ANTIBIOTICS – 2

AMINOGLYCOSIDE ANTIBIOTICS

 

PHARMACOKINETIC PROPERTIES

 

        Absorption: Aminoglycoside are poorly absorbed from the G.I tract. Absorption by i.m route is rapid and complete, however in critically ill patients i.m absorption can vary considerably. Peak serum concentrations of aminoglycosides are reached within 30-120 minutes after i.m. injection.  Therapeutic or toxic concentrations may be obtained by i.p route.  The aminoglycosides are usually  administered by parenteral routes: 30-60 minutes intravenous infusion or intramuscular injection.

 

        Distribution: Aminoglycosides are polar drugs and their distribution is mainly restricted to extracellular fluids. Protein binding of these antibiotics is less than 10%. Aminoglycosides distribute well in synovial, peritoneal, ascitic and pleural fluids. High concentrations of aminoglycosides are obtained in renal tissue especially in renal cortex. Penetration of these drugs is poor in eye and central nervous system. Concentrations of aminoglycosides in biliar and bronchial secretions are variable.

The distribution volume of aminoglycosides aproximates to the extracellular fluid (20-25% of body weight). Modifications of the distribution coefficient of aminoglycosides occur in some kind of patients as those suffering from gram negative sepsis, dehydrated, febrile, critically ill, hematological, burned patients, etc..

 

        Elimination: Aminoglycosides are primarily excreted unchanged through the kidney by glomerular filtration. The 80-90% of the administered dose is excreted in the urine resulting in high urinary concentrations. A small amount of aminoglycoside is excreted by bile. Serum half-life in patients with normal renal function is about 2-3 hours. Linear correlations are obtained between the clearance or the elimination constant  of aminoglycoside and creatinine clearance of the patient.

 

        ADVERSE EFFECTS

 

        Nephrotoxicity: A wide variation in the incidence. Usually reversible. Increase in serum creatinine and BUN.

 

        Otoxicity: Cochlear and vestibular. Bilateral and permanent.

 

        Neuromuscular blockade: Low incidence. Enhanced by concomitant administration of neuromuscular blocking drugs and  anesthetics, patients with hypocalcemia or miastenia gravis or when the i.p or rapid i.v injection are used.

 

        Other adverse effects: Hypersensitivity reactions, superinfection, CNS effects and GI disturbances.

 

        RISK FACTORS ASSOCIATED WITH TOXICITY OF AMINOGLYCOSIDES

 

        Related to characteristics of the patient.

– Older patients.

– Previous renal disfunction

– Previous treatment with aminoglycosides

– Liver disease.

– Hypotension, shock, hypovolemia.

 

Related to the administration of the antibiotic.

– Higher daily doses.

– Prolonged treatment.

– Short dosage intervals.

 

Development of the treatment

– Higher  Cmax and Cmin

– Co-administration with other nephrotoxic drugs.

    

THERAPEUTIC RANGE

 

CONVENTIONAL DOSAGE SCHEDULE

 

                                   Gentamicin      Tobramycin  Amikacin

__________________________________________________________________

Peak (µg/ml)

Serious infection                  6-8                   6-8             20-25

Life-threatening infection    8-10                 8-10            25-30

 

Trough (µg/ml)

Serious infection               0,5-1,5             0,5-1,5            1-4

Life-threatening infection    1-<2                 1-<2             4-8

 

Table.- Serum concentrations associated with  therapeutic efficiency of aminoglycosides.

 

                           NEPHROTOXICITY  OTOTOXICITY

                     Cmax         Cmin                Cmax          Cmin

                     (µg/ml)       (µg/ml)              (µg/ml)        (µg/ml)

 

Amikacin       > 32-34                                   > 10    > 32-34      > 10

Tobramycin > 10-12          > 2                 > 10-12           > 2

Gentamicin  > 10-12          > 2                     > 8               > 4

 

Table.- Serum concentrations associated with aminoglycoside toxicity.

 

PHYSIOPATOLOGICAL AND CLINICAL SITUATIONS WHERE AMINOGLYCOSIDE PHARMACOKINETICS  IS ALTERED.

 

PHYSIOLOGICAL SITUATIONS

 

– Age: neonates, pediatric and older patients

–    Weight: obesity

–    Low degree of hydratation

–    Hematocrit alterations

–    Pregnancy

 

PATHOLOGICAL SITUATIONS

 

           Renal impairment

–    Fever and neutropenia

–    Cystic fibrosis

–    Ascites

–    Neoplastic patients

–    Critically ill patients

–    Burned patients

 

CLINICAL SITUATIONS

 

– Drug interactions: Beta-lactam antibiotics

–    Hemodialysis

–    Peritoneal dialysis

–    Parentheral nutrition

–    Major surgery

Aminoglycosides are a group of bactericidal antibiotics originally obtained from various streptomyces species and sharing chemical, antimicrobial, pharmacologic, and toxic characteristics.

The group includes streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, and others.

Aminoglycosides are used most widely against gram-negative enteric bacteria, especially in bacteremia and sepsis, in combination with vancomycin or a penicillin for endocarditis, and for treatment of tuberculosis. Streptomycin is the oldest and best-studied of the aminoglycosides. Gentamicin, tobramycin, and amikacin are the most widely employed aminoglycosides at present. Neomycin and kanamycin are now largely limited to topical or oral use.

The aminoglycoside class of antibiotics consists of many different agents. Gentamicin, tobramycin, amikacin, streptomycin, neomycin, and paromomycin are approved by the US Food and Drug Administration (FDA) and available for clinical use in the United States. Of these, gentamicin, tobramycin, and amikacin are the most frequently prescribed.

The most common clinical application (either alone or as part of combination therapy) of the aminoglycosides is in the treatment of serious infections caused by aerobic gram-negative bacilli. While less common, aminoglycosides (in combination with other agents) have also been used for the treatment of select gram-positive infections. In addition, certain aminoglycosides have demonstrated clinically relevant activity against protozoa (paromomycin), Neisseria gonorrhoeae (spectinomycin, not available in the United States), and mycobacterial infections (tobramycin, streptomycin, and amikacin).

 

General Properties of Aminoglycosides

Physical and Chemical Properties

Aminoglycosides have a hexose ring, either streptidine (in streptomycin) or 2-deoxystreptamine (other aminoglycosides), to which various amino sugars are attached by glycosidic linkages (Figures 45–1 and 45–2). They are water-soluble, stable in solution, and more active at alkaline than at acid pH. Aminoglycosides frequently exhibit synergism with -lactams or vancomycin in vitro.

In combination they eradicate organisms more rapidly than would be predicted from the activity of either single agent. However, at high concentrations aminoglycosides may complex with –lactam drugs, resulting in loss of activity, and they should not be mixed together for administration.

Figure 45–1.

Spectinomycin

Spectinomycin is an aminocyclitol antibiotic that is structurally related to aminoglycosides. It lacks amino sugars and glycosidic bonds.

While active in vitro against many gram-positive and gram-negative organisms, spectinomycin is used almost solely as an alternative treatment for gonorrhea in patients who are allergic to penicillin or whose gonococci are resistant to other drugs. The vast majority of gonococcal isolates are inhibited by 6 g/mL of spectinomycin.

Strains of gonococci may be resistant to spectinomycin, but there is no cross-resistance with other drugs used in gonorrhea. Spectinomycin is rapidly absorbed after intramuscular injection. A single dose of 40 mg/kg up to a maximum of 2 g is given. There is pain at the injection site and occasionally fever and nausea. Nephrotoxicity and anemia have been observed rarely.

Antibacterial Drugs

Drugs for Treating Bacterial Infections

When bacteria overcome the cutaneous or mucosal barriers and penetrate body tissues, a bacterial infection is present. Frequently the body succeeds in removing the invaders, without outward signs of disease, by mounting an immune response. If bacteria multiply faster than the body’s defenses can destroy them, infectious disease develops with inflammatory signs, e.g., purulent wound infection or urinary tract infection. Appropriate treatment employs substances that injure bacteria and thereby prevent their further multiplication, without harming cells of the host organism (1).

Apropos nomenclature: antibiotics are produced by microorganisms (fungi, bacteria) and are directed “against life” at any phylogenetic level (prokaryotes, eukaryotes). Chemotherapeutic agents originate from chemical synthesis. This distinction has been lost in current usage.

Specific damage to bacteria is particularly practicable when a substance interferes with a metabolic process that occurs in bacterial but not in host cells.

Clearly this applies to inhibitors of cell wall synthesis, because human and animal cells lack a cell wall. The points of attack of antibacterial agents are schematically illustrated in a grossly simplified bacterial cell, as depicted in (2).

In the following sections, polymyxins and tyrothricin are not considered further. These polypeptide antibiotics enhance cell membrane permeability. Due to their poor tolerability, they are prescribed in humans only for topical use.

