Antibacterial agents.

Antibacterial agents

Traditional targets of antibacterial compounds
Nature Chemical Biology 3, (2007)

Cell wall inhibitors Introduction
The cell wall of bacteria contains peptidoglycan, a substance that does not occur in eukaryotes The Gram-positive cell wall is composed of a thick, multilayered peptidoglycan sheath outside of the cytoplasmic membrane The Gram-negative cell wall is composed of an outer membrane linked by lipoproteins to thin, mainly single-layered peptidoglycan

1. Beta lactam antibacterial
Penicillins Cephalosporins & Cephamycins Carbapenems: imipenem Monobactams: aztreonam Beta-lactamase inhibitors: clavulanic acid

Mechanism of action All β-lactam antibiotics interfere with the synthesis of the bacterial cell wall peptidoglycan β-Lactam antibiotics, structural analogs of the natural D-Ala-D-Ala substrate, covalently bind to the active site of PBPs They interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage) This results in cell lysis, either through osmotic pressure or through the activation of autolysins β-Lactam antibiotics are thus bactericidal β-lactam antibiotics are analogues of d-alanyl-d-alanine—the terminal amino acid residues on the precursor NAM/NAG-peptide subunits of the nascent peptidoglycan layer. The structural similarity between β-lactam antibiotics and d-alanyl-d-alanine facilitates their binding to the active site of PBPs. The β-lactam nucleus of the molecule irreversibly binds to (acylates) the Ser403 residue of the PBP active site. This irreversible inhibition of the PBPs prevents the final crosslinking (transpeptidation) of the nascent peptidoglycan layer, disrupting cell wall synthesis. N-acetylmuramic acid

Penicillins The penicillins are a large group of bactericidal compounds They can be subdivided and classified by their chemical structure and spectrum of activity The antibacterial spectrum is determined by their ability to cross the bacterial peptidoglycan cell wall to reach the PBPs in the periplasmic space Bactericidal: The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage), resulting in exposure of the osmotically less stable membrane. Cell lysis can then occur, either through osmotic pressure or through the activation of autolysins. These drugs are bactericidal and work in a time-dependent fashion. Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. Consequently, they are inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi, and viruses. 1. Penicillin-binding proteins: Penicillins also inactivate numerous proteins on the bacterial cell membrane. These penicillin-binding proteins (PBPs) are bacterial enzymes involved in the synthesis of the cell wall and in the maintenance of the morphologic features of the bacterium. Exposure to these antibiotics can therefore not only prevent cell wall synthesis but also lead to morphologic changes or lysis of susceptible bacteria. The number of PBPs varies with the type of organism. Alterations in some of these PBPs provide the organism with resistance to the penicillins. [Note: Methicillinresistant Staphylococcus aureus (MRSA) arose because of such an alteration.] 2. Inhibition of transpeptidase: Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains (Figure 38.3). Penicillins inhibit this transpeptidase-catalyzed reaction, thus hindering the formation of cross-links essential for cell wall integrity. 3. Production of autolysins: Many bacteria, particularly the gram-positive cocci, produce degradative enzymes (autolysins) that participate in the normal remodeling of the bacterial cell wall. In the presence of a penicillin, the degradative action of the autolysins proceeds in the absence of cell wall synthesis. Thus, the antibacterial effect of a penicillin is the result of both inhibition of cell wall synthesis and destruction of the existing cell wall by autolysins.

Penicillins In general, gram-positive microorganisms, in the absence of resistance, are susceptible to penicillins Gram-negative microorganisms have an outer lipopolysaccharide membrane (envelope) surrounding the cell wall that presents a barrier to the water-soluble penicillins The antibacterial spectrum of the various penicillins is determined, in part, by their ability to cross the bacterial peptidoglycan cell wall to reach the PBPs in the periplasmic space. Factors that determine the susceptibility of PBPs to these antibiotics include the size, charge, and hydrophobicity of the particular β-lactam antibiotic. In general, gram-positive microorganisms have cell walls that are easily traversed by penicillins, and, therefore, in the absence of resistance, they are susceptible to these drugs. Gram-negative microorganisms have an outer lipopolysaccharide membrane surrounding the cell wall that presents a barrier to the water-soluble penicillins. However, gram-negative bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to permit transmembrane entry.

Penicillins Penicillins may be classified into four groups:
The antimicrobial activity of penicillin resides in the β-lactam ring Splitting of the β-lactam ring by either acid hydrolysis or β-lactamases results in the formation of penicilloic acid, a product without antibiotic activity Penicillins may be classified into four groups: Natural penicillins (G and V) Antistaphylococcal penicillins Extended-spectrum penicillins Antipseudomonal penicillins

I. Natural Penicillins Are obtained from fermentations of the mold Penicillium chrysogenum The have limited spectrum of antibacterial activity and susceptible to beta-lactmase Clinical uses include treatment of infection caused by a number of gram positive and gram-negative cocci, gram-positive bacilli, , and spirochetes Most strains Staphyloccus aureus and significant number of Neiseria gonorrhoea are resistant Penicillin G is the DOC for syphilis Natural penicillins: Natural penicillins (penicillin G and penicillin V) are obtained from fermentations of the fungus Penicillium chrysogenum. Semisynthetic penicillins, such as amoxicillin and ampicillin (also known as aminopenicillins), are created by chemically attaching different R groups to the 6-aminopenicillanic acid nucleus. Penicillin [pen-i-SILL-in] G (benzyl-penicillin) is the cornerstone of therapy for infections caused by a number of gram positive and gram-negative cocci, gram-positive bacilli, and spirochetes (Figure 38.4). Penicillins are susceptible to inactivation by β-lactamases (penicillinases) that are produced by the resistant bacteria. Despite widespread use and increase in resistance to many types of bacteria, penicillin remains the drug of choice for the treatment of gas gangrene (Clostridium perfringens) and syphilis (Treponema pallidum). Penicillin V has a similar spectrum to that of penicillin G, but it is not used for treatment of bacteremia because of its poor oral absorption. Penicillin V is more acid stable than penicillin G and is often employed orally in the treatment of infections. Spirochaetes are gram-negative bacteria. Spirochaetes English pronunciation: /ˈspʌɪrə(ʊ)kiːt/[1] (also spelled spirochetes) belong to a phylum of distinctive diderm (double-membrane)bacteria Most spirochaetes are free-living and ANAEROBIC, but there are numerous exceptions. Syphilis is a curable, bacterial infection, caused by the bacteriaTreponema pallidum. Treponema pallidum is a spirochaete bacterium with subspecies that cause treponemal diseases such as syphilis Neiseria gonorrhoea gram-negative coffee bean-shaped diplococci bacteria Penicillin was discovered in 1928 when Alexander Fleming's lab assistant accidentally left a window open overnight and mold spores covered his Staphylococcus bacterialspecimens in a Petri dish.[8][9] At first, Fleming was very irritated at the contamination, but, as he was about to throw the specimens away, he noticed something interesting. He looked under the microscope at the bacteria surrounding the blue-green mold and noticed that many were dead or dying. This later turned out to have been due to the mold's prevention of the bacteria from making new cell walls and reproducing. He identified the mold as Penicillium notatum, which releases the antibiotic penicillin G into the medium (his identification has been subsequently shown to be incorrect: the fungal species was actually the related Penicillium rubens).[10] After this, he did some testing on humans and animals and discovered that not only did it kill bacteria but it was suitable for use as a medication in humans and animals. However, the discovery did not attract much attention until the 1940s, when Howard Florey, Norman Heatley, and Ernst Chain developed methods for mass production and application in humans, incited by the urgent war-time need for antibacterial agents. The work of Andrew J. Moyer was important in these early developments.

