Plasma t½ varies from 3–20 hours.
Fluoroquinolones Adverse reactions:
- Fluoroquinolones are well-tolerated.
- Nausea, vomiting, abdominal discomfort, diarrhea, and skin rashes may be seen.
- Tendonitis with the associated risk of tendon rupture has been reported. Fluoroquinolones damage the growing cartilage resulting in arthropathy and are, therefore, contraindicated up to 18 years of age.
Fluoroquinolones CNS effects:
- CNS includes headache, dizziness, and insomnia. In patients receiving NSAIDs and other epileptogenic drugs like theophylline, fluoroquinolones can sometimes precipitate seizures.
- Levofloxacin, gatifloxacin, moxifloxacin and gemifloxacin can cause QTc prolongation.
- Grepafloxacin was found to cause cardiac arrhythmias, trovafloxacin causes hepatotoxicity, and clinafloxacin— phototoxicity due to which all three have already been withdrawn.
CNS Uses:
- Urinary tract infections: FQs are effective in UTIs even those caused by multidrug-resistant bacteria; norfloxacin is generally used (400 mg BD for 5–10 days).
- Typhoid: Ciprofloxacin is the preferred drug (500 mg BD–10 days) but resistance is now seen—it also eradicates the carrier state.
- Diarrhea: Due to Shigella, Salmonella, E. coli, and Campylobacter response.
- Gonorrhea: Single dose 250 mg ciprofloxacin is curative but resistance is now common.
- Chancroid: As an alternative to cotrimoxazole, ciprofloxacin–3 days.
- Respiratory tract infections: Due to H. influenzae, Legionella, and Mycoplasma. Gemifloxacin, moxifloxacin, gatifloxacin, and levofloxacin are called respiratory fluoroquinolones as they are effective against most respiratory pathogens including gram-positive bacteria as well as Legionella, Chlamydia, and Mycoplasma.
- Bone, joint, soft tissue, and intra-abdominal infections: Osteomyelitis, joint infections. Soft tissue infections due to sensitive bacteria can be treated with FQs.
- Tuberculosis: Ciprofloxacin is a second-line drug for resistant tuberculosis and in atypical mycobacterial infections.
- Bacterial prostatitis and cervicitis: FQs are useful. Chlamydial urethritis and cervicitis— ciprofloxacin/sparfloxacin are alternatives to tetracyclines.
- Eye infections: Ciprofloxacin and ofloxacin may be used topically.
- Anthrax: Ciprofloxacin is the drug of choice (DOC) for anthrax. It is also useful for prophylaxis.
- Neutropenic patients: For prophylaxis of infections in neutropenic patients.
- Gram-negative septicemias: FQs may be combined with a III generation cephalosporin/aminoglycosides in the treatment of gram-negative septicemia.
- Meningococcal carrier state: FQs eradicate the carrier state; they are also used in meningitis.
Fluoroquinolones Contraindications:
- Pregnancy.
- To be avoided in patients < 18 years old because FQs damage the growing cartilages and cause arthropathy. However, since the effect is reversible, FQs are being used in some infections even in children.
- To be avoided in patients with prolonged QTc interval, in those receiving other drugs that prolong QTc interval (for example, Mefloquine, Erythromycin), and in class 1 and 2 antiarrhythmics.
- Toxicity due to theophylline (and other epileptogenic drugs) may be precipitated by FQs due to microsomal enzyme inhibition.
- Avoid calcium, iron, and preparations containing divalent cations→ they reduce FQ absorption.
- Dose adjustment should be done in renal failure (except for moxifloxacin).
Individual Agents:
Salient features of some FQs:
Chemotherapy Of Urinary Tract Infection
- Infection of the urinary tract is quite common and may be acute or chronic. Urinary antiseptics are drugs that exert antibacterial activity only in the urinary tract (and no systemic activity).
- They include nitrofurantoin and methenamine mandelate.
Nitrofurantoin:
- Nitrofurantoin, a synthetic nitrofuran, is bacteriostatic, but bactericidal at higher concentrations.
- It is effective against many gram-positive and gram-negative bacteria.
- The mechanism of action is not exactly known. Nitrofurantoin is rapidly reduced by the bacteria to highly reactive derivatives which damage DNA and affect DNA and RNA synthesis.
- Since human cells require a long time to reduce nitrofurantoin, toxicity is not significant. Moreover, the development of resistance is slow.
- It is rapidly and completely absorbed from the gut. Attains high concentration in the urine.
Urinary Tract Infection Adverse effects:
- Nausea, vomiting, diarrhea, allergic reactions, and rarely chronic-active hepatitis.