The effect of antibacterial drugs can be observed in vitro (3). Bacteria multiply in a growth medium under control conditions. If the medium contains an antibacterial drug, two results can be discerned: 1. bacteria are killed—bactericidal effect; 2. bacteria survive, but do not multiply—bacteriostatic effect. Although variations may occur under therapeutic conditions, different drugs can be classified according to their respective primary mode of action (color tone in 2 and 3). When bacterial growth remains unaffected by an antibacterial drug, bacterial resistance is present. This may occur because of certain metabolic characteristics that confer a natural insensitivity to the drug on a particular strain of bacteria (natural resistance). Depending on whether a drug affects only a few or numerous types of bacteria, the terms narrow-spectrum (e.g., penicillin G) or broad-spectrum (e.g., tetracyclines) antibiotic are applied. Naturally susceptible bacterial strains can be transformed under the influence of antibacterial drugs into resistant ones (acquired resistance), when a random genetic alteration (mutation) gives rise to a resistant bacterium. Under the influence of the drug, the susceptible bacteria die off, whereas the mutant multiplies unimpeded. The more frequently a given drug is applied, the more probable the emergence of resistant strains (e.g., hospital strains with multiple resistance)!

Resistance can also be acquired when DNA responsible for nonsusceptibility (so-called resistance plasmid) is passed on from other resistant bacteria by conjugation or transduction.

Inhibitors of Cell Wall Synthesis

In most bacteria, a cell wall surrounds the cell like a rigid shell that protects against noxious outside influences and prevents rupture of the plasma membrane from a high internal osmotic pressure. The structural stability of the cell wall is due mainly to the murein (peptidoglycan) lattice. This consists of basic building blocks linked together to form a large macromolecule. Each basic unit contains the two linked aminosugars N-acetylglucosamine and N-acetylmuramyl acid; the latter bears a peptide chain. The building blocks are synthesized in the bacterium, transported outward through the cell membrane, and assembled as illustrated schematically. The enzyme transpeptidase cross-links the peptide chains of adjacent aminosugar chains.

Inhibitors of cell wall synthesis are suitable antibacterial agents, because animal and human cells lack a cell wall. They exert a bactericidal action on growing or multiplying germs. Members of this class include -lactam antibiotics such as the penicillins and cephalosporins, in addition to bacitracin and vancomycin.

Penicillins (A). The parent substance of this group is penicillin G (benzylpenicillin). It is obtained from cultures of mold fungi, originally from Penicillium notatum. Penicillin G contains the basic structure common to all penicillins, 6-amino-penicillanic acid (p. 271, 6-APA), comprised of a thiazolidine and a 4-membered -lactam ring. 6- APA itself lacks antibacterial activity.

Penicillins disrupt cell wall synthesis by inhibiting transpeptidase. When bacteria are in their growth and replication phase, penicillins are bactericidal; due to cell wall defects, the bacteria swell and burst.

Penicillins are generally well tolerated; with penicillin G, the daily dose can range from approx. 0.6 g i.m. (= 106 international units, 1 Mega I.U.) to 60 g by infusion. The most important adverse effects are due to hypersensitivity (incidence up to 5%), with manifestations ranging from skin eruptions to anaphylactic shock (in less than 0.05% of patients). Known penicillin allergy is a contraindication for these drugs. Because of an increased risk of sensitization, penicillins must not be used locally.

Neurotoxic effects, mostly convulsions due to GABA antagonism, may occur if the brain is exposed to extremely high concentrations, e.g., after rapid i.v. injection of a large dose or intrathecal injection. Penicillin G undergoes rapid renal elimination mainly in unchanged form (plasma t1/2 ~ 0.5 h). The duration of the effect can be prolonged by:

1. Use of higher doses, enabling plasma levels to remain above the minimally effective antibacterial concentration;

2. Combination with probenecid. Renal elimination of penicillin occurs chiefly via the anion (acid)-secretory system of the proximal tubule (-COOH of 6-APA). The acid probenecid (p. 316) competes for this route and thus retards penicillin elimination;

3. Intramuscular administration in depot form. In its anionic form (-COO-) penicillin G forms poorly water-soluble salts with substances containing a positively charged amino group. Depending on the substance, release of penicillin from the depot occurs over a variable interval.

Although very well tolerated, penicillin G has disadvantages (A) that limit its therapeutic usefulness: (1) It is inactivated by gastric acid, which cleaves the -lactam ring, necessitating parenteral administration. (2) The -lactam ring can also be opened by bacterial enzymes (-lactamases); in particular, penicillinase, which can be produced by staphylococcal strains, renders them resistant to penicillin G. (3) The antibacterial spectrum is narrow; although it encompasses many gram-positive bacteria, gram-negative cocci, and spirochetes, many gram-negative pathogens are unaffected.

Derivatives with a different substituent on 6-APA possess advantages (B): (1) Acid resistance permits oral administration, provided that enteral absorption is possible. All derivatives shown in (B) can be given orally. Penicillin V (phenoxymethylpenicillin) exhibits antibacterial properties similar to those of penicillin G. (2) Due to their penicillinase resistance, isoxazolylpenicillins caused penicillinaseproducing staphylococci. (3) Activity spectrum: The aminopenicillin amoxicillin is active against many gramnegative organisms, e.g., coli bacteria or Salmonella typhi. It can be protected from destruction by penicillinase by combination with inhibitors of penicillinase (clavulanic acid, sulbactam, tazobactam).

The structurally close congener ampicillin (no 4-hydroxy group) has a similar activity spectrum. However, because it is poorly absorbed (<50%) and therefore causes more extensive damage to the gut microbial flora (side effect: diarrhea), it should be given only by injection. A still broader spectrum (including Pseudomonas bacteria) is shown by carboxypenicillins (carbenicillin, ticarcillin) and acylaminopenicillins (mezclocillin, azlocillin, piperacillin). These substances are neither acid stable nor penicillinase resistant.

CEPHALOSPORINS

 

I. BACKGROUND

Cephalosporins are beta-lactam compounds in which the beta-lactam ring is fused to a 6-membered dihydrothiazine ring, thus forming the cephem nucleus. Side chain modifications to the cephem nucleus confers 1) an improved spectrum of antibacterial activity, 2) pharmacokinetic advantages, and 3) additional side effects. Based on their spectrum of activity, cephalosporins can be broadly categorized into four generations.

II. MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES

1.     Prevents cell wall synthesis by binding to enzymes called penicillin binding proteins (PBPs). These enzymes are essential for the synthesis of the bacterial cell wall.

2.     Bactericidal.

3.     Concentration-independent bactericidal activity, with maximal killing at 4-5 times the MIC of the organism.

4.     Clinically significant post-antibiotic effect is not observed.

Given these pharmacodynamic properties (concentration-independent bactericidal activity and lack of a post-antibiotic effect, optimal dosing regimens should be designed to continuously maintain drug levels above the MIC of pathogens.

III. SPECTRUM OF ACTIVITY

In general, 1st generation cephalosporins have better activity against gram-positive bacteria and less gram-negative activity, while 3rd generation agents, with a few exceptions, have better gram-negative activity and less gram-positive activity. The only fourth generation agent has both gram-positive and gram-negative activity.

IV. MECHANISMS OF BACTERIAL RESISTANCE

It is not uncommon for several resistance mechanisms to be operating simultaneously.

1.     destruction of beta-lactam ring by beta-lactamases; an intact beta-lactam ring is essential for antibacterial activity

2.     altered affinity of cephalosporins for their target site, the penicillin binding proteins

3.     decreased penetration of antibiotic to the target site, the PBPs. This is only applicable to gram-negative bacteria because gram-positive bacteria lack an outer cell membrane, and therefore penetration to the target site is not a problem.

V. GENERAL INFORMATION FOR CEPHALOSPORINS

1. SPECTRUM OF ACTIVITY.

PHARMACOKINETICS: Generally distributes well into the lung; kidney; urine; synovial, pleural, and pericardial fluids. Penetration into the cerebral spinal fluid (CSF) of some 3rd generation cephalosporins (cefotaxime, ceftriaxone, and ceftazidime) is adequate to effectively treat bacterial meningitis.

Elimination is primarily via the kidneys, though a few exceptions include cefoperazone and ceftriaxone which have significant biliary elimination.

GENERAL CLINICAL USES: Their broad spectrum of activity and safety profile make the cephalosporins one of the most widely prescribed class of antimicrobials. The earlier generation cephalosporins are commonly used for community-acquired infections, while the later generation agents, with their better spectrum of activity against gram-negative bacteria make them useful for hospital-acquired infections or complicated community-acquired infections.

GENERAL SIDE EFFECTS/PRECAUTIONS:

A. Hypersensitivity reactions manifested by rashes, eosinophilia, fever (1-3%); interstitial nephritis. Given the structural similarity of cephalosporins and penicillins, an estimated 1-7% of patients with penicillin allergies will also be hypersensitive to cephalosporins. Cephalosporins should be avoided in patients with immediate allergic reactions to penicillins (eg: anaphylaxis, bronchospasm, hypotension, etc.). Cephalosporins may be tried with caution in patients with delayed or mild reactions to penicillin.