I. Natural Penicillins Penicillin G: is an acid-labile compound & is most appropriate for IM or IV therapy Penicillin G is excreted by the kidneys, with 90% of renal elimination occurring via tubular secretion Probenecid blocks tubular secretion and has been used to increase the serum concentration and prolong its half-life of penicillin Depot IM formulations of penicillin G, including procaine penicillin and benzathine penicillin, have decreased solubility, delayed absorption, and a prolonged half-life Probenecid, also sold under the brandname Probalan, is a medication that increases uric acid excretion in the urine. It is primarily used in treating gout

I. Natural Penicillins Penicillin V:
An oral formulation that resists degradation by gastric acid . Antibacterial spectrum of activity is similar to that of penicillin G Penicillin V is used to treat streptococcal infections when oral therapy is appropriate and desirable Streptococcus is a genus of coccus gram-positive bacteria Use Treatment of infections caused by susceptible organisms involving the respiratory tract, otitis media, sinusitis, skin, and soft tissues; prophylaxis in rheumatic fever Use: Off-LabelBite wounds (animal); Community-acquired pneumonia (children); Cutaneous anthrax; Cutaneous erysipeloid; GAS chronic carrier; Pneumococcal prophylaxis in asplenia/sickle cell; Chronic antimicrobial suppression of prosthetic joint infection Cutaneous anthrax, community-acquired (off-label use) Pharyngitis (streptococcal) Prophylaxis of recurrent rheumatic fever infections:

II. Antisatphylococcal penicillins
Agents: Methicillin, nafcillin (IV), oxacillin, Are more resistant to bacterial β-lactamases than is penicillin G Their use is restricted to the treatment of infections known or suspected staphylococcal infections Methicillin resistant S aureus (MRSA) and S epidermidis (MRSE) are resistant They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and gram-negative cocci and rods. Nafcillin, oxacillin, cloxacillin and dicloxacillin Because of its toxicity (interstitial nephritis), methicillin is not used clinically in the United States except in laboratory tests to identify resistant strains of S. aureus. The penicillinase- resistant penicillins have minimal to no activity against gram-negative infections . They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and gram-negative cocci and rods. Enterococci are Gram-positive cocci

III. Extended-spectrum penicillins
Agents: Ampicillin and amoxicillin Antibacterial spectrum similar to that of penicillin G more effective against gram-negative bacilli, but remains susceptible to penicillinases Ampicillin: Treatment of meningitis caused by Listeria monocytogenes. Enterococcal endocarditis Pneumonia caused by β-lactamase-negative H. influenzae Shigellosis

III. Extended-spectrum penicillins
Amoxicillin Acute nonserious bacterial infections like otitis media and sinusitis. Multidrug regimens for the eradication of H. pylori in duodenal and gastric ulcers Prophylactically by dentists for patients with abnormal heart valves who are to undergo extensive oral surgery

IV. Antipseudomonal penicillins
Agents: ticarcillin, and piperacillin They are effective against many gram-negative rods, including Pseudomonas, enterobacter and in SOME CASES klebsiella species Susceptible to penicillinase Syngestic effect when used in combination with aminoglycosides Antipseudomonal penicillins: Piperacillin [pip-er-a-SILL-in] and ticarcillin [tye-kar-SILL-in] are called antipseudomonal penicillins because of their activity against Pseudomonas aeruginosa (Figure 38.5B). These agents are available in parenteral formulations only. Piperacillin is the most potent of these antibiotics. They are effective against many gram-negative bacilli, but not against Klebsiella because of its constitutive penicillinase. Formulation of ticarcillin or piperacillin with clavulanic acid or tazobactam, respectively, extends the antimicrobial spectrum of these antibiotics to include penicillinase-producing organisms (for example, most Enterobacteriaceae and Bacteroides species). Figure 38.6 summarizes the stability of the penicillins to acid or the action of penicillinase.

Resistance Elaboration of the enzyme ß-lactamase, which hydrolyzes the ß-lactam ring (loss of bactericidal activity) Alteration of penicillin-binding proteins (PBPs) either by mutation of existing PBP genes or, more importantly, by acquiring new PBP genes (e.g. staphlococcal resistance to methicillin) or by acquiring new "pieces" of PBP genes (e.g. pneumococcal, gonococcal and meningococcal resistance) Resistance seen in gram-negative bacteria, is due to alteration of genes that specify outer membrane proteins (porins) and reduce permeability to penicillins

Adverse Reactions to Penicillins
Hypersensitivity reactions: Are the most common All penicillins are cross-sensitizing and cross-reacting Include:Macropapular rash, urticarial rash, fever , bronchospasm , vasculitis , exfoliative dermatitis, stevens-Johnson syndrome, anaphylaxis (very rare-0.05% of recipients) GIT disturbances: with oral penicillin caused by direct GIT irritation or overgrowth of gram positive organism or yeast

β-lactamase inhibitors
Agents: Clavulanic acid, sulbactam, & tazobactam They Contain β-lactam ring but do not have significant antibacterial activity They bind to & inactivate β-lactamases, thereby protecting the antibiotics that are normally substrates for these enzymes

β-lactamase inhibitors
Penicillin plus β-lactamase Inhibitors: Amoxicillin-clavulanic acid Ticarcillin-clavulanic acid Ampicillin-sulbactam Piperacillin-tazobactam Absorption of most oral penicillins (amoxicillin being an exception) is impaired by food, and the drugs should be administered at least 1–2 hours before or after a meal Dicloxacillin, ampicillin, and amoxicillin are acid-stable and relatively well absorbed nafcillin and oxacillin must be administered intravenously (IV) or intramuscularly (IMAbsorption: Most of the penicillins are incompletely absorbed after oral administration, and they reach the intestine in sufficient amounts to affect the composition of the intestinal flora. Food decreases the absorption of all the penicillinase-resistant penicillins because as gastric emptying time increases, the drugs are destroyed by stomach acid. Therefore, they should be taken on an empty stomach. 3. Distribution: The β-lactam antibiotics distribute well throughout the body. All the penicillins cross the placental barrier, but none have been shown to have teratogenic effects. However, penetration into bone or cerebrospinal fluid (CSF) is insufficient for therapy unless these sites are inflamed (Figures 38.7 and 38.8). [Note: Inflamed meninges are more permeable to the penicillins, resulting in an increased ratio of the drug in the CSF compared to the serum.] Penicillin levels in the prostate are insufficient to be effective against infections. 4. Metabolism: Host metabolism of the β-lactam antibiotics is usually insignificant, but some metabolism of penicillin G may occur in patients with impaired renal function

