In this book, the clinically useful antibacterial drugs are organized into six families: penicillins, cephalosporins, tetracyclines, aminoglycosides, macrolides, and fluoroquinolones, plus a seventh group labeled “other” used to represent any drug not included in one of the other six drug families. Here and throughout the book, these seven groups are graphically presented as a bar chart (Figure 1). The drug(s) of choice within each family that is/are used for treating a specific bacterial infection are indicated. This chapter illustrates the spectra of bacteria for which a particular class of antibiotics is therapeutically effective. The general mechanisms of action and antibacterial spectra of the major groups of antibiotics are presented below.

Fig1. Bar chart showing the most commonly used drug families. The group labeled “Other” represents drugs not included in one of the six drug families.

A. Penicillins

Penicillins are β-lactam antibiotics, named after the β-lactam ring that is essential to their activity. Penicillins selectively interfere with the synthesis of the bacterial cell wall, a structure not found in mammalian cells. Penicillins are inactive against organisms devoid of a peptidoglycan cell wall, such as mycoplasma, protozoa, fungi, and viruses. To be maximally effective, penicillins require actively proliferating bacteria, and they have little or no effect on bacteria that are not dividing. Their action is usually bactericidal . Penicillins are the most widely effective antibiotics. For example, penicillin G is the cornerstone of therapy for infections caused by several different types of bacteria (Figure 2). The major adverse reaction to penicillins is hypersensitivity. Unfortunately, many bacteria have developed resistance to these drugs.

Fig2. Summary of therapeutic applications of penicillin G.

 B. Cephalosporins

Cephalosporins are β-lactam antibiotics that are closely related both structurally and functionally to the penicillins, and they are also bactericidal. Cephalosporins have the same mode of action as the penicillins, but they tend to be more resistant than the penicillins to inactivation by β-lactamases produced by some bacteria. Cephalosporins are classified as first, second, or third generation, largely on the basis of bacterial susceptibility patterns and resistance to β-lactamases (Figure 3). In this classification system, first-generation agents are active primarily against gram-positive organisms, including methicillin-sensitive Staphylococcus aureus, and have limited activity against gram-negative bacilli. Second-generation agents have increased activity against gram-negative bacilli and variable activity against gram-positive cocci. Third-generation agents have significantly increased activity against gram-negative bacilli, with some of these agents active against Pseudomonas aeruginosa. [Note: Cefepime has been classified by some as fourth-generation because of its extended spectrum of activity against both gram-positive and gram-negative organisms that include P. aeruginosa.]

Fig3. Summary of therapeutic applications of cephalosporins. [Note: Not shown is cefepime (a fourth-generation cephalosporin) and ceftobiprole (a fifth-generation cephalosporin), which offer potential advantages over third-generation agents, particularly against organisms with inducible, chromosomal resistance.] 1[Note: Pseudomonas aeruginosa is not susceptible to ceftriaxone.]

 C. Tetracyclines

A number of antibiotics, including tetracyclines, aminoglycosides, and macrolides, exert antimicrobial effects by targeting the bacterial ribosome, which has components that differ structurally from those of the mammalian cytoplasmic ribosomes. Binding of tetracyclines to the 30S subunit of the bacterial ribosome is believed to block access of the amino acyl-tRNA to the mRNA-ribosome complex at the acceptor site, thereby inhibiting bacterial protein synthesis. Tetracyclines are broad-spectrum antibiotics (that is, many bacteria are sensitive to these drugs, Figure4). Tetracyclines are generally bacteriostatic .

Fig4. Summary of therapeutic applications of tetracyclines.

 D. Aminoglycosides

 Aminoglycosides inhibit bacterial protein synthesis. Susceptible organisms have an oxygen-dependent system that transports the antibiotic across the cell membrane. All aminoglycosides are bactericidal. They are effective only against aerobic organisms because anaerobes lack the oxygen-requiring transport system. Gentamicin is used to treat a variety of infectious diseases including those caused by many of the Enterobacteriaceae (Figure 5) and, in combination with penicillin, endocarditis caused by viridans-group streptococci.

Fig5. Summary of therapeutic applications of aminoglycosides.