B. Thrombophlebitis (1-5%).

VI. FIRST GENERATION CEPHALOSPORINS

SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: Very active against Streptococci pyogenes (Group A strep), Streptococcus agalactiae (Group B strep), viridans streptococci. Methicillin-resistant Staphylococci, Enterococci, penicillin-resistant Streptococcus pneumoniae are resistant.

Gram-negative aerobes: Commonly active against Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae, though susceptibilities may vary. Inadequate activity against Moraxella catarrhalis and Hemophilus influenzae.

Anaerobes: Active against most penicillin-susceptible anaerobes found in the oral cavity, except those belonging to the Bacteroides fragilis group.

GENERAL CLINICAL USES. Uncomplicated, community-acquired infections of the skin and soft tissue and urinary tract. Useful for respiratory tract infections caused by pencillin-sensitive Streptococcus pneumoniae but not for Hemophilus influenzae and Moraxella catarrhalis. While effective for these infections, other less expensive alternatives should be used when appropriate because of their efficacy and narrower spectrum of activity (eg: penicillins, trimethoprim/sulfamethoxazole). Parenteral 1st generation agents are used for surgical wound prophylaxis.

SPECIFIC AGENTS:

A. Cefazolin (Ancef , Kefzol, Cephalothin (Keflin , Vantage, Cephpirin (Cefadyl). IV/IM formulations. Spectrum of cephalothin and cefazolin are similar except that cefazolin is slightly more active against Escherichia coli and Klebsiella species. The longer half-life of cefazolin allows less frequent dosing.

B. Cephalexin (Keflex, Keftab, Biocef), Cephradine (Anspor, Velosef), Cefadroxil (Duricef, Ultracef). PO formulations. Less frequent dosing with cefadroxil.

VI. SECOND GENERATION CEPHALOSPORINS

There are 2 groups within the 2nd generation agents that differ in their: 1) spectrum of activity and 2) adverse reaction profile. These groups are the “true” second generation cephalosporins (cefamandole, cefuroxime) and the cephamycins (cefoxitin, cefotetan, cefmetazole).

SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: In general, true 2nd generation agents are comparable to 1st generation agents against nonenterococcal streptococci; are less active invitro, but still have adequate activity against MSSA. Compared to the 1st generation agents, the cephamycins are less active against gram-positive cocci. Both groups of cephalosporins are inactive against methicillin-resistant Staphylococci and Enterococci.

Gram-negative aerobes. The “true” cephalosporins are more active than 1sts for Hemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, and some Enterobacteriaceae. The cephamycins in some instances (eg: cefotetan) have improved activity against Enterobacteriaceae.

Anaerobes: Cephamycins are active against most anaerobes found in the mouth as well as colon (eg: Bacteroides species, including Bacteroides fragilis).

GENERAL CLINICAL USES. The “true” 2nd generation agents are useful for community-acquired infections of the respiratory tract (Hemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae) and uncomplicated urinary tract infections (Escherichia coli). The cephamycin group is useful for mixed aerobic/anaerobic infections of the skin and soft tissues, intra-abdominal, and gynecologic infections, and surgical prophylaxis.

SIDE EFFECTS/PRECAUTIONS. The cephamycin agents have a side chain called the methylthiotetrazole (MTT) group which predisposes patients to:

1) hypoprothrombinemia and bleeding by disturbing synthesis of vitamin-k dependent clotting factors.

Risk factors are renal or hepatic disease, poor nutrition, the elderly, and cancer.

2) alcohol intolerance by causing a disulfiram-like reaction, avoid alcohol products for several days after antibiotics have stopped.

SPECIFIC AGENTS:

A. Cefamandole (MandolR). (IV/IM) formulations. Better activity against selected methicillin-susceptible Staphylococcus aureus than cefazolin. May not be reliable therapy for Hemophilus influenzae. Although not a cephamycin, it contains an NMTT side chain.

B. Cefurxoime (Zinacef, Kefurox). IV/IM/PO formulations. Somewhat less potent against Staphylococcus aureus, but more potent against Streptococcus pneumoniae and Streptococcus pyogenes than 1st generation cephalosporins. Active against Hemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Proteus mirabilis, Klebsiella species.

Although cefuroxime has been used for the treatment of bacterial meningitis caused by H. influenzae, it is not recommended because studies show neurologic deficits are more frequent in children treated with cefuroxime versus selected 3rd generation cephalosporins (cefotaxime, ceftriaxone). This finding is related to delayed sterilization of cerebral spinal fluid.

C. Cefonicid (MonocidR). IV/IM formulation. Similar to cefamandole and cefuroxime, though less active against gram-positive cocci (methicillin-susceptible Staphylococcus aureus, Group A strep, Streptococcus pneumoniae). Long half-life allows once daily dosing.

D. Cefoxitin (MefoxinR). IV/IM formulations. A cephamycin, which is less active than 1st generation agents against gram-positive bacteria. Active against Neisseria gonorrhea, but less active than “true” second generation cephalosporins against Hemophilus influenzae.

E. Cefotetan (CefotanR). IV/IM formulations. A cephamycin with similar activity to cefoxitin. Compared to second generation cephalosporins and cefoxitin, has improved activity against Enterobacteriaceae including Enterobacter. Also active against Hemophilus influenzae, Neisseria gonorrhea, Neisseria meningitidis. Generally 2-4 fold less active than cefoxitin against gram-positive cocci. For Bacteroides fragilis, is comparable to cefoxitin; but less active than cefoxitin against non-Bacteroides fragilis species within the Bacteroides fragilis group; the clinical significance of which is unknown. Used in surgical wound prophylaxis when activity against Bacteroides fragilis is needed.

F. Cefmetazole (ZefazoneR). IV/IM formulations. A cephamycin, similar to cefoxitin and cefotetan. Similar to cefoxitin and more active than cefotetan against methicillin-susceptible Staphylococcus aureus. 2-4 fold more active than cefoxitin against Enterobacteriaceae (eg: Escherichia coli, Klebsiella sp, Proteus mirabilis). Also active against Hemophilus influenzae and Moraxella catarrhalis. Bacteroides fragilis is similar to cefoxitin, against other Bacteroides species, is similar or slightly less active than cefoxitin. Used in surgical wound prophylaxis when activity against Bacteroides fragilis is needed, repeat dose would be necessary in procedures lasting more than 4 hours.

G. Cefaclor (Ceclor), Cefprozil (Cefzil), Loracarbef(Lorabid), Cefpodoxime proxetil (Vantin). PO formulations. Cefaclor is more commonly associated with a serum sickness like illness. Loracarbef is a new category of compounds called the carbacephems, which are analogues of cephalosporins. Loracarbef is the carbacephem analogue of cefaclor.

H. Cefuroxime axetil (CeftinR). PO formulation of cefuroxime. Is the oral ester of cefuroxime that is hydrolyzed to cefuroxime during absorption.

VI. THIRD GENERATION CEPHALOSPORINS

Improved activity against Enterobacteriaceae associated with hospital-acquired infections; some agents are also active against Pseudomonas aeruginosa which is a frequent cause of hospital-acquired pneumonia.

SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: Cefotaxime, ceftriaxone, and ceftizoxime are active against 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, particularly intermediately-penicillin resistant Streptococcus pneumoniae. None are active against methicillin-resistant Staphylococci, Enterococci, and Listeria monocytogenes.

Gram-negative aerobes: Very active against Hemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, and Enterobacteriaceae (eg: Escherichia coli, Klebsiella species, Proteus mirabilis, Providencia)found in hospital and community-acquired infections. Some Enterobacter species have a tendency to become resistant during cephalosporin therapy, and thus cephalosporins are not the drugs of choice for Enterobacter infections.

Only and ceftazidime and cefoperazone are active against Pseudomonas aeruginosa, and ceftazidime is preferred because it is more potent than cefoperazone against gram-negative bacteria.

Anaerobes: Cefotaxime, ceftriaxone, and ceftizoxime are adequate for oral anaerobes.

GENERAL CLINICAL USES. For infections involving gram-negative bacteria, particularly hospital-acquired infections or complicated community-acquired infections of the respiratory tract, blood, intra-abdominal, skin and soft tissue, and urinary tract. Because of their activity includes the aerobic gram negative bacteria covered by aminoglycosides, they may be an alternative to aminoglycosides in some patients with renal dysfunction.

The clinical situations requiring use of 3rd generation cephalosporins are likely to be encountered in patients who are hospitalized, have recently received antibiotics, or are immunocompromised.