Cephalosporins & Cephamycins
Cephalosporins are similar to penicillins, but more stable to many bacterial β-lactamases and therefore have a broader spectrum of activity Cephalosporins can be classified into five major groups or generations, depending mainly on the spectrum of antimicrobial activity & resistance to β-lactamases Spectrum of activity: Good gram-positive cocci coverage: Staphylococcus aureus, Staphylococcus epidermis, group A β-hemolytic streptococci, group B streptococci, and Streptococcus pneumoniae. NOT active against enterococci, methicillin-resistant Staph. aureus, penicillin-resistant Strep. pneumoniae. Modest gram-negative bacteria coverage: Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae, though susceptibilities may vary. Poor activity against Moraxella catarrhalis andHemophilus influenzae. Active against most penicillin-susceptible anaerobes found in the oral cavity, except Bacteroides fragilis group. Uses: Uncomplicated skin and soft-tissue infections, uncomplicated urinary tract infections, streptococcal pharyngitis, surgical prophylaxis. Good alternatives to antistaphylococcal penicillins. NOT indicated for otitis media. First generation cephalosporins do not penetrate well into the cerebral spinal fluid and are not good for CNS infections. Cefazolin is the most commonly used 1st generation cephalosporin. Second-Generation Cephalosporins

I. First generation Agents: Cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, & cephradine Penicillin G substitiutes Have good activity against gram-positive cocci (with the exception of enterococci, methicillin-resistant S. aureus, and S. epidermidis) and relatively modest activity against gram-negative microorganisms Most mouth anaerobes are sensitive, but the B. fragilis group is resistant Cefazolin penetrates well into most tissues. It is the drug of choice for surgical prophylaxis. Cefazolin DOES NOT penetrate the CENTRAL NERVOUS SYSTEM and cannot be used to treat meningitis

II. Second Generation Cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil, loracarbef, and ceforanide, cephamycins cefoxitin, cefmetazole, and cefotetan Have somewhat increased activity against gram-negative microorganisms: H influenzea Enterobacter areogenes Some Niesseria species As with 1st generation: none is active against enterococci or P aeuroginosa

Clinical Uses Used to treat otitis, sinusitis and lower RTI (H influenza & B catarrhallis) Cefoxitin, cefotetan or cefmetazole: used to treat mixed anaerobic infections such as peritonitis or diverticulitis Cefuroxime community acquired pneumonia Answer: because of their activity against anerobes (ncluding B fragilis) cefomandoles Diverticulitis: inflammation of a diverticulum, especially in the colon, causing pain and disturbance of bowel function. Cefuroxime is used to treat community-acquired pneumonia because it is active against β-lactamase-producing H influenzae and K pneumoniae and also most pneumococci. Amoxicillin : Acute nonserious bacterial infections like otitis media and sinusitis Cefuroxime is used to treat community-acquired pneumonia, particularly in cases where beta-lactamase-producing H influenzae or Klebsiella pneumoniae is a consideration, but this drug has few other uses. Cefuroxime is the only second-generation drug that crosses the blood-brain barrier, but it is less effective in treatment of meningitis than ceftriaxone or cefotaxime and should not be used. "True" second generation cephalosporins: cefaclor (Ceclor, Raniclor) cefamandole (Mandol) cefprozil (Cefzil) cefuroxime (Ceftin, Zinacef) loracarbef (Lorabid), is a carbacephem, but it is sometimes grouped with the second-generation cephalosporins Cephamycins: cefmetazole (Zefazone) cefotetan (Cefotan) cefoxitin (Mefoxin) Cephamycins have a 7-alpha-methoxy group that gives resistance to beta-lactamases and makes them different from other cephalosporins. Cephamycins are grouped with the second-generation cephalosporins because they have similar activity, with one important exception -- anaerobes. The second generation cephalosporins have a greater gram-negative spectrum while retaining some activity against gram-positive bacteria. They are also more resistant to beta-lactamase. Spectrum of activity: Gram-positive cocci: "True" 2nd generation cephalosporins are almost comparable to 1st generation agents against Streptococci. Slight loss of activity against Staphylococci (NOT active against methicillin-resistant strains). Cephamycins are less active against gram-positive cocci than 1st generation agents. Gram-negative aerobes: Hemophilus influenzae, Moraxella catarrhalis, Proteus mirabilis, E. Coli,Klebsiella, Neisseria gonorrheae. Anaerobes: Unlike 2nd generation cephalosporins, cephamycins (cefotetan, cefoxitin, and cefmetazole) have activity against gram-negative bacilli Bacteroides fragilis. No efficacy against Pseudomonas, enterococci. Uses: Upper and lower respiratory tract infections, acute sinusitis, otitis media, uncomplicated urinary tract infections. Cephamycins are useful for mixed aerobic/anaerobic infections of the skin and soft tissues, intra-abdominal, and gynecologic infections, and surgical prophylaxis. Second generation cephalosporins don't cross the blood-brain barrier and are NOT used for CNS infections. The only to cross the BBB, however less effective 3rd generation

