Antiinfectives should never be given casually for mild infections. Ideally, a culture & sensitivity should be done before administering the antiinfective of choice. Antibiotics are ineffective against viruses. The product labeling should be consulted for specific information about organism sensitivity and resistance and for detailed microbiological indications. Advise patients to continue taking medication until course of treatment is finished (usually 7–10 days) unless severe allergic reactions occur. When selecting antibiotics for the prevention of bacterial endocarditis, the physician or dentist should read the full joint statement of the American Heart Association and the American Dental Association. Treatment of strep infections usually requires at least 10 days of therapy.
Interactions: Antibiotics may reduce efficacy of oral contraceptives. Bactericidal drugs are primarily active against actively dividing cells. Therefore, bacteriostatic antibiotics (eg, tetracyclines) may interfere with the action of bactericidal antibiotics (eg, penicillins).
Adverse Reactions: Pseudomembranous colitis may occur following the administration of antibacterial agents. This may range in severity from mild to life-threatening. This diagnosis should be considered in patients who present with diarrhea subsequent to antibiotic therapy. Mild cases usually respond to discontinuing the drug; more severe cases may need supportive care and/or therapy with an agent effective against Clostridium difficile. Anti-motility drugs should be avoided since they may precipitate toxic megacolon. Also, overgrowth of nonsusceptible organisms, including fungal overgrowth (superinfection) may occur with the prolonged use of antibiotics.
AMINOGLYCOSIDES: The aminoglycosides (eg, gentamycin, tobramycin, streptomycin, amikacin) bind to the 30S ribosomal subunit of bacteria resulting in decreased protein synthesis and misreading of mRNA. These agents exert concentration-dependent bactericidal effects and demonstrate a post-antibiotic effect to persistently suppress bacterial growth after concentrations fall below the MIC. Aminoglycosides are active against gram-negative aerobic and facultative bacilli, including Pseudomonas aeruginosa. Aminoglycosides have limited activity against gram-positive organisms when used alone; however, when combined with a cell wall-active agent (eg, penicillins, vancomycin), in vitro synergistic bactericidal activity against enterococci and staphylococci is observed. Aminoglycosides are not active against anaerobes or atypicals.
β-LACTAMS: β-lactam antibiotics inhibit bacterial cell wall synthesis by binding to and inactivating penicillin-binding proteins to exert time-dependent bactericidal activity. The β-lactam antibiotics can be divided into penicillins, cephalosporins, carbapenems, and monobactams, which are further divided into different groups according to spectra of activity.
Penicillins are primarily active against gram-positive cocci and some gram-negative bacilli. These agents can be subdivided into 5 distinct groups: natural penicillins, penicillinase-resistant penicillins, aminopenicillins, carboxypenicillins, and ureidopenicillins. β-lactamase inhibitors (eg, clavulanic acid, sulbactam sodium) may be formulated in combination with penicillins to restore the spectrum of activity of the corresponding β-lactam to include pathogens that were resistant due to their production of β-lactamases.
Natural penicillins (eg, penicillin G, penicillin V) are active against non-β-lactamase-producing gram-positive bacteria, anaerobes, and select gram-negative cocci. Penicillinase-resistant penicillins (eg, nafcillin, oxacillin) are semi-synthetic penicillins stable against staphylococcal penicillinase.
Aminopenicillins (eg, ampicillin, amoxicillin) have a spectrum of activity similar to penicillin G with added activity against gram-negative cocci and Enterobacteriaceae that do not produce β-lactamase.
Carboxypenicillins (eg, ticarcillin) have an expanded spectrum of activity against non-β lactamase-producing gram-negative aerobic bacilli.
Ureidopenicillins (eg, piperacillin) have a broader spectrum of activity compared to carboxypenicillins. Relative to carboxypenicillins, piperacillin offers activity against Enterococcus faecalis and Klebsiella and has greater efficacy against Pseudomonas. In addition, piperacillin has excellent activity against non-β-lactamase-producing anaerobic cocci and bacilli.
Cephalosporins
Cephalosporins are divided into 4 different generations based on microbiologic activity. In general, gram-positive activity diminishes while gram-negative activity increases moving from the first- to third-generations. Fourth-generation cephalosporins demonstrate similar activity to first-generation agents against gram-positive cocci and are also active against most gram-negative bacilli (including Pseudomonas). All cephalosporins are considered inactive against methicillin-resistant staphylococci, enterococci, Listeria, Legionella, Chlamydia, Mycoplasma, and Acinetobacter species.
First-generation cephalosporins (eg, cefazolin, cephalexin, cefadroxil, cephradine) are most often used as alternatives to penicillins for infections caused by methicillin-sensitive staphylococci and streptococci.
Second-generation cephalosporins can be further subdivided into true cephalosporins and the cephamycins. True cephalosporins (eg, cefuroxime, cefprozil, cefaclor) have similar activity against staphylococci and noneterococcal streptococci compared to first-generation agents but have increased activity against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria. The cephamycins (eg, cefotetan and cefoxitin) have reduced activity against gram-positive pathogens but enhanced activity against certain Enterobacteriaceae and are active against anaerobes, especially Bacteriodes fragilis.