SPECIFIC AGENTS:

A.    Cefotaxime (Claforan), Ceftriaxone (Rocephin), Ceftizoxime (cefizox) . IV/IM formulations. Activity against Enterobacteriaceae (eg: Escherchia coli, Klebsiella pneumoniae) are similar. None are active against Pseudomonas aeruginosa. Only cefotaxime and ceftriaxone achieve adequate drug levels in the cerebral spinal fluid to constitute reliable empiric therapy for bacterial meningitis. Ceftriaxone is eliminated to a significant degree by the biliary system, and as a result, biliary pseudo-lithiasis has been reported as a side effect of this agent.

B.    

B. Ceftazidime (Fortaz, Tazidime, Tazicef), Cefoperazone (Cefobid). IV/IM formulations. Spectrum includes Pseudomonas aeruginosa (against which ceftazidime is more active) and Enterobacteriaceae covered by the 3rd generation agents in item A above. Disadvantages of cefoperazone are: 1) the least active 3rd generation agent against Enterobacteriaceae and 2) contains MTT side chain (see SIDE EFFECTS/PRECAUTIONS under 2nd generation agents).

C. Cefixime (Suprax), Ceftibuten (Cedax) .PO formulations administered once or twice daily. Inactive against methicillin-susceptible Staphylococcus aureus, thus not good choices for skin and soft tissue infections. Generally very active against gram-negative bacteria causing community-acquired infections(Hemophilus influenzae, Moraxella catarrhalis). Cefixime is effective as a single dose therapy for uncomplicated Neisseria gonorrhea infection. While used in otitis media, cefixime may not routinely eradicate Streptococcus pneumoniae.

VII. FOURTH GENERATION CEPHALOSPORIN

Has the excellent activity against Enterobacteriaceae and Pseudomonas aeruginosa which is similar to ceftazidime. In addition, it also has better gram-positive activity than ceftazidime.

SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: Active against Streptococcus pneumoniae, and Groups A and B streptococci. Though active against methicillin-susceptible Staphylococcus aureus, it is less potent than the 1st and 2nd generation agents.

Gram-negative aerobes: Similar to ceftazidime.

Anaerobes: Not active against Bacteroides fragilis.

GENERAL CLINICAL USES. Similar to 3rd generation agents.

SPECIFIC AGENT:

A. Cefepime (MaxipimeR). IV/IM formulations.

Cephalosporins (C). These -lactam antibiotics are also fungal products and have bactericidal activity due to inhibition of transpeptidase.

Their shared basic structure is 7-aminocephalosporanic acid, as exemplified by cephalexin (gray rectangle). Cephalosporins are acid stable, but many are poorly absorbed. Because they must be given parenterally, most—including those with high activity—are used only in clinical settings. A few, e.g., cephalexin, are suitable for oral use.

 

Cephalosporins are penicillinase-resistant, but cephalosporinase-forming organisms do exist. Some derivatives are, however, also resistant to this -lactamase.

Cephalosporins are broad-spectrum antibacterials. Newer derivatives (e.g., cefotaxime, cefmenoxin, cefoperazone, ceftriaxone, ceftazidime, moxalactam) are also effective against pathogens resistant to various other antibacterials. Cephalosporins are mostly well tolerated. All can cause allergic reactions, some also renal injury, alcohol intolerance, and bleeding (vitamin K antagonism).

Other inhibitors of cell wall synthesis.

Bacitracin and vancomycin interfere with the transport of peptidoglycans through the cytoplasmic membrane and are active only against gram-positive bacteria.

Bacitracin is a polypeptide mixture, markedly nephrotoxic and used only topically.

Vancomycin is a glycopeptide and the drug of choice for the (oral) treatment of bowel inflammations occurring as a complication of antibiotic therapy (pseudomembranous enterocolitis caused by Clostridium difficile). It is not absorbed.

Inhibitors of Tetrahydrofolate Synthesis

Tetrahydrofolic acid (THF) is a co-enzyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and required for cell growth and replication. Lack of THF leads to inhibition of cell proliferation. Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is made from folic acid, a vitamin that cannot be synthesized in the body, but must be taken up from exogenous sources. Most bacteria do not have a requirement for folate, because they are capable of synthesizing folate, more precisely DHF, from precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim.

Sulfonamides structurally resemble p-aminobenzoic acid (PABA), a precursor in bacterial DHF synthesis. As false substrates, sulfonamides competitively inhibit utilization of PABA, hence DHF synthesis. Because most bacteria cannot take up exogenous folate, they are depleted of DHF. Sulfonamides thus possess bacteriostatic activity against a broad spectrum of pathogens. Sulfonamides are produced by chemical synthesis. The basic structure is shown in (A). Residue R determines the pharmacokinetic properties of a given sulfonamide.

Most sulfonamides are well absorbed via the enteral route. They are metabolized to varying degrees and eliminated through the kidney. Rates of elimination, hence duration of effect, may vary widely. Some members are poorly absorbed from the gut and are thus suitable for the treatment of bacterial bowel infections. Adverse effects may include, among others, allergic reactions, sometimes with severe skin damage, displacement of other plasma protein-bound drugs or bilirubin ieonates (danger of kernicterus, hence contraindication for the last weeks of gestation and in the neonate). Because of the frequent emergence of resistant bacteria, sulfonamides are now rarely used.

Introduced in 1935, they were the first broad-spectrum chemotherapeutics. Trimethoprim inhibits bacterial DHF reductase, the human enzyme being significantly less sensitive than the bacterial one (rarely bone marrow depression). A 2,4-diaminopyrimidine, trimethoprim, has bacteriostatic activity against a broad spectrum of pathogens. It is used mostly as a component of cotrimoxazole. Co-trimoxazole is a combination of trimethoprim and the sulfonamide sulfamethoxazole. Since THF synthesis is inhibited at two successive steps, the antibacterial effect of co-trimoxazole is better than that of the individual components. Resistant pathogens are infrequent; a bactericidal effect may occur.

Adverse effects correspond to those of the components. Although initially developed as anantirheumatic agent, sulfasalazine (salazosulfapyridine) is used mainly in the treatment of inflammatory bowel disease (ulcerative colitis and terminal ileitis or Crohn’s disease). Gut bacteria split this compound into the sulfonamide sulfapyridine and mesalamine (5-aminosalicylic acid). The latter is probably the anti-inflammatory agent (inhibition of synthesis of chemotactic signals for granulocytes, and of H2O2 formation in mucosa), but must be present on the gut mucosa in high concentrations. Coupling to the sulfonamide prevents premature absorption in upper small bowel segments. The cleaved-off sulfonamide can be absorbed and may produce typical adverse effects (see above).

Dapsone (p. 280) has several therapeutic uses: besides treatment of leprosy, it is used for prevention/prophylaxis of malaria, toxoplasmosis, and actinomycosis.

Inhibitors of DNA Function

Deoxyribonucleic acid (DNA) serves as a template for the synthesis of nucleic acids. Ribonucleic acid (RNA) executes protein synthesis and thus permits cell growth. Synthesis of new DNA is a prerequisite for cell division. Substances that inhibit reading of genetic information at the DNA template damage the regulatory center of cell metabolism. The substances listed below are useful as antibacterial drugs because they do not affect human cells.

Gyrase inhibitors. The enzyme gyrase (topoisomerase II) permits the orderly accommodation of a ~1000 µmlong bacterial chromosome in a bacterial cell of ~1 µm. Within the chromosomal strand, double-stranded DNA has a double helical configuration. The former, in turn, is arranged in loops that are shortened by supercoiling. The gyrase catalyzes this operation, as illustrated, by opening, underwinding, and closing the DNA double strand such that the full loop need not be rotated.

Derivatives of 4-quinolone-3-carboxylic acid (green portion of ofloxacin formula) are inhibitors of bacterial gyrases.

They appear to prevent specifically the resealing of opened strands and thereby act bactericidally. These agents are absorbed after oral ingestion. The older drug, nalidixic acid, affects exclusively gram-negative bacteria and attains effective concentrations only in urine; it is used as a urinary tract antiseptic.

Norfloxacin has a broader spectrum. Ofloxacin, ciprofloxacin, and enoxacin, and others, also yield systemically effective concentrations and are used for infections of internal organs. Besides gastrointestinal problems and allergy, adverse effects particularly involve the CNS (confusion, hallucinations, seizures). Since they can damage epiphyseal chondrocytes and joint cartilages in laboratory animals, gyrase inhibitors should not be used during pregnancy, lactation, and periods of growth.

Azomycin (nitroimidazole) derivatives, such as metronidazole, damage DNA by complex formation or strand breakage. This occurs in obligate anaerobes, i.e., bacteria growing under O2 exclusion. Under these conditions, conversion to reactive metabolites that attack DNA takes place (e.g., the hydroxylamine shown). The effect is bactericidal. A similar mechanism is involved in the antiprotozoal action on Trichomonas vaginalis (causative agent of vaginitis and urethritis) and Entamoeba histolytica (causative agent of large bowel inflammation, amebic dysentery, and hepatic abscesses). Metronidazole is well absorbed via the enteral route; it is also given i.v. or topically (vaginal insert). Because metronidazole is considered potentially mutagenic, carcinogenic, and teratogenic in the human, it should not be used longer than 10 d, if possible, and be avoided during pregnancy and lactation. Timidazole may be considered equivalent to metronidazole.