III. Third Generation ceftriaxone, cefotaxime, ceftazidime, ceftizoxime, cefoperazone, cefixime, cefpodoxime proxetil, cefdinir, cefditoren pivoxil, ceftibuten, and moxalactam Expanded gram negative coverage (except cefoperazone) The ability to cross the BBB Active against citrobacter, Serratia marscens and providentia (but not the resistant strains) Active against B-lactamase producing strains of haemophilus and neisseria Ceftazidime & cefoperazone: the 2 third generation which are active against P aeureginosa First and second generation cephalosporins (except cefuroxime) penetrate the cerebrospinal fluid (CSF) barrier poorly and should not be used to treat infections of the central nervous system. The third generation cephalosporins achieve much more reliable CSF levels in patients with meningeal irritation. Peak CSF concentrations of several cephalosporins given at meningeal doses are shown in the table (table 2). Cefotaxime, ceftriaxone, and ceftazidime are approved for the treatment of bacterial meningitis. Providencia is a Gram negative, motile bacterium of the family Enterobacteriaceae Citrobacter is a genus of Gram-negative coliform bacteria Serratia marcescens is a species of rod-shaped Gram negative bacterium in the family Enterobacteriaceae. The third generation cephalosporins have a marked activity against gram-negative bacteria due to enhanced beta-lactamase stability and the ability to penetrate the gram-negative cell wall. They have more favorable pharmacologic properties than previous generations. Third-generation cephalosporins are notorious for inducing resistance among Gram-negative bacilli9. Spectrum of activity: NONE are active against methicillin-resistant Staphylococci, Enterococci, and Listeria. Gram-positive cocci: Limited activity against gram-positive cocci (particularly drugs available in an oral formulation). Cefotaxime, Ceftriaxone, and Ceftizoxime have the best gram-positive coverage of the third-generation agents: methicillin-susceptible Staphylococcus aureus (though less than 1st and some 2nd generation agents), very active against Groups A and B streptococci, and viridans streptococci. Cefotaxime and ceftriaxone are more active than ceftizoxime against Streptococcus pneumoniae. Cefixime and Ceftibuten lack Staphylococcus activity. Gram-negative bacteria: Very active against Hemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, Enterobacteriaceae (Escherichia coli, Klebsiella species, Proteus (including strains resistant to aminoglycosides)), Providencia, Citrobacter, Serratia. Anaerobes: Cefotaxime, ceftriaxone, and ceftizoxime have adequate activity against oral anaerobes. Moxalactam has good activity against Bacteroides fragilis. No Pseudomonal activity. Uses: Gram-negative bacillary meningitis3, serious infections of Enterobacteriaceae, upper respiratory tract infections5, otitis media, pyelonephritis, skin and soft tissue infections. Ceftriaxone is indicated for Lyme disease and gonorrhea. Cefotaxime, ceftazidime, ceftriaxone, ceftizoxime, and moxalactam have excellent penetration into the cerebrospinal fluid. Enterobacter species have a tendency to become resistant during cephalosporin therapy, and thus cephalosporins are not the drugs of choice for Enterobacter infections. AntiPseudomonal Cephalosporins Ceftazidime (Fortaz, Tazicef, Tazidime) and Cefoperazone (Cefobid) are the two third generation cephalosporins with antipseudomonal activity. Spectrum of activity: Pseudomonas aeruginosa - main indication. Gram-negative bacteria: Enterobacteriaceae covered by the 3rd generation agents. Poor activity against Gram-positive Cocci.

Third Generation-kinetics
They penetrate body fluids and tissues well Achieve levels in the CSF (With the exception of cefoperazone, cefixime, cefpodoxime proxetil) sufficient to inhibit most pathogens Excretion of cefoperazone and ceftriaxone is mainly through biliary tract The rest are excreted by the kidney Activity against staphylococci and streptococci is less with the third-generation compounds than with the first- and second-generation compounds Ceftriaxone (half-life 7-8 hours) can be injected once every 24 hours at a dosage of mg/kg/d. A single daily 1 g dose is sufficient for most serious infections, with 4 g once daily recommended for treatment of meningitis. Cefoperazone (half-life 2 hours) can be injected every 8-12 hours in a dosage of mg/kg/d. The remaining drugs in the group (half-life hours) can be injected every 6-8 hours in dosages between 2 and 12 g/d, depending on the severity of infection. Cefixime can be given orally (200 mg twice daily or 400 mg once daily) for respiratory or urinary tract infections. Cefpodoxime proxetil and ceftibuten are administered as a 200 mg dose twice daily. The excretion of cefoperazone and ceftriaxone is mainly through the biliary tract, and no dosage adjustment is required in renal insufficiency. The others are excreted by the kidney and therefore require dosage adjustment in renal insufficiency. Streptococci are facultatively anaerobic, Gram-positive organisms

Fourth Generation V. Fifth generation Cefepime
it may be useful in treatment of enterobacter infections. Otherwise, its clinical role is similar to that of third-generation cephalosporins. Cefepime has good activity against most penicillin-resistant strains of streptococci V. Fifth generation Agents: Ceftaroline fosamil, the prodrug of ceftaroline Effectively bind to and inhibit penicillin-binding protein 2a, which mediates methicillin-resistance in staphylococci It has good activity against P aeruginosa, Enterobacteriacea, S aureus and S pneumoniae more resistant to hydrolysis by chromosomal beta-lactamases (eg, those produced by enterobacter) and some extended-spectrum beta-lactamases that inactivate many of the third-generation cephalosporins. Cefepime has similar activity to cefotaxime and ceftriaxone against pneumococci (including penicillin-intermediate strains) and oxacillin-sensitive S. aureus. Like the earlier third generation agents, it is active against the Enterobacteriaceae, Neisseria, and H. influenzae but has greater activity against the gram-negative enterics that have a broad-spectrum, inducible, chromosomal AmpC beta-lactamase (Enterobacter, indole-positive Proteus, Citrobacter, and Serratia) [18]. The role of cefepime in therapy of infections due to stably-derepressed mutants of these organisms has not yet been fully defined, but some data suggest that it may be effective

Adverse Effects of cephalosporins
Allergy: identical to penicillins- cross allerginicity 5-10% Toxicity Severe pain (IM) Thrombophelebitis (IV) Renal toxicity, Hypoprothrombinemia Disulfiram like reaction Superinfection

Monobactams: Aztreonam
Spectrum of activity is limited to aerobic gram-negative rods, including P. aeruginosa Has no activity against gram-positive bacteria or anaerobes It is administered either IV or IM and is excreted in the urine it shows little cross-reactivity with other β-lactam antibiotics ADRs: phlebitis, skin rash, and abnormal liver function tests . Aztreonam is stable to the metallo-β-lactamases, but many IMP and VIM producers are resistant, owing to other mechanisms

Carbapenems: Imipenem
It is a carbapenem with low susceptibility to B-lactamses Wide spectrum activity against many gram-negative rods, including P aeruginosa, gram-positive organisms, and anaerobes It is resistant to most β-lactamases. Administered parenterally The drug of choice for enterobacter infections Rapidly metabolised by tubular dehydropeptidase Agents: Doripenem, ertapenem, imipenem, and meropenem Dehydropeptidase is an enzyme found in the kidney he mean plasma half-life of imipenem varied from 52 min in subjects with normal renal function to 173 min in subjects with end-stage renal failure Enterobacter is a genus of common Gram-negative, facultatively anaerobic, rod-shaped, non-spore-forming bacteria of the family Enterobacteriaceae. Several ...

IMIPENEM-CILASTATIN CILASTATIN is a peptidase inhibitor that blocks renal degradation of Imipenem Cilastatin increases the plasma half-life of imipenem and inhibits the formation of potentially nephrotoxic metabolite ADE: GI distress, skin rash, CNS toxicity (confusion, encephalopathy and seizures) Partial cross allergenicity with penicillins • Anaphylaxis/hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylaxis, have been reported (some without a history of previous allergic reactions to beta-lactams).

