The cell wall provides protection and structure to bacteria.  It is composed primarily of proteoglycans that are, in turn, composed of glycopeptide polymers.  The terminal steps in the synthesis of the cell wall includes the incorporation of D-alanine into the polymer and cross-linking between the polymers by the enzyme transpeptidase, as illustrated below.

While the cell walls of bacteria are synthesised by similar mechanisms, there are differences in the cell walls of Gram positive vs. Gram negative bacteria.  The cell wall of Gram positive organisms is composed of approximately 50 layers of glycoproteins that provide the outer surface of the organism.  The cell wall of Gram negative organisms is only 2 to 3 layers thick, but includes a second bilayer lipid membrane on the outer portion of the cell.  This is NOT the cell membrane (it is beneath the glycoprotein layer of the cell wall) but is part of the cell wall of the bacteria, as illustrated below.

In both types of bacteria, there are several integral proteins in the cell membrane that provide numerous functions.  Included in the actions of these proteins are the following

1) Transpeptidase activity -- as described above, this permits cross-linking in the formation of the cell wall -- inhibition of this action will reduce the structural and functional integrity of the cell wall.

2) Contribute to the shape of the bacteria (i.e. rod, coccus, et c.) -- inhibition of this action will also reduce the structural integrity of the organism.

3) Contribute to septum formation during replication/division -- inhibition of this action will decrease the viability of daughter cells of the bacteria.

4) Inhibition the action of autolysin (an enzyme that causes destruction of the bacteria) -- inhibition of this action will allow autolysin to proceed, resulting in cell death.

Resistance to Antibiotic Action --

Bacteria may be or develop resistance to specific antibiotics by a variety of mechanisms.The structure of the cell wall may provide resistance to drug effect.  As an example, consider the Gram negative bacteria.  With their extra lipid bilayer, many antibiotics may not reach the sites of action (transpeptidase and the PBP).  Therefore any antibiotic drug that is not lipid soluble enough to traverse the outer lipid bilayer AND small enough to traverse the porin channel (illustrated above) will have no effect on the microorganism.  Alternately, a small drug with suitable solubility profile may pass through the porin channel and exert an antibacterial effect.

The PBP may also undergo modification, decreasing the binding affinity for the antibiotic.  As this occurs, the efficacy that these agents possessed will be lost.  This is generally accomplished by the bacteria modifying the protein characteristics of the PBP, preserving their function but decreasing the ability of the antibiotic to bind to and inhibit it.

The production of beta-lactamase, a specific enzyme that destroys the antibiotic before it may exert its effect.  As the bacteria multiply and evolve, they may become capable of producing more of this enzyme.  NOTE that there is a difference in the beta-lactamase producing ability between Gram positive and Gram negative bacteria.  Gram positive organisms typically secrete large quantities of the enzyme to the outer portion of the cell wall, inactivating the drug before it reaches the site of action.  Gram negative bacteria secrete smaller amounts of the enzyme into the space between the cell membrane and the cell wall (as illustrated above).  NOTE ALSO that the beta-lactamase may exhibit preferential activity against penicillins (penicillinase) or cephalosporins (cephalosporinase) OR it may act to destroy either class.

Older Penicillins -- Penicillin G and Penicillin V
Spectrum of Activity -- These agents are effective against Gram + aerobic organisms including Streptococcus, Neisseria gonorrhœa, and the anaerobic Clostridium spp.  Extensive resistance has developed to the efficacy of the these agents.

Therapeutic Uses -- Susceptible forms of Streptococcal pneumonia, gonorrhœa and syphilis, anthrax, rat bite fever, and numerous other infections including respiratory tract, urinary tract, and soft tissue infections.

Penicillinase-Resistant Penicillins -- Oxacillin, Cloxacillin, Dicloxacillin, Methicillin, and Nafcillin.
Spectrum -- These agents are effective against Staphylococcus spp. that produce beta-lactamase (penicillinase).  They are NOT as effective against the other organisms that older penicillins are effective against.  NOTE that there are numerous strains that are now resistant to these agents -- so-called methicillin-resistant staph.

Therapeutics -- These agents are typically used only in skin infections caused by susceptible organisms.

Aminopenicillins -- Ampicillin, Amoxicillin, Bacampicillin (a pro-drug, converted in vivo to ampicillin)
Spectrum -- These penicillins are more effective against Gram negative organisms than the older drugs of the class.  These include Hæmophilus influenzæ (H. flu), Escherichia coli, and Proteus mirabilis.

Therapeutics -- These penicillins are most often used in the treatment of urinary tract infections (UTI), respiratory tract infections (RTI), and otitis media (OM) caused by susceptible organisms.

Extended Spectrum Penicillins -- Carbenicillin, Ticarcillin, Mezlocillin, and Piperacillin
Spectrum -- These agents are more active against Gram negative and anærobic organisms including Pseudomonas spp., Enterobacter spp., and Proteus spp.  Mezlocillin and Piperacillin show the greatest activity against Pseudomonas and Klebsiella spp.

Therapeutics -- The extended spectrum penicillins are used primarily in the treatment of infections caused by susceptible organisms, often associated with bacteræmia and burns.


Adverse Effects of the Penicillins -- The most life threatening adverse effects of the penicillins occurs in those patients that develop allergies to them.  The type of reaction in truly allergic patients may range from rash, fever, through broncospasm, vasculitis, serum sickness, exfoliative dermatitis, and Steven-Johnson Syndrome to anaphylaxis.  Allergic reactions occur in 0.7-20% of patients taking penicillins (the exact number is not known, due to the often erroneous reporting of GI upset as "allergy") and anaphylactic reactions result in as many as 300 deaths per year.  More common side effects include nausea, vomiting, and diarrhœa.  Taking the medication with food will decrease these side effects but also limits the absorption of the drug.  Therefore, penicillins should be taken on an EMPTY stomach (with the exception of amoxicillin and bacampicillin, with may be taken with food).  Another effect that must be observed for is the elimination of susceptible intestinal microflora that allows the overgrowth of resistant organisms, primarily Clostridium difficile, causing severe, life-threatening diarrhœa in a condition known as pseudomembranous colitis.