Rifampin inhibits the bacterial enzyme that catalyzes DNA template-directed RNA transcription, i.e., DNA-dependent RNA polymerase. Rifampin acts bactericidally against mycobacteria (M. tuberculosis, M. leprae), as well as many gram-positive and gram-negative bacteria. It is well absorbed after oral ingestion. Because resistance may develop with frequent usage, it is restricted to the treatment of tuberculosis and leprosy (p. 280). Rifampin is contraindicated in the first trimester of gestation and during lactation. Rifabutin resembles rifampin but may be effective in infections resistant to the latter.

Inhibitors of Protein Synthesis

Protein synthesis means translation into a peptide chain of a genetic message first copied (transcribed) into m- RNA (p. 274). Amino acid (AA) assembly occurs at the ribosome. Delivery of amino acids to m-RNA involves different transfer RNA molecules (t-RNA), each of which binds a specific AA. Each t-RNA bears an “anticodon” nucleobase triplet that is complementary to a particular m-RNA coding unit (codon, consisting of 3 nucleobases. Incorporation of an AA normally involves the following steps (A):

1. The ribosome “focuses” two codons on m-RNA; one (at the left) has bound its t-RNA-AA complex, the AA having already been added to the peptide chain; the other (at the right) is ready to receive the next t-RNA-AA complex.

2. After the latter attaches, the AAs of the two adjacent complexes are linked by the action of the enzyme peptide synthetase (peptidyltransferase). Concurrently, AA and t-RNA of the left complex disengage.

3. The left t-RNA dissociates from m-RNA. The ribosome can advance along the m-RNA strand and focus on the next codon.

4. Consequently, the right t-RNAAA complex shifts to the left, allowing the next complex to be bound at the right. These individual steps are susceptible to inhibition by antibiotics of different groups. The examples shown originate primarily from Streptomyces bacteria, some of the aminoglycosides also being derived from Micromonospora bacteria.

 

1a. Tetracyclines inhibit the binding of t-RNA-AA complexes. Their action is bacteriostatic and affects a broad spectrum of pathogens.

1b. Aminoglycosides induce the binding of “wrong” t-RNA-AA complexes, resulting in synthesis of false proteins.

Aminoglycosides are bactericidal. Their activity spectrum encompasses mainly gram-negative organisms. Streptomycin and kanamycin are used predominantly in the treatment of tuberculosis. Note on spelling: -mycin designates origin from Streptomyces species; -micin (e.g., gentamicin) from Micromonospora species.

2. Chloramphenicol inhibits peptide synthetase. It has bacteriostatic activity against a broad spectrum of pathogens. The chemically simple molecule is now produced synthetically.

3. Erythromycin suppresses advancement of the ribosome. Its action is predominantly bacteriostatic and directed against gram-positve organisms.

For oral administration, the acid-labile base (E) is dispensed as a salt (E. stearate) or an ester (e.g., E. succinate). Erythromycin is well tolerated. It is a suitable substitute in penicillin allergy or resistance. Azithromycin, clarithromycin, and roxithromycin are derivatives with greater acid stability and better bioavailability. The compounds mentioned are the most important members of the macrolide antibiotic group, which includes josamycin and spiramycin. An unrelated action of erythromycin is its mimicry of the gastrointestinal hormone motiline (interprandial bowel motility).

Clindamycin has antibacterial activity similar to that of erythromycin. It exerts a bacteriostatic effect mainly on gram-positive aerobic, as well as on anaerobic pathogens. Clindamycin is a semisynthetic chloro analogue of lincomycin, which derives from a Streptomyces species. Taken orally, clindamycin is better absorbed than lincomycin, has greater antibacterial efficacy and is thus preferred. Both penetrate well into bone tissue.

Tetracyclines are absorbed from the gastrointestinal tract to differing degrees, depending on the substance, absorption being nearly complete for doxycycline and minocycline. Intravenous injection is rarely needed (rolitetracycline is available only for i.v. administration).

The most common unwanted effect is gastrointestinal upset (nausea, vomiting, diarrhea, etc.) due to (1) a direct mucosal irritant action of these substances and (2) damage to the natural bacterial gut flora (broad-spectrum antibiotics) allowing colonization by pathogenic organisms, including Candida fungi. Concurrent ingestion of antacids or milk would, however, be inappropriate because tetracyclines form insoluble complexes with plurivalent cations (e.g., Ca2+, Mg2+, Al3+, Fe2+/3+) resulting in their inactivation; that is, absorbability, antibacterial activity, and local irritant action are abolished. The ability to chelate Ca2+ accounts for the propensity of tetracyclines to accumulate in growing teeth and bones. As a result, there occurs an irreversible yellowbrown discoloration of teeth and a reversible inhibition of bone growth.

 

Because of these adverse effects, tetracycline should not be given after the second month of pregnancy and not prescribed to children aged 8 y and under. Other adverse effects are increased photosensitivity of the skin and hepatic damage, mainly after i.v. administration. The broad-spectrum antibiotic chloramphenicol is completely absorbed after oral ingestion. It undergoes even distribution in the body and readily crosses diffusion barriers such as the blood-brain barrier. Despite these advantageous properties, use of chloramphenicol is rarely indicated (e.g., in CNS infections) because of the danger of bone marrow damage. Two types of bone marrow depression can occur:

(1) a dose-dependent, toxic, reversible form manifested during therapy and, (2) a frequently fatal form that may occur after a latency of weeks and is not dose dependent. Due to high tissue penetrability, the danger of bone marrow depression must also be taken into account after local use (e.g., eye drops).

Aminoglycoside antibiotics consist of glycoside-linked amino-sugars (cf. gentamicin C1, a constituent of the gentamicin mixture). They contaiumerous hydroxyl groups and amino groups that can bind protons. Hence, these compounds are highly polar, poorly membrane permeable, and not absorbed enterally. Neomycin and paromomycin are given orally to eradicate intestinal bacteria (prior to bowel surgery or for reducing NH3 formation by gut bacteria in hepatic coma). Aminoglycosides for the treatment of serious infections must be injected (e.g.,

gentamicin, tobramycin, amikacin, netilmicin, sisomycin). In addition, local inlays of a gentamicin-releasing carrier can be used in infections of bone or soft tissues.

Aminoglycosides gain access to the bacterial interior by the use of bacterial transport systems. In the kidney, they enter the cells of the proximal tubules via an uptake system for oligopeptides. Tubular cells are susceptible to damage (nephrotoxicity, mostly reversible). In the inner ear, sensory cells of the vestibular apparatus and Corti’s organ may be injured (ototoxicity, in part irreversible).

Contraindications: Hypersensitivity for ester-type local anesthetic (eg, procaine).

Warnings/precautions: Use with caution in patients with severe liver disease, spinal deformities, existing neurologic disease, severe uncontrolled hypotension, septicemia, infection at site of injection, abnormal or reduced levels of serum cholinesterase.

Editorial comments: If an oxytocic drug has been administered along with tetracaine, extreme care must be used when a vasopressor agent is used to treat the hypotension that frequently accompanies spinal anesthesia. Such vasopressors may cause severe and persistent hypertension and/or rupture of cerebral blood vessels.

• This drug is listed in the Physician’s Desk Reference, 54^th edition, 2000 only for topical application.

• For additional information, see bupivacaine, p. 113. Tetracycline

Brand names: Achromycin, Tetracycline.

Class of drug: Tetracycline antibiotic.

Mechanism of action: Inhibits bacterial protein synthesis after specific ribosomal binding.

 Susceptible organisms in vivo: Borrelia burgdorferi, Borrelia recurrentis, Brucella sp, Calymmatobacterium granulomatis, Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Ehrlichia sp, Helicobacter pylori, Rickettsia (Q fever), Rickettsia sp, Vibrio sp.

Adjustment of dosage

• Kidney disease: None.

• Liver disease: None.

• Elderly: None.

• Pediatric: Not to be used in children 8 years unless all other drugs are either ineffective or contraindicated.

Food: Take 1 hour before or 2 hours after meals. Dairy products interfere with tetracycline absorption.

Pregnancy: Category D.

Lactation: Appears in breast milk. Considered compatible by American Academy of Pediatrics.

Contraindications: Hypersensitivity to any tetracycline, patients with esophageal obstruction, children ≤8 years.

Warnings/precautions

• Use with caution in patients with impaired kidney function.

• Administer IM by deep injection into large muscle. If injected inadvertently SC or into fat layer, severe pain may result. This can be relieved by means of an ice pack. IM solution should be used within 24 hours of preparation.