Vancomycin It is active only against gram-positive bacteria, particularly staphylococci No activity against gram-negative organisms Vancomycin is poorly absorbed from the intestinal tract and is administered orally only for the treatment of antibiotic-associated enterocolitis caused by C difficile Enterocolitis: inflammation of both the small intestine and the colon.

VANCOMYCIN Mechanism of action: Inhibits bacterial cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide Resistance: modification of the D-Ala-D-Ala binding site of the peptidoglycan in which D-Ala is replaced by D-lactate (enerococci & vancomycin resistant S aureus) Vancomycin kills staphylococci relatively slowly and only if cells are actively dividing; The combination of vancomycin and gentamicin is synergistic against Staphylococcus aureus and enterococci Enterococci are Gram-positive cocci that often occur in pairs Vancomycin inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide. This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking. The peptidoglycan is thus weakened and the cell becomes susceptible to lysis. The cell membrane is also damaged, which contributes to the antibacterial effect. These findings may explain the mechanism of the synergy between gentamicin and vancomycin in pneumococci. The underlying mechanism is not completely understood, but these data strongly suggest that the inhibition of cell wall synthesis by vancomycin alters the permeability of the cell wall, which probably acts as a natural barrier to aminoglycosides, and facilitates the penetration of gentamicin into the cell.

Clinical uses of vancomycin
Main indication is: sepsis or endocarditis caused by MRSA Methicillin-susceptible staphylococci in patients who are allergic to penicillins or cephalosporins Vancomycin in combination with gentamicin is an alternative regimen for treatment of enterococcal endocarditis in a patient with serious penicillin allergy Vancomycin (in combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for treatment of meningitis suspected or known to be caused by a highly penicillin-resistant strain of pneumococcus Oral vancomycin is used to treat antibiotic-associated enterocolitis caused by Clostridium difficile The main indication for parenteral vancomycin is sepsis or endocarditis caused by methicillin-resistant staphylococci. However, vancomycin is not as effective as an antistaphylococcal penicillin for treatment of serious infections such as endocarditis caused by methicillin-susceptible strains. Enterococcal endocarditis is an indication for ampicillin

Adverse reactions Phlebitis at site of injection
Ototoxicity and Nephrotoxicity are rare with current preparations. AVOID coadministration with aminoglycosides Red man or red neck syndrome: infusion related flushing due to histamine release (slow infusion over 2hrs, increase dilution volume, or pretreat with antihistamine) Chills and fever may occur. Ototoxicity is rare and nephrotoxicity uncommon with current preparations. However, administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities. Ototoxicity can be minimized by maintaining peak serum concentrations below 60 mcg/mL. This syndrome, usually appearing within 4–10 min after the commencement or soon after the completion of an infusion, is characterized by flushing and/or an erythematous rash that affects the face, neck, and upper torso. Peak 20-40 Trough 10-20

Protein Synthesis Inhibitors
Target the bacterial ribosome, which has components that differ structurally from those of mammalian cytoplasmic ribosomes The bacterial ribosome consists of a 50S subunit and a 30S subunit, whereas in the mammalian ribosome the subunits are 60S and 40S Chloramphenicol 2. Tetracyclines 3. Macrolides 4. Clindamycin 5. Aminoglycosides 6. Linezolide 7. Streptogramines

Aminoglycosides Agents: streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin Aminoglycosides have been used in paediatric patients for more than 60 years They have concentration-dependent killing & a significant postantibiotic effect They are not available for oral administration, so they are mainly used in parenteral form Predominantly used to treat gram-negative treat bacteria infections including Pseudomonas spp, They are useful in the treatment of UTIs, intra-abdominal infections, neonatal sepsis, complicated infections in cystic fibrosis, and as empiric therapy for febrile neutropenic patients Inside the cell, aminoglycosides bind to specific 30S-subunit ribosomal proteins. Protein synthesis is inhibited by aminoglycosides in at least three ways (Figure 45–3): (1) interference with the initiation complex of peptide formation; (2) misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide and results in a nonfunctional protein; and (3) breakup of polysomes into nonfunctional monosomes. These activities occur more or less simultaneously, and the overall effect is irreversible and leads to cell death. Continual inhibition of bacterial growth after exposure to an antimicrobial agent; the time for the organism to recover from the effects of antimicrobial exposure. PAE is shown in vitro by demonstrating bacterial growth kinetics after the drug is removed. Aminoglycosides are used for the treatment of serious infections due to aerobic gram-negative bacilli. However, their clinical utility is limited by serious toxicities. The term “aminoglycoside” stems from their structure—two amino sugars joined by a glycosidic linkage to a central hexose nucleus. Aminoglycosides are derived from either Streptomyces sp. (have –mycin suffixes) or Micromonospora sp. (end in -micin). Aminoglycosides diffuse through porin channels in the outer membrane of susceptible organisms. These organisms also have an oxygen-dependent system that transports the drug across the cytoplasmic membrane. Inside the cell, they bind the 30S ribosomal subunit, where they interfere with assembly of the functional ribosomal apparatus and/or cause the 30S subunit of the completed ribosome to misread the genetic code (Figure 39.2). Antibiotics that disrupt protein synthesis are generally bacteriostatic; however, aminoglycosides are unique in that they are bactericidal. The bactericidal effect of aminoglycosides is concentration dependent; that is, efficacy is dependent on the maximum concentration (Cmax) of drug above the minimum inhibitory concentration (MIC) of the organism. For aminoglycosides, the target Cmax is eight to ten times the MIC. They also exhibit a postantibiotic effect (PAE), which is continued bacterial suppression after drug levels fall below the MIC. The larger the dose, the longer the PAE. Because of these properties, extended interval dosing (as ingle large dose given once daily) is now more commonly utilized than divided daily doses. This reduces the risk of nephrotoxicity and increases convenience.

Aminoglycosides Aminoglycosides have concentration-dependent killing & a significant postantibiotic effect Optimal dosing strategies of aminoglycosides include high doses administered once daily (extended-interval dosing) The three most commonly used agents are: gentamicin, tobramycin, and amikacin Aminoglycosides frequently exhibit synergism with beta lactams

Adverse effects Ototoxicity Nephrotoxicity Neuromuscular paralysis:
Most often occurs after direct intraperitoneal or intrapleural application of large doses of aminoglycosides Caused by a decrease in both the release of acetylcholine from prejunctional nerve endings and the sensitivity of the postsynaptic site Reversible by calcium gluconate (promptly) or neostigmine Calcium gluconate may reverse the neuromuscular block IV Neostigmine indirect acting cholenomimmetic

Tetracylcins Agents: Tetracyclin, minocycline, doxycycline, demeclocycline, & oxytetracycline Bacteriostatic broad spectrum antibiotics: active against a wide range of aerobic and anaerobic gram-positive and gram-negative bacteria, as well as against some protozoa, eg, amebas Bind reversibly to 30S of bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex

Tetracylcins The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may be susceptible to doxycycline, minocycline, and tigecycline Absorption is impaired by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products and antacids, and by alkaline pH Tetracyclines cross the placenta to reach the fetus and are also excreted in milk Tetracyclin is pregnancy risk factor D: positive evidence of risk Food Interactions Serum concentrations may be decreased if taken with dairy products. Management: Take on an empty stomach 1 hour before or 2 hours after meals to increase total absorption. Administer around-the-clock to promote less variation in peak and trough serum levels.