Third-generation cephalosporins (eg, ceftriaxone, cefotaxime, cefixime, cefdinir) have enhanced activity against gram-negative bacilli that are resistant to other β-lactams.
Fourth-generation cephalosporins (eg, cefepime) have the widest activity spectrum. Cefepime has enhanced activity against Enterobacter, Citrobacter, and Serratia and is active against Pseudomonas while maintaining potency against gram-positive cocci.
Carbapenems
The carbapenems (eg, imipenem, meropenem, ertapenem, doripenem) are primarily active against gram-positive cocci, gram-negative bacilli, and anaerobes. These agents are not active against atypicals.
Monobactams
Aztreonam is active only against gram-negative aerobic bacilli. Because of structural differences, aztreonam can be safely given to patients with immediate hypersensitivity reactions to other β-lactams.
FLUOROQUINOLONES: Fluoroquinolones (eg, ciprofloxacin, levofloxacin, moxifloxacin) exert concentration-dependent bactericidal activity. These agents inhibit bacterial DNA synthesis and promote cleavage of DNA leading to bacterial cell death. These agents inhibit the activity of DNA gyrase and topoisomerase IV to prevent uncoiling of DNA strands and decatenation of daughter DNA strands during the replication process, respectively. In general, fluoroquinolones primarily inhibit DNA gyrase in gram-negative bacteria, whereas topoisomerase IV is the main target in gram-positive bacteria. Fluoroquinolones are most active against aerobic gram-negative bacilli and gram-negative cocci and have some activity against atypicals but provide poor anaerobic coverage.
FOLATE SYNTHESIS INHIBITORS: Sulfonamides (eg, sulfamethoxazole, sulfisoxazole), trimethoprim, and pyrimethamine are bacteriostatic agents that inhibit microbial synthesis of folate, a necessary component of bacterial nucleotide synthesis. Only bacteria which must self-synthesize folic acid are susceptible to these agents. Sulfonamides and trimethoprim/pyrimethamine exert their inhibitory effects at different stages of the folate synthesis pathway. Sulfonamides competitively inhibit dihydropteroate synthase which acts to incorporate para-aminobenzoic acid (PABA) into dihydropteroic acid, the precursor to folic acid. Trimethoprim and pyrimethamine inhibit dihydrofolate reductase, which is responsible for the conversion of dihydrofolic acid to the active tetrahydrafolic acid. Thus, the combination of sulfonamides with trimethoprim or pyrimethamine acts synergistically to reduce intracellular folate and subsequently inhibit nucleotide synthesis and bacterial cell growth.
Sulfonamides and trimethoprim are active against gram-positive and gram-negative bacteria, Actinomyces, Nocardia spp., Chlamydia, Plasmodium, and Toxoplasma. Trimethoprim is 20100 times greater in potency than a sulfonamide, making the synergistic combination of sulfisoxazole/trimethoprim more effective therapy than a sulfonamide alone. Pyrimethamine is highly selective against Plasmodium and Toxoplasma gondii; its activity against Toxoplasma is enhanced when combined with a sulfonamide.
GLYCOPEPTIDES: Vancomycin exerts time-dependent bactericidal activity by inhibiting cell wall synthesis. Vancomycin forms stable complexes with cell wall precursor units to prevent polymerization (transglycosylaton) of precursor units for the formation of a functional cell wall. Vancomycin is active only against gram-positive organisms. Vancomycin is not absorbed when given orally and is not appropriate for treatment of systemic infections. However, it achieves high concentration within the gastrointestinal tract and therefore is used for the treatment of pseudomembranous colitis caused by C. difficile or pseudomembranous enterocolitis caused by Staphylococcus aureus.
GLYCYLCYCLINES: Glycylcyclines (eg, tigecycline) are derivatives of minocycline that bind to the 30S subunit of bacterial ribosome to inhibit bacterial protein synthesis to exert bacteriostatic activity against gram-positive and gram-negative organisms, atypicals, and anaerobes.
KETOLIDES: Ketolides (eg, telithromycin) are derivatives of erythromycin that bind to the 50S subunit of bacterial ribosome and inhibit RNA-dependent protein synthesis of susceptible bacteria, similarly to macrolides. Telithromycin differs from macrolides in that it is more acid stable and demonstrates a higher binding affinity for the ribosome, which may contribute to its improved activity against macrolide-resistant pathogens. Telithromycin is bacteriostatic and has improved activity against gram-positive aerobic bacteria compared to macrolides. It is also active against gram-positive and gram-negative bacteria, atypicals, and some anaerobes.