- Hemolytic anemia can occur in G6PD-deficient individuals. Nitrofurantoin turns urine dark brown by its metabolites.
- Pneumonitis and interstitial pulmonary fibrosis may occur after long term which may be due to the generation of oxygen radicals in the lung.
- Long-term treatment can also result in neurological disorders due to the formation of toxic metabolites in the body. Dose: 50–100 mg 6 hourly.
Urinary Tract Infection Uses:
- An alternative in acute UTI, in sensitive microorganisms. Since the alkalinity of the urine can reduce its antimicrobial activity, acidification of urine with ascorbic acid/organic acids is useful.
- Long-term suppression of chronic UTI and for prophylaxis of UTI (single dose 100 mg at bedtime).
Methenamine Mandelate:
- Methenamine mandelate, a salt of mandelic acid and methenamine, releases formaldehyde in acidic urine below pH 5.5. Formaldehyde is bactericidal and resistance does not develop to it.
- The acidic pH of the urine should be maintained. Acidic pH itself is bacteriostatic—an added advantage of maintaining low pH.
- Urea-splitting microorganisms like Proteus may counter the effects of methenamine by raising the urinary pH.
- Hence, it is important to keep a watch on the urinary pH of such organisms. E. coli and gram-negative bacteria are suppressed.
- Dose: 1 g 3–4 TDimes a day.
- High doses can cause nausea and epigastric distress due to the release of formaldehyde in the stomach—given as enteric-coated tablets to prevent this.
- Long-term use can cause hematuria, chemical cystitis, and painful micturition. Methenamine mandelate should be avoided in renal failure as mandelic acid adds to acidosis.
Urinary Tract Infection Drug interactions:
- Methenamine binds sulfonamides and neutralizes their action.
- Also sulfonamides are precipitated in the acidic urine. Hence, the combination should be avoided.
Urinary Tract Infection Uses:
- Used orally in chronic UTIs that are resistant to other drugs.
- Other drugs used in UTI: Sulfonamides, cotrimoxazole, nalidixic acid, fluoroquinolones, ampicillin, cloxacillin, carbenicillin, aminoglycosides, tetracyclines, and cephalosporins.
Urinary Analgesic:
Phenazopyridine:
- An azo dye has analgesic actions on the urinary tract (not an antibacterial) and relieves burning symptoms of dysuria and urgency in cystitis and UTI.
- It can cause nausea and gastric irritation. It colors the urine orange-red.
- Dose: 200–400 mg TDS.
Mind map of Fluoroquinolones, for example, Ciprofloxacin
Beta-Lactam Antibiotics
The β-lactam antibiotics have a β-lactam ring in their structure. Penicillins, cephalosporins, monobactams, and carbapenems are β-lactams.’
Beta-Lactam Antibiotics Penicillins:
“Sir Alexander Fleming’ discovered penicillin in 1928 from Penicillium notatum. Penicillin is now obtained from the fungus Penicillium chrysogenum for therapeutic use.
Beta-Lactam Antibiotics Mechanism of Action:
- The rigid cell wall of the bacterium protects it from lysis due to osmotic pressure. The cell wall is made up of peptidoglycans which are glycan chains cross-linked by peptide chains and the cross-linking provides strength to the cell wall.
- The glycan chain is made up of alternating sugars N-acetylglucosamine and N-acetylmuramic acid.
- The synthesis of the peptidoglycan requires enzymes called transpeptidases. The last step in the synthesis of the peptidoglycan chain is the process of cross-linking with the help of the enzymes transpeptidases or penicillin-binding proteins (PBPs).
- β-lactam antibiotics covalently bind to PBPs and inhibit the synthesis of peptidoglycans, resulting in the formation of cell wall-deficient bacteria.
These undergo lysis thus penicillins are bactericidal:
- Gram-positive bacteria have a thick cell wall → hence more susceptible to penicillins.
- Gram-negative bacteria have a thin cell wall → most are not susceptible.
- Pencillins are highly safe because—the peptidoglycan layer is unique to bacteria and is absent in higher animals.
Beta-lactams Resistance: By one of the following mechanisms:
- Produce penicillinase/beta-lactamase which opens the β-lactam ring and inactivates penicillins. Carbapenems are inactivated by carbapenemases.
- Alter PBPs on the bacterial cell and reduce affinity for penicillins.
- Poor penetration of the drug into the bacteria as in gram-negative bacteria.
- Efflux of penicillin from the gram-negative bacteria by an efflux pump.