First Generation -- Cefazolin (highly susceptible to beta-lactamase), Cephalothin, Cephalexin, Cephradine, Cefadroxil
Spectrum -- These agents show good Gram positive activity and relatively good Gram negative activity.  They are NOT effective against methicillin-resistant Staph.
Second Generation -- Cefamandole, Cefaclor, Loracarbef, Cefuroxime, Cefonicid, Cefprozile, Ceforanide, Cefoxitin, Cefotetan, and Cefmetazole
Spectrum -- The second generation cephalosporins are more effective against Gram negative organisms (but less effective against Gram positive bacteria) including Enterobacter, Klebsiella, Hæmophilus, and Proteus spp.  Additionally, cefoxitin, cefotetan, and cefmetazole are effective against Bacteroides spp.
Third Generation Cephalosporins -- Cefotaxime, Moxalactam, Ceftizoxime, Ceftriaxone, Cefixime, Cefpodoxime, Ceftazidime, and Cefoperazone
Spectrum -- The third generations show even greater Gram negative (and less Gram positive) activity and are more resistant to the effects of beta-lactamase.  Ceftazidime and Cefoperazone are also effective against the anærobe Pseudomonas.
Fourth Generation -- Cefepime
Spectrum -- Similar to the third generation cephalosporins but even more resistant to beta-lactamase activity.

Adverse Effects -- Hypersensitivity (there is some cross-sensitivity with the penicillins, with 1-20% of patients exhibiting sensitivity to both classes).  These agents may also suppress bone marrow resulting in granulocytopænia (relatively rare).  Additionally, vitamin K dependent bleeding disorders have been reported with moxalactam.  The cephalosporins may also be nephrotoxic (cephaloridine is the worst offender) which is additive with the aminoglycoside antibiotics (refer to section below).

Mechanism of Action -- These agents act in a manner identical to the penicillins and cephalosporins.  Imipenem is given with the agent cilastatin.  Imipenem is rapidly metabolised by renal dehydropeptidases.  Cilastatin inhibits this renal metabolism, allowing renal reabsorption and an extended half-life of the drug.  Meropenem demonstrated a long half-life with higher blood levels and therefore does not require the co-administration of cilastatin.

Spectrum/Activity -- The spectrum of  the carbapenems is similar to the beta-lactam antibiotics.  They are extremely resistant to the actions of beta-lactamase, however they are not overly effective against methicillin resistant staph. Meropenem shows slightly greater activity against Gram negative and slightly less activity against Gram positive organisms, relative to imipenem.

Therapeutics -- Imipenem/Cilastin  and meropenem are used in the treatment of UTI, lower RTI, gynecological infections, and soft tissue infections caused by susceptible organisms.

Adverse Effects -- Imipenem may cause nausea, vomiting, and rarely, seizures at high doses.  Meropenem is less likely to cause seizures.

Mechanism -- Similar to beta-lactams

Spectrum -- Aztreonam has little Gram positive and anærobic activity but is highly effective against Gram negative organisms, especially H. flu, gonococcus, Enterobacter spp. and Pseudomonas spp. (Anærobic).

Adverse Effects -- Aztreonam is generally well tolerated with minimal side effects.  There is no cross sensitivity with the beta lactam antibiotics.

Other Inhibitors of Cell Wall Synthesis

Vancomycin
Mechanism of Action -- Vancomycin binds to the D-alanyl-D-alanine terminus of the glycopeptide polymer, inhibiting the loss of the terminal D-alanine, this inhibiting cross-linking and weakening the cell wall of the organism.  It is bactericidal in action.

Spectrum -- Vancomycin has activity against Gram positive organisms including those that produce penicillinase, some Gram negative and anærobic bacteria including Staphylococcus, Streptococcus, Enterococcus, Corynebacterium, and Clostridium spp.

Therapeutics -- Vancomycin is generally used only for parenteral administration (it is poorly absorbed from the GI tract) in serious infections and orally in the treatment of pseudomembranous colitis.

Adverse Effects -- Rapid infusion of intravenous vancomycin may cause the "redman" or "redneck" syndrome (also known as the vancomycin flush syndrome), characterised by flushing and hypotension with reflex tachycardia.  This is thought to be due to vancomycin-induced histamine release.  Other adverse effects include hypersensitivity, chills, fever, rash, and, at high doses, ototoxicity and nephrotoxicity.

Cycloserine -- Refer to the section on Tuberculosis

Polymixin B and Colistin (Polymixin E) -- These agents are highly nephrotoxic and are only used topically for superficial infections.

Mechanism of Action -- The polymixins bind to and disrupt cell membranes, altering the membrane permeability of the microorganism (similar to the anti-fungal effects of amphotericin).  They also bind to and inhibit the endotoxin produced by many bacteria that cause allergic/toxic reactions.

Spectrum -- These agents are effective only against Gram negative organisms, including Enterobacter spp., E. coli, Klebsiella, Salmonella, Pasteurella, Bordetella, and Shigella spp. and the anærobe Pseudomonas.

Therapeutics -- These agents are used topically to treat infections of the eye, ear, and superficial skin.

Bacitracin -- Acts in a manner similar to the polymixins, but with activity against Gram positive organisms.