• The drug may permanently discolor (yellow brown to gray) deciduous or permanent teeth or cause enamel hypoplasia. Premature infants may experience decreased fibula growth.

• Do not administer antacids that contain calcium, aluminum, or magnesium.

Advice to patient

• Discard drug if it is beyond expiration date. Outdated drug can cause severe kidney toxicity (Fanconi-like syndrome).

• To minimize possible photosensitivity reaction, apply adequate sunscreen and use proper covering when exposed to strong

sunlight.

• Store drug away from light, heat, and high humidity.

• Use two forms of birth control including hormonal and barrier methods.

• Do not take drug at bedtime.

Adverse reactions

• Common: nausea, vomiting, diarrhea, anorexia.

• Serious: renal toxicity, hypersensitivity reactions, benign intracranial hypertension (pseudotumor cerebri), pericardits, diabetes insipidus, pseudomembranous colitis, hepatitis, anaphylaxis.

Clinically important drug interactions

• Drugs that decrease effects/toxicity of tetracyclines: aluminum antacids, iron preparations, calcium salts, magnesium salts, sodium bicarbonate, zinc salts, bismuth salts, cimetidine.

• Tetracyclines increase effects/toxicity of oral anticoagulants, bumetanide, digoxin, thiazide diuretics, ethacrynic acid, furosemide, insulin, methoxyflurane.

• Tetracyclines decrease effects/toxicity of penicillins.

Parameters to monitor

• Serum BUN and creatinine, liver enzymes.

• Signs of possible oliguria, which may result in accumulation of the drug.

• Signs and symptoms of pseudotumor cerebri in adults: headaches, diplopia.

• Signs and symptoms of pseudomembraneous colitis: Discontinue drug if possible. If necessary, treat with vancomycin, metronidazole, and cholestyramine.

• Signs and symptoms of phlebitis from IV injections.

• Renal function in patients with preexisting renal impairment. If indicated, monitor serum drug levels. Maintain level below 15 g/mL.

• Serum enzymes in patients with preexisting kidney or liver disease or those receiving concomitant hepatotoxic drug.

Editorial comments

• Uses for tetracyclines include treatment of early Lyme disease, Vibrio infections such as cholera, and rickettsial infections including typhus, Q fever, and Rocky Mountain spotted fever.

They are also used to treat genital infections (granuloma inguinale, nongonococcal urethritis, pelvic inflammatory disease, and other infections caused by C. rachomatis).

Streptomycin

Brand name: Streptomycin.

Class of drug: Antibiotic, aminoglycoside.

Mechanism of action: Binds to ribosomal units in bacteria, inhibits protein synthesis.

Susceptible organisms in vivo : Mycobacterium tuberculosis, Yersinia pestis, Francisella tularensis, Brucella; synergism against enterococci and streptococcoi.

Adjustment of dosage

• Kidney disease: Creatinine clearance 10–50 mL/min: administration interval 24–72 hours; creatinine clearance 10 mL/ min: administration interval 72–96 hours.

• Liver disease: None.

• Elderly: None.

• Pediatric: See above.

Food: No restrictions.

Pregnancy: Category D.

Lactation: Appears in breast milk. Considered compatible by American Academy of Pediatrics.

Contraindications: Hypersensitivity to aminoglycoside antibiotics.

Warnings/precautions

• Use with caution in patients with renal disease, neuromuscular disorders (eg, myasthenia gravis, parkinsonism), hearing disorders.

• Do not combine this drug with any other drug in the same IV bag.

Adverse reactions:

• Common: none.

• Serious: renal toxicity, ototoxicity, neuromuscular paralysis, respiratory depression (infants), superinfection.

Clinically important drug interactions

• Drugs that increase effects/toxicity of aminoglycosides: loop diuretics, amphotericin B, enflurane, vancomycin, NSAIDs.

• Drugs that decrease effects/toxicity of aminoglycosides: penicillins (high dose), cephalosporins.

Parameters to monitor

• Peak and trough serum levels 48 hours after beginning therapy and every 3–4 days thereafter as well as after changing doses. Peak (therapeutic): 15–40 g/mL; trough: 4 g/mL.

• Signs of ototoxicity: tinnitus, vertigo, hearing loss. The drug should be stopped if tinnitus or vertigo occurs. Limit administration to 7–10 days to decrease the risk of ototoxicity.

• Renal function periodically. If serum creatinine increases by more than 50% over baseline value, it may be advisable to discontinue drug treatment and use a less nephrotoxic agent, eg, a quinolone or cephalosporin.

• Efficacy of drug action. If there is no response in 3–7 days, reculture and consider another drug.

• Neuromuscular function when administering the drug IV. Too rapid administration may cause paralysis and apnea. Have calcium gluconate or pyridostigmine available to reverse such an effect.

• Neurologic status if the drug is given for hepatic encephalopathy.

• Signs and symptoms of allergic reaction.

Editorial comments

• Streptomycin has the greatest activity of all the aminoglycosides against M. tuberculosis. It is a first-line drug for tuberculosis though not as effective as isoniazid and rifampin.

• Streptomycin is the drug of choice to treat plague and brucellosis.

• Streptomycin and gentamicin are the drugs of choice to treat tularemia.

Succinylcholine (Suxamethonium)

Brand names: Anectine, Sucostrin, Quelicin.

Class of drug: Skeletal muscle relaxant (depolarizing).

Mechanism of action: Depolarizes motor endplate at myoneural junction, preventing stimulation by endogenous acetylcholine.

Indications/dosage/route: IV, IM.

• Skeletal muscle paralysis after induction of anesthesia for surgical procedures Ð Adults: Short procedures: IV or IM 0.3–1.1 mg/kg over 10–30 seconds. Maintenance: 0.04–0.07 mg/kg q5–10min.

Maximum: 150 mg. Ð Infants: IV 1–2 mg/kg. Maintenance: 0.3–0.6 mg/kg q5– 10 min. – Older children, adolescents: 1 mg/kg IV or 3-4 mg/kg IM. Maximum 150 mg.

Note: Succinylcholine should be reserved for use in children who require emergency intubation, who do not have an accessible vein, and for whom an airway can be readily secured.

Adjustment of dosage

• Kidney disease: Use with caution; may precipitate hyperkalemia in renal failure patients.

• Liver disease: Use cautiously, high risk for side effects; reduce dose.

• Elderly: Use with caution.

• Pediatric: See above.

Pregnancy: Category C.

Lactation: No data available; best to avoid.

Contraindications: Hypersensitivity to succinylcholine, low plasma pseudocholinesterase (hepatocellular disease), atypical plasma cholinesterase, malnutrition, severe anemia, severe burns, cancer, dehydration, collagen diseases, family or personal history of acute malignant hyperthermia, acute narrow-angle glaucoma, myopathies (high serum creatinine phosphokinase), penetrating eye injuries, multiple traumas, denervation of skeletal muscle (due to CNS injury).

Warnings/precautions

• Use with caution in patients undergoing cesarean section; in patients with kidney and severe liver disease, respiratory depression, severe anemia, severe burns, hyperkalemia, cerebrovascular accident, myasthenia gravis, thyroid disorders, porphyria, eye surgery, pheochromocytoma, chronic abdominal infection, subarchnoid hemorrhage, degenerative neuromuscular disease, patients receiving cardiac glycosides, fractures, dislocations; and in patients recovering from severe trauma.

• Patient should be premedicated with atropine or scopolamine to prevent excessive salivation.

• Neostigmine or pyridostigmine should be available to counteract neuromuscular blockade after drug is stopped.

• Patient is fully conscious and thus aware of surroundings, including conversations.

• Tachyphylaxis may occur with continuous infusion or repeated administration. It is preferable to administer the drug by continuous infusion rather than fractional doses to minimize tachyphylaxis.

• Atest dose of succinylcholine may be administered initially to determine the degree of sensitivity of the patient as well as recovery time. This test dose should consist of 5–10 mg or 0.1 mg/kg.

• Patient with fracture or muscle spasm may experience additional trauma because of muscle fasciculations. Administer tubocurarine to prevent this.

Adverse reactions

• Common: muscle fasciculations, postoperative muscle pain, increased intraocular pressure, hypertension, salivation.

• Serious: malignant hyperthermia, bradycardia, hypotension, tachycardia, arrthymias, cardiac arrest, hyperkalemia, severe prolonged neuromuscular blockade, severe prolonged respiratory depression or apnea.

Clinically important drug interactions: Drugs that increase effects/toxicity of succinylcholine: cholinesterase inhibitors, oral contraceptives, cyclophosphamide, thiotepa, inhalation anesthetics, aminoglycosides, tetracyclines, vancomycin, cyclosporine, isofluorophate, echothiophate, aminoglycosides, clindamycin, quinidine, procainamide, blockers, lithium, non-potassiumsparing diuretics, opioids, digitalis glycosides.

Parameters to monitor

• Signs and symptoms of toxicity, particularly in those with low plasma pseudocholinesterase activity.