E. Macrolides

 Macrolides are a group of antibiotics with a macrocyclic lactone structure. Erythromycin was the first of these to find clinical application, both as the drug of first choice and as an alternative to penicillin in individuals who are allergic to β-lactam antibiotics. Newer macrolides, such clarithromycin and azithromycin, offer extended activity against some organisms and less severe adverse reactions. The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thereby inhibiting the translocation steps of protein synthesis. Generally considered to be bacteriostatic, they may be bactericidal at higher doses (Figure 6).

Fig6. Summary of therapeutic applications of macrolides.

F. Fluoroquinolones

Fluoroquinolones uniquely inhibit the replication of bacterial DNA by interfering with the action of DNA gyrase (topoisomerase II) during bacterial growth. Binding quinolone to both the enzyme and DNA to form a ternary complex inhibits the rejoining step, and, thus, can cause cell death by inducing cleavage of the DNA. Because DNA gyrase is a distinct target for antimicrobial therapy, cross-resistance with other more commonly used antimicrobial drugs is rare but is increasing with multidrug-resistant organisms. All of the fluoroquinolones are bactericidal. Figure 7 shows some of the applications of the fluoroquinolone ciprofloxacin.

Fig7. Typical therapeutic applications of ciprofloxacin.

 G. Carbapenems

Carbapenems are synthetic β-lactam antibiotics that differ in structure from the penicillins. Imipenem, meropenem, doripenem, and ertapenem are the drugs of this group currently available. Imipenem is compounded with cilastatin to protect it from metabolism by renal dehydropeptidase. Imipenem resists hydrolysis by most β-lactamases. This drug plays a role in empiric therapy because it is active against β-lactamase–producing gram-positive and gram-negative organisms, anaerobes, and P. aeruginosa (Figure 8). Meropenem and doripenem have antibacterial activity similar to that of imipenem. However, ertapenem is not an alternative for P. aeruginosa coverage because most strains exhibit resistance. Ertapenem also lacks coverage against Enterococcus species and Acinetobacter species.

Fig8. Antimicrobial spectrum of imipenem.

 H. Other important antibacterial agents

1. Vancomycin: Vancomycin is a tricyclic glycopeptide that has become increasingly medically important because of its effective ness against multidrug-resistant organisms such as methicillin resistant staphylococci. Vancomycin inhibits synthesis of bacterial cell wall phospholipids as well as peptidoglycan polymerization at a site earlier than that inhibited by β-lactam antibiotics. Vancomycin is useful in patients with serious allergic reactions to β-lactam antibiotics and who have gram-positive infections. Vancomycin is also used for potentially life-threatening antibiotic associated colitis caused by Clostridium difficile or staphylococci. To curtail the increase in vancomycin-resistant bacteria, use of this agent should be restricted to the treatment of serious infections caused by β-lactam–resistant gram-positive microorganisms. Vancomycin is ineffective against gram-negative bacteria.

 2. Trimethoprim-sulfamethoxazole: A combination called co-trimoxazole shows greater antimicrobial activity than equivalent quantities of either drug used alone. The synergistic antimicrobial activity of co-trimoxazole results from its inhibition of two sequential steps in the synthesis of tetrahydrofolic acid: sulfamethoxazole inhibits incorporation of PABA into folic acid, and trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate. It is effective in treating urinary tract infections and respiratory tract infections as well as in Pneumocystis jiroveci pneumonia and ampicillin- and chloramphenicol-resistant systemic Salmonella infections. It has activity versus methicillin-resistant S. aureus and can be particularly useful for community acquired skin and soft tissue infections caused by this organism.

مواضيع ذات صلة

Drug Resistance

Antimicrobial Susceptibility Testing and Therapy for Bacillus and Similar Organisms

Penicillin- resistant bacteria

المضادات الميكروبية التي ترتبط الى الوحدة الرايبوسومية الكبيرة 50S

المضادات المكروبية التي ترتبط الى الوحدة الرايبوسومية الصغيرة 30S

اختبارات الحساسية للمضادات الحيوية

أوجه الشبه والاختلاف في تركيب جدار الخلية الموجبة - لغرام والسالبة – لغرام التي تؤثر على الحساسية للمضادات الحيوية

الأهداف التي تصيبها المضادات الحيوية في البكتيريا

المضادات الحيوية للبكتيرية Antibacterial Antibiotics

Ethambutol

Pyrazinamide

Isoniazid