Typical therapeutic applications of tetracyclines
Lymphogranuloma venereum (LGV) is a chronic (long-term) infection of the lymphatic system. Chlamydophila psittaci and contracted from parrots, gram-negative bacterium. In certain contexts, the word "psittacosis" is used when the disease is carried by any species of bird belonging to the Psittacidae family, whereas "ornithosis" is used when other birds carry the disease.[1] In humans, after an incubation period of 5–19 days, the symptoms of the disease range from inapparent illness to systemic illness with severe pneumonia. It presents chiefly as an atypical pneumonia. In the first week of psittacosis the symptoms mimic typhoid fever: prostrating high fevers, joint pains, diarrhea, conjunctivitis, nose bleeds and low level of white blood cells in the blood.[2] Rose spots can appear and these are called Horder's spots.[3] Spleen enlargement is common towards the end of the first week. Diagnosis can be suspected in case of respiratory infection associated with splenomegaly and/or epistaxis. Headache can be so severe that it suggests meningitis and some nuchal rigidity is not unusual. Towards the end of the first week stupor or even coma can result in severe cases. Rocky Mountain spotted fever (RMSF), also known as blue disease,[1] is the most lethal[2] and most frequently reported rickettsialillness in the United States. Long-term health problems following acute Rocky Mountain spotted fever infection include partial paralysis of the lower extremities, gangrene requiring amputation of fingers, toes, or arms or legs, hearing loss, loss of bowel or bladder control, movement disorders, and language disorders. These complications are most frequent in persons recovering from severe, life-threatening disease, often following lengthy hospitalizations LYME DISEASE S&S is a bacterial infection spread to humans by infected ticks. pain and swelling in the joints (inflammatory arthritis) problems affecting the nervous system – such as numbness and pain in your limbs, paralysis of your facial muscles, memory problems and difficulty concentrating heart problems – such as inflammation of the heart muscle (myocarditis) or sac surrounding the heart (pericarditis), heart block and heart failure inflammation of the membranes surrounding the brain and spinal cord (meningitis) – which can cause a severe headache, a stiff neck and increased sensitivity to light

Adverse effects GIT: N,V, and diarrhea (most common) due to direct irritation of the intestine. Modify normal flora Bony Structures and Teeth:deposition in the bone and primary dentition occurs during calcification in growing children. This causes discoloration and hypoplasia of the teeth and a temporary stunting of growth Therefore, tetracyclines are generally avoided in pregnancy & for long periods to children under 8 years of age

Adverse effects Fatal hepatotoxicity: especially during pregnancy
Phototoxicity: such as severe sunburn, occurs when a patient receiving a tetracycline ,especially demeclocycline, is exposed to sun or ultraviolet rays Local Tissue Toxicity (IV & IM injections) Vestibular Reactions (dizziness, vertigo, N, & V) particularly with minocycline Superinfections: Overgrowths of Candida (for example, in the vagina) or of resistant staphylococci (in the intestine) Hepatic toxicity during pregnancy, potentially associated with tetracycline use, has been widely reported in the literature. As a class, tetracyclines are generally considered second-line antibiotics in pregnant women and their use should be avoided

Macrolides Agents: erythromycin, clarithromycin, azithromycin, telithromycin (Ketolide) The macrolides, in general, are bacteriostatic Erythromycin may be bactericidal, particularly at higher concentrations, for susceptible organisms Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA Erythromycin base is destroyed by gastric acid. Thus, either enteric-coated tablets or esterified forms of the antibiotic are administered Prevent movement of ribosome across mRNA

Typical therapeutic applications of macrolides
Diphtheria (from Greek: διφθέρα diphthera, meaning leather) is an infection caused by the bacterium Corynebacterium diphtheriae.[1] Signs and symptoms may vary from mild to severe.[2] They usually start two to five days after exposure.[1] Symptoms often come on fairly gradually beginning with a sore throat and fever.[2] In severe cases a grey or white patch develops in the throat.[1][2] This can block the airway and create a barking cough as in croup.[2] The neck may swell in part due to large lymph nodes.[1] A form of diphtheria that involves the skin, eyes, or genitals also exists.[1][2] Complications may include myocarditis,inflammation of nerves, kidney problems, and bleeding problems due to low blood platelets. Myocarditis may result in an abnormal heart rate and inflammation of the nerves may result in paralysis. Diphtheria is usually spread between people by direct contact or through the air.[1][3] It may also be spread by contaminated objects. Diphtheria causes a swollen neck, sometimes referred to as a "bull neck". Legionnaires’ disease is a serious lung infection caused by Legionella bacteria. It's usually caught by breathing in small droplets of contaminated water. The infection isn't contagious and can't be spread directly from person to person. Initial symptoms usually include flu-like symptoms, Once bacteria begin to infect your lungs, you may also experiencesymptoms of pneumonia, such as: a persistent cough – which is usually dry at first, but as the infection develops you may start coughing up phlegm or, rarely, blood shortness of breath chest pains

Macrolides-ADRs Epigastric distress: Anorexia, nausea, vomiting, and diarrhea. Can lead to poor patient compliance for erythromycin Cholestatic jaundice: especially with the estolate form of erythromycin as the result of a hypersensitivity reaction Prolongate the QTc interval in some patients (Telithromycin): avoided in patients with congenital prolongation of the QTc interval and in those patients with proarrhythmic conditions Prolongation of the QTc interval can cause life-threatening polymorphic ventricular tachycardia also known as torsade de pointes.

Lincosamides Agents: Clindamycin
Similar mechanism of action to macrolides Clindamycin is employed primarily in the treatment of infections caused by ANAEROBIC bacteria, such as Bacteroides fragilis, which often causes abdominal infections associated with trauma It is also significantly active against nonenterococcal, gram-positive cocci B. fragilis is involved in 90% of anaerobic peritoneal infections.[8] It also causes bacteremia[9] associated with intraabdominal infections, peritonitis and abscesses following rupture of viscus, and subcutaneous abscesses or burns near the anus.[10]Though it is gram negative, it has an altered LPS and does not cause endotoxic shock.

Clindamycin ADRs: Skin rash
Pseudomembranous colitis caused by overgrowth of C. Difficile characterized as potentially fatal diarrhea coupled with abdominal cramping and excretion of blood or mucus Oral administration of either vancomycin or metronidazole is usually effective in controlling this serious condition Impaired liver function Clostridium difficile, also known as C. difficile or C. diff, is a bacterium that can infect the bowel and cause diarrhoea.