• Respiratory status continuously. If respirations do not return in a few seconds after discontinuing administration, use of oxygen is necessary.

• Neuromuscular response using a peripheral nerve stimulator.

Responses should be determined during and after surgery to monitor efficacy and recovery.

• Cardiovascular status throughout. Monitor for bradycardia, arrhythmias, hypotension.

• Signs of malignant hyperthermia: muscle spasm, particularly of the jaw, loss of laryngeal relaxation, hyperthermia, unstable BP, tachyarrthymias, hypercarbia. Hyperthermia is a late manifestation. Stop infusion if these symptoms are noted.

• Electrolytes: calcium and in particular potassium for hyperkalemia. This is especially necessary for patients with severe trauma or burns.

• Signs and symptoms of increased intraocular pressure. This is usually transient; if it persists this could be dangerous to the eyes.

Editorial comments

• Succinylcholine should be used only by individuals who are well versed and experienced in endotracheal intubation. Equipment for intubation should be available immediately if needed.

• Succinylcholine has no effect on pain threshold. If a painful or long procedure is anticipated, an analgesic must be administeredalong with succinylcholine. A benzodiazepine or conventional analgesic should be used.

Carbenicillin

Brand name: Geocillin.

Class of drug: Antibiotic, penicillin family, carboxypenicillin.

Mechanism of action: Inhibits bacterial cell wall synthesis.

Susceptible organisms in vivo: Staphylococci, Streptococcus pneumoniae, beta-hemolytic streptococci, Escherichia coli, Proteus mirabilis, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Enterobacter sp, Pseudomonas aeruginosa.

Is destroyed by B-lactamases.

• Less effective than ampicillin against Streptococcus pyogenes (Group A), Streptococcus pneumoniae, Enterococcus faecalis.

Most Staphylococcus aureus are resistant. Inactive against Klebsiella.

Indications/dosage/route: Oral only (to treat UTI and prostatitis due to aerobic gram-negative bacteria).

• UTIs due to Escherichia coli, Proteus Ð 382-764 mg q.i.d.

• UTIs caused by Pseudomonas, enterococci Ð 764 mg q.i.d.

• Prostatitis caused by E. coli, Proteus mirabilis, Enterobacter, enterococci Ð 764 mg q.i.d.

Adjustment of dosage

• Kidney disease: creatinine clearance 10–20 mL/min: dosage adjustment may be necessary, exact guidelines are not available; creatinine clearance 10 mL/min: therapeutic urine levels will not be achieved.

• Liver disease: Increase dosage.

• Elderly: None.

• Pediatric: Safety and efficacy have not been established.

Food: Take on empty stomach, 1 hour before or 2 hours after eating.

Pregnancy: Category B.

Lactation: No data available. Best to avoid.

Contraindications: Hypersensitivity to penicillin or cephalosporins.

Editorial comments: This was the first penicillin with activity against Pseudomonas aeruginosa. It is not used frequently because other more effective drugs are available. Oral carbenicillin is currently used to treat UTIs and prostatitis. The parenteral form is no longer available in the United States. In general, carbenicillin is not used in patients with kidney disease because of the requirement for large doses, increased toxicity, and the availability of better alternatives.

Editorial comments

• Oral first-generation cephalosporins are used for Staphylococcus aureus and streptococcal infection when penicillins are to be avoided, generally due to rash. Common uses are cellulitis, other infections of the skin, osteomyelitis, streptococcal pharyngitis.

They should not be used for sinusitis, otitis media, or lower respiratory infections because of poor coverage of Strepto-coccus pneumoniae and especially Moraxella catarrhalis and Hemophilus influenzae. They are not suitable coverage for bite

wounds as they do not cover Pasteurella multocida.

Cefazolin

Brand name: Ancef.

Class of drug: Cephalosporin, first generation, parenteral.

Mechanism of action: Binds to penicillin-binding proteins and disrupts or inhibits bacterial cell wall synthesis.

Susceptible organisms in vivo: Very effective against staphylococci and streptococci, potentially active against Streptococcus pneumoniae, active against enterococci. Not effective against MRSA. Gram-negative spectrum is limited to communityacquired Escherichia coli, Moraxella catarrhalis, indolenegative Proteus mirabilis, and some Klebsiella pneumoniae. Not useful against nosocomial gram-negative oral anaerobes.

Mechanism of action: Binds to penicillin-binding proteins and disrupts or inhibits bacterial cell wall synthesis.

Susceptible organisms in vivo

• Gram positive: excellent against streptococci and Streptococcus pneumoniae. Does not cover staphylococci and Enterococcus.

• Gram negative: excellent against Neisseria meningitidis, Neisseria gonorrhoeae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella.

Indications/dosage/route: IV or IM.

• General infections

Ð Adults: IV, IM 1–2 g/d q24h. Maximum: 4 g/d.

Ð Children, other than meningitis: IV, IM 50–75 mg/d in divided

doses. Maximum: 2 g/d.

• Meningitis

Ð Adults: IV, IM 2 g/d q12h (or 1 g/d q12h).

Ð Children: IV, IM 100 mg/kg/d, once daily or 2 doses/d.

Maximum: 4 g/d. Usual duration of therapy: 7–14 days.

• Serious miscellaneous infections other than meningitis including skin and skin structure infections

Ð Children: IV, IM 50–75 mg/kg/d, divided doses q12h. Maximum:

2 g/d.

• Acute otitis media (bacterial)

Ð Children: IM 50 mg/kg as single dose. Maximum: 1 g.

Ð Uncomplicated gonorrhea

Ð Adults: IM 250 mg as single dose.

Adjustment of dosage: None.

Food: Not applicable.

Pregnancy: Category B.

Lactation: Appears in breast milk. American Academy of Pediatrics considers cephalosporins to be compatible with breastfeeding.

Contraindications: Hypersensitivity to other cephalosporins or related antibiotics, eg, penicillin.

Warnings/precautions

• Use with caution in patients with the following conditions:

kidney disease, penicillin allergy, elderly.

• Avoid in orthotopic liver transplant because of the risk of biliary sludge formation.

• It is recommended to continue therapy for at least 2–3 days after symptoms are no longer present. For group A beta-hemolytic streptococcal infections, therapy should be continued for 10 days.

• Before use, determine if patient had previous hypersensitivity reaction to cephalosporins or penicillins. Incidence of cross-sensitivity to penicillins is 1–16%. Anegative response to penicillin does not preclude allergic reaction to a cephalosporin.

•Watch bilirubin levels if the use is prolonged.

Advice to patient: None.

Adverse reactions

• Common: None.

• Serious: hepatitis, hypersensitivity reactions, pseudomembranous colitis, nephrotoxicity, bone marrow suppression, hemolytic anemia.

Clinically important drug interactions

• Drug that increases effects/toxicity of ceftriaxone: probenecid.

• Ceftriaxone increases effects/toxicity of following drugs: aminoglycosides, loop diuretics.

Parameters to monitor

• CBC with differential and platelets, serum BUN and creatinine, liver enzymes.

• Temperature for sign of drug-induced persistent fever.

• Signs and symptoms of antibiotic-induced bacterial or fungal superinfection.

• Signs and symptoms of renal toxicity.

• Signs and symptoms of fluid retention, particularly in patients receiving sodium salts of cephalosporins.

Editorial comments

• Uses for ceftriaxone are as follows: Acute bacterial meningitis: effective against Neisseria meningitidis, Hemophilus influenzae, and, most importantly, Streptococcus pneumoniae even wheot susceptible to penicillin. It does not cover Listeria.

Community-acquired pneumonia: effective against all important pathogens other than atypical organisms for which a macrolide or a quinolone is added (Legionella, Mycloplasma, Chlamydia).  Nosocomial infection, eg, pneumonia; not recommended as monotherapy because of resistance from Pseudomonas aeruginosa and ESBL-producing Enterobacteriaceae.

• Agreat advantage of ceftriaxone is once-a-day use (other than in meningitis). It is therefore often used for home IV infusion.

Mechanism of action: Binds to penicillin-binding proteins and disrupts or inhibits bacterial cell wall synthesis.

Susceptible organisms in vivo: Staphylococcus aureus, Streptococcus pneumoniae, beta-hemolytic streptococci, gram-negative organisms (especially Hemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Proteus mirabilis, Klebsiella, Citrobacter, Morganella, Neisseria gonorrhoeae, Neisseria meningitidis.

Tetracycline (INN) /ˌtɛtrəˈsaɪkliːn/ is a broad-spectrum polyketide antibiotic produced by the Streptomyces genus of Actinobacteria, indicated for use against many bacterial infections. It is a protein synthesis inhibitor. It is commonly used to treat acne today, and, more recently, rosacea, and is historically important in reducing the number of deaths from cholera. Tetracycline is marketed under the brand names Sumycin, Tetracyn, and Panmycin, among others. Actisite is a thread-like fiber formulation used in dental applications. It is also used to produce several semisynthetic derivatives, which together are known as the tetracycline antibiotics. The term “tetracycline” is also used to denote the four-ring system of this compound; “tetracyclines” are related substances that contain the same four-ring system.