Beta-lactams Classification
- Natural:
- Regular: Penicillin G
- Repository penicillins: Procaine penicillin, benzathine penicillin
- Semisynthetic:
- Acid resistant: Penicillin V
- Penicillinase resistant: Methicillin, oxacillin cloxacillin, nafcillin
- Aminopenicillins: Ampicillin, bacampicillin bacampicillin, pivampicillin, amoxicillin
- Antipseudomonal penicillins: Carboxypenicillins—carbenicillin, carbenicillin-indanyl, ticarcillin
- Ureidopenicillins: Azlocillin, Mezlocillin, Piperacillin
Natural Penicillins
Penicillin G (Benzylpenicillin):
Antibacterial spectrum: Narrow antibacterial spectrum—gram-positive cocci and bacilli and a few gram-negative cocci
Natural Penicillins Pharmacokinetics:
- Benzylpenicillin is destroyed by gastric juice (acid label), low bioavailability → given parenterally.
- Food interferes with its absorption—given 2 hours before or after food.
- Penicillins are widely distributed into most tissues and body fluids but remain mostly extracellularly (polar compounds).
- Though penicillins do not readily cross the BBB, in the presence of inflammation, therapeutic concentrations are attained in the CSF because inflammation weakens the BBB and allows penicillins to reach the brain. Benzylpenicillin attains peak levels in 15–30 minutes and has
t½ of 30–60 minutes. - Penicillin G is rapidly excreted by the kidneys—about 90% by renal tubular secretion.
- Probenecid competes for renal tubular secretion and thereby prolongs the duration of action of penicillins. In renal failure and in neonates, penicillins t½ may be increased to 10 hours.
Repository penicillins: Oral penicillin is useful only in minor infections and is short-acting.
Hence, repository forms like procaine penicillin and benzathine penicillin are produced so that they are slowly absorbed with prolonged blood levels and are longer acting. Given deep IM they release penicillin slowly from the site.
- Procaine penicillin is given 12–24 hourly
- Benzathine penicillin single injection effective for 3–4 weeks.
Preparations and dose: Benzylpenicillin is given IV—irritant and hence painful—
- Procaine penicillin IM and benzathine penicillin deep IM.
- Sodium penicillin G: 0.5–5 MU, IV 4–6 hourly.
- Procaine penicillin G: 0.5–1 MU, IM 12–24 hourly. Procaine penicillin G 0.5,1 MU dry powder vial. Fortified procaine penicillin → procaine penicillin 3 lakh units + Sodium penicillin G 1 lakh units/vial.
- Benzathine penicillin G: 1.2–2 MU deep IM every 3–4 weeks.
- Penicillin G potassium: 200–800 mg QID.
Natural Penicillins Adverse effects:
Penicillins are highly safe drugs with a high therapeutic index (>100); most adverse effects are not serious in therapeutic doses except hypersensitivity reactions.
1. Hypersensitivity: PnG is the most common cause of drug allergy. Degradation products of penicillin like penicilloic acid are antigenic. The procaine component of procaine penicillin is also allergenic.
- Allergic reactions range from skin rashes, urticaria, pruritus, fever, bronchospasm, serum sickness, and rarely exfoliative dermatitis and anaphylaxis.
- Topical penicillins are highly sensitizing and their use is banned. There is cross-sensitivity among different penicillins.
- Anaphylaxis is more common following parenteral than oral preparations. History of allergy to penicillins should be taken before prescribing; Incidence is higher among atopic individuals.
- A scratch test or intradermal sensitivity test with 2–10 units should be done. Even if this is negative, it does not completely rule out allergy. Penicillin should be given cautiously in all patients and a syringe loaded with adrenaline to treat anaphylaxis should be kept ready.
- Avoid penicillins in patients allergic to it. However, if the use of penicillin is inevitable in a person allergic to it, desensitization/hyposensitization can be done by starting with a low dose and gradually increasing the dose—given intradermally at hourly intervals.
2. Other Adverse Effects:
- Local: Due to irritation it can cause pain at the site of IM injection and thrombophlebitis one IV injection.
- CNS: Large doses of PnG (>20 mega units) injected IV → confusion, muscle twitchings, convulsions, and coma particularly in the presence of renal dysfunction.
- Suprainfections: Suprainfections are rare because penicillins are narrow-spectrum antibiotics.
- Jarisch-Herxheimer reaction: There is sudden destruction of spirochetes and release of their lytic products. This triggers a reaction with fever, myalgia, shivering, exacerbation of syphilitic lesions, and vascular collapse.
Natural Penicillins Uses:
Penicillin G is the antibiotic of choice for several infections unless the patient is allergic to it.
- Pneumococcal infections: For infections like pneumonia, meningitis, and osteomyelitis due to penicillin-sensitive pneumococci, PnG is the drug of choice.