Chloramphenicol Clinical Uses
Chloramphenicol is a broad-spectrum antibiotic that is active against both aerobic and anaerobic gram-positive and gram-negative organisms It binds reversibly to the 50S of bacterial ribosomes It is active also against rickettsiae The drug is either bactericidal or (more commonly) bacteriostatic, depending on the organism Clinical Uses Topically in the treatment of eye infections b/c of its broad spectrum and its penetration of ocular tissues and the aqueous humor Haemophilus influenzae, Neisseria meningitidis, and some strains of bacteroides are highly susceptible, and for them chloramphenicol may be bactericidal. Carbapenems: Imipenem

Clinical Uses Adverse Effects GIT disturbances: NVD
Alternative to a β-lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci Treatment of serious rickettsial infections such as typhus Adverse Effects GIT disturbances: NVD Oral or vaginal candidiasis: overgrowth of Candida albicans Chloramphenicol is occasionally used topically in the treatment of eye infections because of its wide antibacterial spectrum and its penetration of ocular tissues and the aqueous humor. typhus <disease, microbiology> An acute infectious disease characterised by high fever, a skin eruption and severe headache. In the past, typhus has been a disease of war, famine or catastrophe, being spread by lice, ticks or fleas. The infecting organism is Rickettsia prowazekii, sensitive to sulpha drugs or tetracycline. typhoid <disease, microbiology> An infectious febrile illness usually spread by contamination of food, milk or water supplies with Salmonella typhi, either directly by sewage, indirectly by flies or by faulty personal hygiene. There are less than 600 cases per year in the US. Asymptomatic carriers harbor the organism in their gallbladder and excrete it in their stools for years. Average incubation time is days. Fever, diarrhoeal stools (often bloody), abdominal pain, malaise and a rose coloured rash on the upper abdomen are seen. Severe cases may progress to delirium and obtundation. Complications include glomerulonephritis. Treatment includes intravenous fluids and antibiotics (chloramphenicol or ampicillin). Vaccines are recommended for travel to endemic areas. Vancomycin (in combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for treatment of meningitis suspected or known to be caused by a highly penicillin-resistant strain of pneumococcus

Chloramphenicol Adverse Effects
3. Bone Marrow Disturbances: dose-related reversible suppression of RBCs production & aplastic anemia especially in patients with low levels of glucose 6-phosphate dehydrogenase 4. Gray baby syndrom: vomiting, flaccidity, hypothermia, gray color, shock, and collapse Neonates have a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol Most common inherited enzyme deficiency affecting red blood cells. G6PD is a critical antioxidant—a deficiency can predispose to oxidation and subsequent hemolysis of the red blood cell. sulfonamides, furantoins, chloramphenicol, large doses of ascorbic acid, dapsone(>200mg/day), chloroquine, methylene blue, nalidixic acid, penicillamine, primaquine, quinadine & quinine. The degree of hemolysis induced by a drug may be accentuated by the presence of additional factors (infection or disease state etc).The severity of the reaction is dependent on the type of G6PD deficiency (Mediterranean deficiency-Caucasian (most severe) ; Blacks (usually mild to moderate). The sex of the patient is also important—males are at greater risk based on severity compared to females.

Streptogramines A combination of 2 antibiotics: quinupristin & dalfopristin in a 3:7 wt/wt ratio Each component bind to a separate site on the 50S bacterial ribsome, forming a stable ternary compound (synergistic effect) Bactericidal primarily against G+ve cocci including those resistant to other antibiotics (MRSA and VERSA) Bacteriostatic against Enterococcus faecium Approved for treatment of infections caused by staphylococci or by vancomycin-resistant strains of E faecium Vancomycin-resistant E. faecium is often referred to as VRE Enterococcus faecium is a Gram-positive, alpha-hemolytic or nonhemolytic bacterium in the genus Enterococcus.[1] It can be commensal(innocuous, coexisting organism) in the human intestine, but it may also be pathogenic, causing diseases such as neonatal meningitis orendocarditis. Important clinical infections caused by Enterococcus include urinary tract infections, bacteremia, bacterial endocarditis, diverticulitis, and meningitis.

Streptogramines- ADRs
Pain at infusion site Arthralgia & myalgia (high doses) Hyperbilirubinema (25% of patients)

Antimetabolites Sulfonamides and trimethoprim
Indirect nucleic acid synthesis inhibitors Sulfonamides: Bacteriostatic rather than bactericidal Strctural/ synthetic analogus of p-aminobenzoic acid: they are competitive inhibitors of dihydropteroate synthase The selective toxicity of sulfonamides results from the inability of mammalian cells to synthesize folic acid; they must use preformed folic acid that is present in the diet

GTP is a purine

Sulfonamides The sulfonamides may be classified as:
Topical (not commonly b/c of the risk of sensitization) Oral nonabsorbable (Sulfasalazine) Oral absorbable Short-acting (eg, sulfisoxazole) Intermediate-acting (eg, sulfamethoxazole) Long-acting (eg, sulfadoxine)

Sulfonamides – Clinical uses
Oral abosrbable: Toxoplasmosis: Oral sulfadiazine plus pyrimethamine (a DHF reductase inhibitor) plus folinic acid Simple urinary tract infections: Sulfisoxazole and sulfamethoxazole Topical agents: Bacterial conjunctivitis: sodium sulfacetamide ophthalmic solution or ointment Prevention of infection of burn wounds: silver sulfadiazine Oral nonabsorbalbe: ulcerative colitis, rheumatoid arthritis: Oral (sulfasalazine; sulfapyridine and 5-aminosalicylic acid (5-ASA)) SUILPHADIAZINE Half-life elimination: 10 hours Mechanism of Action of sulfasalazine: 5-aminosalicylic acid (5-ASA) is the active component of sulfasalazine; the specific mechanism of action of 5-ASA is unknown; however, it is thought that it modulates local chemical mediators of the inflammatory response, especially leukotrienes, and is also postulated to be a free radical scavenger or an inhibitor of tumor necrosis factor (TNF); action appears topical rather than system Metabolism via colonic intestinal flora to sulfapyridine and 5-aminosalicylic acid (5-ASA). Following absorption, sulfapyridine undergoes acetylation to form AcSP and ring hydroxylation while 5-ASA undergoes N-acetylation (non-acetylation phenotype dependent process); rate of metabolism via acetylation dependent on acetylation phenotype Because sulfasalazine and its metabolite mesalazine (or 5-aminosalicylic acid (5-ASA)) are poorly absorbed into the bloodstream, it is surprising that the drug is effective against symptoms outside of the intestine. One possible explanation is that, given that ulcerative colitis produces arthritic symptoms, the arthritic symptoms resolved by sulfasalazine are actually[tone] a product of unrecognized[clarify] ulcerative colitis,[citation needed] which is effectively treated with sulfasalazine. The other metabolite, sulfapyridine, is absorbed into the blood, and is believed to be the source of the side-effects discussed above. It is possible that the sulfapyridine is responsible for some of the anti-arthritic effects of sulfasalazine. Toxoplasmosis is an infection caused by a parasite called Toxoplasma gondii (T. gondii). s toxoplasmosis serious? Toxoplasmosis is usually nothing to worry about because the immune system is normally strong enough to fight the infection and stop it from causing serious illness. After getting the infection, most people are immune to it for the rest of their life. However, it can lead to serious problems in: women who become infected while they're pregnant –toxoplasmosis could cause a miscarriage or stillbirth, or the infection could spread to the baby and cause serious complications (congenital toxoplasmosis: The infection can damage the baby's eyes, nervous system, skin, and ears.) people with weak immune systems, such as those who've had an organ transplant, those with HIV, and those havingchemotherapy – this could mean the infection is able to spread to the eyes, heart, lungs or brain The parasite that causes toxoplasmosis is found in the poo (faeces) of infected cats and in infected meat.