Contents

• 1 Mechanism of action

• 2 Spectrum of bacterial susceptibility and resistance

• 2.1 Mechanisms of Resistance

• 3 History

• 4 Cautions, contraindications, side effects

• 5 Indications

• 6 Other uses

• 7 Cell culture

• 8 Notes

• 9 External links

Mechanism of action

Tetracycline binds to the 30S subunit of microbial ribosomes. It inhibits protein synthesis by blocking the attachment of charged aminoacyl-tRNA to the A site on the ribosome. Thus, it prevents introduction of new amino acids to the nascent peptide chain.^[1] The action is usually inhibitory and reversible upon withdrawal of the drug. Mammalian cells are less vulnerable to the effect of tetracyclines, despite the fact that tetracycline binds to the small ribosomal subunit of both prokaryotes and eukaryotes (30S and 40S respectively). This is because bacteria actively pump tetracycline into their cytoplasm, even against a concentration gradient, whereas mammalian cells do not. This accounts for the relatively small off-site effect of tetracycline on human cells.^[2]

Spectrum of bacterial susceptibility and resistance

Tetracyclines have a broad spectrum of antibiotic action. Originally, they possessed some level of bacteriostatic activity against almost all medically relevant aerobic and anaerobic bacterial genera, both Gram-positive and Gram-negative, with a few exceptions, such as Pseudomonas aeruginosa and Proteus spp., which display intrinsic resistance. However, acquired (as opposed to inherent) resistance has proliferated in many pathogenic organisms and greatly eroded the formerly vast versatility of this group of antibiotics. Resistance amongst Staphylococcus spp., Streptococcus spp., Neisseria gonorrhoeae, anaerobes, members of the Enterobacteriaceae and several other previously sensitive organisms is now quite common. Tetracyclines remain especially useful in the management of infections by certain obligately intracellular bacterial pathogens such as Chlamydia, Mycoplasma and Rickettsia. They are also of value in spirochaetal infections, such as syphilis, leptospirosis and Lyme disease. Certain rare or exotic infections, including anthrax, plague and brucellosis, are also susceptible to tetracyclines. These agents also have activity against certain eukaryotic parasites, including those responsible for diseases such as malaria and balantidiasis.

Mechanisms of Resistance

Bacteria usually acquire resistance to tetracycline from horizontal transfer of a gene that either encodes an efflux pump or a ribosomal protection protein. Efflux pumps actively eject tetracycline from the cell, preventing the buildup of an inhibitory concentration of tetracycline in the cytoplasm.^[3] Ribosomal protection proteins interact with the ribosome and dislodge tetracycline from the ribosome, allowing for translation to continue.^[4]

History

The tetracyclines, a large family of antibiotics, were discovered as natural products by Benjamin Minge Duggar in 1945 and first prescribed in 1948.^[5] Under Yellapragada Subbarao, Benjamin Duggar made his discovery of the first tetracycline antibiotic, chlorotetracycline (Aureomycin), at Lederle Laboratories in 1945.^[6]

In 1950, Harvard University professor Robert Burns Woodward determined the chemical structure of the related substance, oxytetracycline (Terramycin); the patent protection for its fermentation and production was also first issued in 1950. A research team of seven scientists (K.J. Brunings, Francis A. Hochstein, C.R. Stephens, Lloyd Hillyard Conover, Abraham Bavley, Richard Pasternack, and Peter P. Regna) at Pfizer,^[7][8] in collaboration with Woodward, participated in the two-year research leading to the discovery.^[9]

Pfizer was of the view that it deserved the right to a patent on tetracycline and filed its Conover application in October 1952. Cyanamid filed its Boothe-Morton application for similar rights in March 1953, while Heyden Chemicals filed its Minieri application in September 1953, named after scientist P. Paul Minieri, to obtain a patent on tetracycline and its fermentation process. This resulted in tetracycline litigation in which the winner would have to prove beyond reasonable doubt of priority invention and tetracycline’s natural state.^[10]

Nubian mummies studied in the 1990s were found to contain significant levels of tetracycline; the beer brewed at the time could have been the source.^[11] Tetracycline sparked the development of many chemically altered antibiotics, so has proved to be one of the most important discoveries made in the field of antibiotics.^{[citation needed]} It is used to treat many Gram-positive and Gram-negative bacteria.^{[citation needed]} Like some other antibiotics, it is also used in the treatment of acne.

Cautions, contraindications, side effects

See also: List of dental abnormalities associated with cutaneous conditions

Use of the tetracycline antibiotics group is problematic; they can:^{[citation needed]}

• Stain developing teeth (even when taken by the mother during pregnancy)

• Discolor permanent teeth (yellow-gray-brown), from infancy and childhood to eight years old

• Be inactivated by Ca²⁺ ion, so are not to be taken with milk, yogurt, and other dairy products

• Be inactivated by aluminium, iron and zinc, not to be taken at the same time as indigestion remedies (common antacids and over-the-counter heartburn medicines)

• Cause skin photosensitivity. so exposure to the sun or intense light is not recommended

• Cause drug-induced lupus, and hepatitis

• Cause microvesicular fatty liver

• Cause tinnitus

• Suppress sperm production.^[12]

• Interfere with methotrexate by displacing it from the various protein binding sites

• Cause breathing complications, as well as anaphylactic shock, in some individuals

• Affect bone growth of the fetus, so should be avoided during pregnancy

Caution should be exercised in long-term use with breastfeeding. Short-term use is safe; bioavailability in milk is low to nil.^[13] In 2010, the FDA added tetracycline to its Adverse Event Reporting System (AERS).^[14] The AERS contains a list of medications under investigation by the FDA for potential safety issues. The list is published quarterly and available online. The AERS cites a potential link between the use of tetracycline products and Stevens–Johnson syndrome, toxic epidermal necrolysis and erythema multiforme.^[14]

Indications

It is first-line therapy for Rocky Mountain spotted fever (Rickettsia), Lyme disease (B. burgdorferi), Q fever (Coxiella), psittacosis and lymphogranuloma venereum (Chlamydia), and to eradicate nasal carriage of meningococci. Tetracycline tablets were used in the plague outbreak in India in 1992.^[15]

Other uses

Since tetracycline is absorbed into bone, it is used as a marker of bone growth for biopsies in humans. Tetracycline labeling is used to determine the amount of bone growth within a certain period of time, usually a period of approximately 21 days. Tetracycline is incorporated into mineralizing bone and can be detected by its fluorescence.^[16] In “double tetracycline labeling”, a second dose is given 11–14 days after the first dose, and the amount of bone formed during that interval can be calculated by measuring the distance between the two fluorescent labels.^[17]

Tetracycline is also used as a biomarker in wildlife to detect consumption of medicine- or vaccine-containing baits.^[18]

In genetic engineering, tetracycline is used in transcriptional activation. It is also one of the antibiotics used to treat ulcers caused by bacterial infections. In cancer research at Harvard Medical School, tetracycline has been used to switch off leukemia in genetically altered mice, and to do so reliably, when added to their drinking water.^[19]

A technique being developed for the control of the mosquito species Aedes aegypti uses a strain that is genetically modified to require tetracycline to develop beyond the larval stage. Modified males raised in a laboratory will develop normally as they are supplied with this chemical and can be released into the wild. Their subsequent offspring will inherit this trait, but will find no tetracycline in their environment and so will never develop into adults.^[20]

The Clinical Use of Antibiotics in Combination

The recent appearance on the market of preparations containing two antibiotics in the same capsule calls for an appraisal of the rationale of such therapy. Theoretical or practical reasons for administering more than one antibiotic to a patient at one time are as follows:

1.     A second antibiotic may delay the emergence of bacteria resistant to the first antibiotic.

2.     Two antibiotics may be synergistic with one another.

3.     In the initial emergency treatment of seriously ill patients where the establishment of an etiological diagnosis and appropriate antibiotic sensitivity tests may be delayed, two or more drugs may properly be used as “insurance.”

4.     Mixed infections caused by more than one micro-organism may be better treated by antibiotics found most effective against each one.

5.     Reduction of dosage of each of two “additive” drugs may result in lowered incidence of toxic effects to each, as in the case of streptomycin-dihydrostreptomycin.

The emergence of streptomycin-resistant tubercle

 

1.     http://www.youtube.com/watch?v=RedO6rLNQ2o&feature=related

2.     2 http://www.youtube.com/watch?v=SqRVLIPof90&feature=related

3.     http://www.youtube.com/watch?v=sMp-y8qx9D0&feature=related

4.     http://www.youtube.com/watch?v=yG2PWCJnX2Q&feature=related

5.     http://www.apchute.com/moa.htm