- Streptococcal infections: Pharyngitis, sinusitis, pneumonia, meningitis, and endocarditis are all treated with penicillin. Infective endocarditis due to Strep. viridian is treated with high-dose PnG in combination with an aminoglycoside.
- Meningococcal infections: PnG is the drug of choice for all meningococcal infections.
- Staphylococcal infections: Since most staphylococci produce penicillinase, a penicillin-resistant penicillin-like cloxacillin should be used.
- Syphilis: Procaine penicillin for 10 days or with benzathine penicillin.
- Diphtheria: Antitoxin → only effective treatment. PnG eliminates carrier state.
- Anaerobic infections: Pulmonary, periodontal and brain abscesses due to anaerobes response to PnG.
- Actinomycosis: PnG is the drug of choice for all forms of actinomycosis. 12–20 MU for 6 weeks.
- Tetanus and gas gangrene: Antitoxin is the treatment for tetanus—but PnG has adjuvant value. Gas gangrene—PnG is the drug of choice.
- Other infections: PnG is the agent of choice for infections like anthrax, trench mouth, rat bite fever, and listeria infections.
- Prophylactic uses:
- Rheumatic fever: Benzathine penicillin 1.2 MU every month prevents colonization by streptococci and thereby decreases the recurrences of rheumatic fever. It is to be continued for 5 years but most physicians use it for several more years.
- Gonorrhea and syphilis: Sexual contact can be protected when treated with penicillin within 12 hours of exposure.
- Valvular heart diseases: Patients with valvular heart diseases undergoing dental extractions, endoscopies and other minor surgical procedures that may cause bacteremia should be given penicillin prophylaxis.
Natural Penicillins Disadvantages:
- Narrow spectrum of activity
- Not effective orally—acid labile
- Susceptible to penicillinase
- Risk of hypersensitivity
Semisynthetic penicillins were obtained in an effort to overcome these disadvantages.
Semisynthetic Penicillins
Acid-Resistant Penicillins:
- Penicillin V (phenoxymethylpenicillin) is acid stable and can be given orally. It is used only in mild infections as it has a low bioavailability, short action (6 hourly dosings), and a narrow spectrum of activity. It may be given in streptococcal pharyngitis, sinusitis and trench mouth.
- Dose: 250–500 mg 6 hourly. Penicillin V potassium—125, 250 mg tab.
Penicillinase-Resistant Penicillins:
- Resistant to hydrolysis by penicillinase produced by bacteria.
- Less effective than PnG against non-penicillinase-producing microorganisms.
- Methicillin: Methicillin is destroyed by gastric juice—hence given parenterally. Methicillin-resistant Staph. aureus (MRSA) is also resistant to other penicillins.
- Oxacillin, cloxacillin, and dicloxacillin: These are relatively acid stable but food interferes with their absorption—to be given 1 hour before or after food.
- Nafcillin: Nafcillin is highly resistant to penicillinase and also has useful activity against non-penicillinase-producing organisms. It requires parenteral administration.
Penicillinase-Resistant Uses:
- Penicillinase-resistant penicillins are the drugs of choice for infections with susceptible penicillinase-producing staphylococci.
- For more severe staphylococcal infection, nafcillin/oxacillin may be given by intermittent IV infusion. Methicillin-resistant strains are treated with vancomycin.
- Cloxacillin and Dicloxacillin Dose: 250–500 mg 4 times a day.
Aminopenicillins:
- Extended-spectrum penicillins—including many gram-negative bacilli.
- Orally effective but are sensitive to beta-lactamases.
Ampicillin:
Antibacterial spectrum:
- Both gram-positive and gram-negative organisms including streptococci, meningococci, pneumococci, and H. influenzae are sensitive.
- Aminopenicillins were very effective against E. coli, Proteus, most enterobacter, Salmonella, Shigella, and Klebsiella but most strains are now resistant.
- The spectrum of activity can be widened by the addition of a beta-lactamase inhibitor.
- Ampicillin is acid stable and well-absorbed orally; food interferes with its absorption. On IM inj. peak levels are attained in about 60 minutes.
- It is excreted mainly through kidneys and t½ gets prolonged in renal failure.
- Dose: 0.5–2 g 6 hourly—oral or IM/IV inj.
Ampicillin Adverse Effects:
- Diarrhea: Diarrhea due to irritation of the gut by the unabsorbed drug is the most common adverse effect.
- Skin rashes: Skin rashes are also fairly frequent, particularly in patients with infectious mononucleosis,
AIDS and in those receiving allopurinol:
Ampicillin Uses:
- Respiratory tract infection: Bronchitis, sinusitis, and otitis media respond to ampicillin.