Sulfonamides – Adverse effects
Hypersensitivity: Allergic reactions, including skin rashes and fever Cross-allergenicity between the individual sulfonamides should be assumed and may also occur with chemically related drugs (eg, oral hypoglycemics, thiazides) GIT: NVD Hematotoxicity: granulocytopenia, aplastic anemia, & thrombocytopenia Acute hemolysis may occur in persons with glucose-6-phosphate dehydrogenase deficiency Crystalluria: Sulfonamides may precipitate in the urine at acidic pH Adequate hydration and alkalinization of urine prevent the problem 5. Kernicterus: Sulfonamides can displace bilirubin from plasma proteins & bilirubin is then free to pass into the CNS Should be avoided in newborns and infants less than 2 months of age as well as in pregnant women at term

Trimethoprim – Mechanism of action
An analog of dihydrofolic acid Trimethoprim is a selective inhibitor of bacterial dihydrofolate reductase that prevents formation of the active tetrahydro- form of folic acid Bacterial dihydrofolate reductase is four to five orders of magnitude more sensitive to inhibition by trimethoprim than the mammalian enzyme Alone can be given in acute urinary tract infections Adverse effects may cause the predictable adverse effects of an antifolate drug, including Megaloblastic anemia Leukopenia Granulocytopenia These effects are usually ameliorated by supplementary folinic acid

Trimtethoprim plus sulfamethoxazole (TMP-SMZ)
The combination of trimethoprim with sulfamethoxazole is called cotrimoxazole When the two drugs are used in combination, antimicrobial synergy results from the sequential blockade of folate synthesis The drug combination is bactericidal against susceptible organisms Adverse effects The combination of trimethoprim-sulfamethoxazole may cause any of the adverse effects associated with the sulfonamides AIDS patients given TMP-SMZ have a high incidence of adverse effects, including fever, rashes, leukopenia, and diarrhea.

Typical therapeutic applications of co-trimoxazole (sulfamethoxazole plus trimethoprim).
LISTERIA- MENINGITIS Shigellosis, also known as bacillary dysentery or Marlow syndrome, in its most severe manifestation, is a foodborne illnesscaused by infection by bacteria of the genus Shigella. Shigellosis rarely occurs in animals other than humans.[1] The causative organism is frequently found in water polluted with human feces, and is transmitted via the fecal-oral route. The usual mode of transmission is directly person-to-person hand-to-mouth, in the setting of poor hygiene among children Signs and symptoms may range from mild abdominal discomfort to full-blown dysentery characterized by cramps, diarrhea, with slimy-consistent stools, fever, blood, pus, ormucus in stools or tenesmus.[2] Onset time is 12 to 96 hours, and recovery takes 5 to 7 days. Typhoid fever, also known simply as typhoid, is a bacterial infection due to Salmonella typhi that causes symptoms.[1] Symptoms may vary from mild to severe and usually begin six to thirty days after exposure.[2][3] Often there is a gradual onset of a high fever over several days.[2] Weakness, abdominal pain, constipation, and headaches also commonly occur.[3][4] Diarrhea is uncommon and vomiting is not usually severe

Direct nucleic acid synthesis inhibitors
Antimetabolite Quinolone Fluoroquinolones Ciprofloxacin Norflxacin Moxifloxacin Levofloxacin Direct nucleic acid synthesis inhibitors

Fluoroquinolones Broad-spectrum antibiotic effective against a variety of gram-positive and gram-negative bacteria They block bacterial DNA synthesis by inhibiting bacterial: Topoisomerase II (DNA gyrase): prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication Topoisomerase IV: interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division Originally developed because of their excellent activity against gram-negative aerobic bacteria; they had limited activity against gram-positive organisms

Fluoroquinolones Several newer agents have improved activity against gram-positive cocci The relative activity against gram-negative vs. gram-positive species is useful for classification of these agents. Clinical uses UTI even when caused by multidrug-resistant bacteria, eg, pseudomonas Bacterial diarrhea caused by shigella, salmonella, toxigenic E coli, and campylobacter First-generation drugs (e.g., nalidixic acid) achieve minimal serum levels. Second-generation quinolones (e.g., ciprofloxacin) have increased gram-negative and systemic activity. Third-generation drugs (e.g., levofloxacin) have expanded activity against gram-positive bacteria and atypical pathogens. Fourth-generation quinolone drugs (currently only trovafloxacin) add significant activity against anaerobes.

Clinical uses Quinolones – Clinical uses
Infections of soft tissues, bones, and joints and in intra-abdominal and respiratory tract infections, including those caused by multidrug-resistant organisms such as pseudomonas and enterobacter (except norfloxacin) Quinolones – Clinical uses Ciprofloxacin is a DOC for prophylaxis and treatment of anthrax Ciprofloxacin and levofloxacin are effective in treating chlamydial urethritis or cervicitis Ciprofloxacin, levofloxacin, or moxifloxacin is occasionally used for treatment of tuberculosis and atypical mycobacterial infections Respiratory fluoroquinolones (e.g. levofloxacin, gatifloxacin, gemifloxacin, & moxifloxacin): upper and lower RTI

Adverse effects GIT: NVD (most common)
CNS: headache and dizziness or light-headedness Phototxicity Connective tissue problems: may damage growing cartilage and cause an arthropathy. Thus, these drugs are not routinely recommended for patients under 18 years of age QT interval prolongation: with gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin Tendon inflammation/rupture: [US Boxed Warning]: There have been reports of tendon inflammation and/or rupture with quinolone antibiotics in all ages; risk may be increased with concurrent corticosteroids, solid organ transplant recipients, and in patients >60 years of age. In a database study of 6.4 million patients, 28,907 cases of Achilles tendinopathy and 7685 cases of tendon rupture were identifie Prolongate the QTc interval in some patients (Telithromycin):

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