LICOPEPTIDES: Daptomycin is a lipopeptide antibiotic that exerts concentration-dependent bactericidal activity. Daptomycin binds to the cell membrane of gram-positive bacteria in a calcium-dependent manner, resulting in loss of cell membrane depolarization. This action results in inhibition of protein, DNA, and RNA synthesis, leading to cell death. Daptomycin has a spectrum of activity that resembles that of vancomycin while maintaining activity against pathogens with reduced susceptibility to vancomycin (eg, vancomycin intermediate S. aureus and vancomycin-resistant enterococci).
LINCOSAMIDES: Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis through interactions with the 50S bacterial ribosomal subunit. Clindamycin primarily exhibits bacteriostatic activity against anaerobes and gram-positive organisms; it has been shown to be bactericidal against Streptococcus pneumoniae, Streptococcus pyogenes, and S. aureus.
MACROLIDES: Macrolides (eg, erythromycin, clarithromycin, azithromycin) bind to the 50S subunit of the prokaryotic bacterial ribosome and inhibit RNA-dependent protein synthesis of susceptible bacteria to exert bacteriostatic effects. Macrolides are active against gram-positive cocci and bacilli and atypicals and have some activity against gram-negative bacteria.
NITROIMIDAZOLES: Nitroimidazoles (eg, metronidazole) are prodrugs that exert their antibacterial actions by interfering with DNA synthesis to induce apoptosis; they are amebacidal, bactericidal, and trichomonacidal. By passive diffusion, these agents cross bacterial cell membranes and undergo nitro reduction to form free radicals. These reactive intermediates exert their cytotoxic effects via damage to nucleic acids and proteins. Metronidazole is active against anaerobic cocci, anaerobic gram-negative bacilli, anaerobic spore-forming gram-positive bacilli and microaerophilic pathogens. Due to its excellent penetration, metronidazole is used for the treatment of brain abscess or other central nervous system infections, as well as anaerobic infections involving the bones and joints, soft tissues, oral cavity, head and neck.
OXAZOLIDINONE: Linezolid is an oxazolidinone that binds to the 50S ribosomal subunit of the 30S unit to prevent the formation of the 70S initiation complex. Linezolid is generally bacteriostatic, however it is bactericidal against some strains of S. pneumoniae and S. pyogenes. It is active against gram-positive pathogens including gram-positive anaerobic cocci, as well as mycobacteria. Linezolid lacks activity against most gram-negative aerobes and anaerobes. In addition to its antibiotic effects, linezolid is also a weak monoamine oxidase inhibitor, thus concomitant use with adrenergics, serotonergics, or consumption of tyramine-rich foods may lead to palpitations, headache, hypertensive crisis, fever, and mental status changes.
RIFAMYCINS: Rifamycins (eg, rifampin and rifaximin) are broad-spectrum antibacterials. These agents bind to DNA-dependent RNA polymerase, resulting in a drug-enzyme complex. Formation of this complex inhibits activity of the RNA polymerase, preventing the initiation of chain formation in the synthesis of RNA, but not chain elongation. Rifamycins are most active against gram-positive organisms, but are also active against gram-negative pathogens. Additionally, rifampin is moderately active against slow-growing mycobacteria and has some activity against Legionella.
STREPTOGRAMINS: Quinupristin and dalfopristin are streptogramins that bind to the 50S ribosomal subunit of the 70S unit in the elongation phase of protein synthesis. Quinupristin acts at the same site as macrolides and causes protein synthesis termination at a later phase, whereas dalfopristin directly blocks the addition of amino acids into the peptide chain to inhibit early polypeptide elongation. The streptogramins are active against most gram-positive aerobic pathogens. Available as combination therapy, the synergistic activity of quinupristin/dalfopristin accounts for its bactericidal activity; it is bacteriostatic against Enterococcus faecium.
TETRACYCLINES: Tetracyclines (eg, tetracycline, doxycyline, minocycline) are bacteriostatic antibiotics that bind to the 30S subunit of bacterial ribosome to inhibit bacterial protein synthesis. Tetracyclines primarily exhibit activity against atypicals and have some activity against gram-positive and gram-negative bacteria.
OTHER CLASSES: Fosfomycin exerts its antibacterial effect by inhibiting the enzyme enolpyruvyl transferase to irreversibly block an initial step in bacterial cell wall synthesis and, additionally, decreasing bacteria adherence to uroepithelial cells. Fosfomycin has a broad spectrum of activity against gram-positive and gram-negative pathogens.
Nitrofurantoin is used exclusively for prophylaxis against recurrent urinary tract infections (UTI); and treatment of uncomplicated cystitis or uncomplicated UTIs. Nitrofurantoin is rapidly eliminated and thus only achieves adequate concentrations in the urine. Reduction of nitrofurantoin by bacteria in the urine leads to formation of reactive intermediates that subsequently damage bacterial DNA; the antibacterial activity of nitrofurantoin is enhanced in the presence of acidic urine. Macrocrystalline preparations of nitrofurantoin (eg, Macrodantin, Macrobid) are absorbed and excreted more slowly than microcrystalline preparations (eg, Furadantin).
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by
Akshaya Srikanth,
Pharm.D Intern,
Hyderabad, India.
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