- Urinary tract infection: Though ampicillin was the drug of choice earlier, many organisms have now become resistant.
- Meningitis: Ampicillin is given with a cephalosporin/chloramphenicol—but many meningeal pathogens are now resistant to ampicillin.
- Typhoid: Ampicillin is an alternative to ciprofloxacin and chloramphenicol.
- Septicemia due to gram-negative organisms: Intravenous ampicillin may be used with an aminoglycoside or a third-generation cephalosporin.
- Bacillary dysentery: Caused by Shigella used to be successfully treated with ampicillin but several strains are now resistant and is, therefore, not the preferred drug.
- Bacterial endocarditis: IV ampicillin + gentamicin—alternative to benzylpenicillin.
1. Bacampicillin:
- Bacampicillin an ester of ampicillin is a prodrug that is better absorbed (hence diarrhea is less common) and longer-acting than ampicillin.
- Dose: 400 mg BD.
2. Pivampicillin: Pivampicillin and talampicillin are esters of ampicillin, which are prodrugs.
3. Amoxicillin: Amoxicillin is similar to ampicillin but differs from ampicillin in the following:
- Amoxicillin is better absorbed orally.
- Food does not interfere with its absorption.
- Attains high blood levels after oral administration; also less protein bound.
- Diarrhea is rare (because it is well absorbed).
- Given thrice daily—as it is longer acting than ampicillin.
Amoxicillin Uses:
- Amoxicillin is used in similar infections as ampicillin like respiratory infections, Salmonella gastroenteritis, and urinary tract infections.
- It is a component of the various regimens to eradicate H. pylori. Amoxicillin is preferred over ampicillin except for shigellosis.
- Dose: 250– 500 mg TDS.
Antipseudomonal Penicillins
1. Carboxypenicillins:
- Carbenicillin: In addition to activity against gram-positive and gram-negative organisms, carbenicillin is also effective against Pseudomonas aeruginosa and Proteus infections and may be combined with an aminoglycoside. Carbenicillin is given parenterally.
- Dose: 2–5 g 6 hourly IM/IV.
- Carbenicillin indanyl: Carbenicillin indanyl is effective orally as it is acid-stable.
- Ticarcillin: Ticarcillin, an analog of carbenicillin, has better activity than carbenicillin against P. aeruginosa. It may be combined with an aminoglycoside for synergistic activity against
- Pseudomonas. It reaches the CSF, pleural fluid, and sputum—given both IM and IV. All three carboxypenicillins are susceptible to penicillinase.
- Temocillin: Temocillin is a penicillinase-resistant carboxypenicillin effective against H. influenzae and Enterobacteriaceae.
Antipseudomonal Adverse effects:
- Carbenicillin is used as a sodium salt.
- Higher doses this excess sodium may cause edema and CCF; may cause bleeding due to abnormal platelet aggregation.
Antipseudomonal Uses:
- Ureidopenicillins are preferred to carboxypenicillins in all indications. Carbenicillin indanyl and ticarcillin are not available in India.
- Carbenicillin may be used in serious infections by Pseudomonas and Proteus like in burns.
2. Ureidopenicillins:
- Piperacillin, azlocillin and mezlocillin are ureidopenicillins.
- They have a wide antibacterial spectrum → effective against many gram-negative organisms including Pseudomonas, Klebsiella, Proteus, and H. influenzae.
- Have greater activity against Pseudomonas than ticarcillin.
- Their sodium content is low.
- Hence, ureidopenicillins have almost replaced carboxypenicillins.
- Piperacillin is given IV though it can also be given IM. When combined with a beta lactamase inhibitor, piperacillin has the broadest antibacterial spectrum among penicillins.
- It crosses the BBB and is, therefore, useful in meningitis. Dose: 100–150 mg/kg IV in 3 divided doses.
Ureidopenicillins Uses:
- For severe infections particularly due to Pseudomonas and Klebsiella—ureidopenicillin can be used with a beta-lactamase inhibitor tazobactam.
- In serious gram-negative infections in immunosuppressed patients, an aminoglycoside may be added.
Amidinopenicillins:
Mecillinam:
- Mecillinam has high efficacy against some gram-negative organisms (but not gram-positive bacteria) including Salmonella, Shigella, E. coli, Proteus,
- Klebsiella and Aerobacter (but not Pseudomonas).
- It acts by inhibiting cell wall synthesis by a mechanism that is different from that of penicillins. It is given IM as oral absorption is poor. Pivmecillinam is a prodrug of mecillinam that is effective orally.
- The two drugs are tried in urinary tract infection, typhoid, and dysentery. Amidinopenicillins are not available in India.
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