The rest is history awakening to the possibilities and confronting the challenges

Subsequently, more broad-spectrum penicillins and other aminoglyco-sides were developed, followed by more antibiotic classes. More than 5000 antibiotics are now known. Approximately a thousand of these have been carefully investigated, and about 100 are currently used to treat infections. Most are produced by actinomycetes and bacteria, many of which are then chemically modified (semisynthetic). Others are completely synthetic.

The b-lactams

Penicillin, the prototype b-lactam, is a 6-aminopenicillanic acid consisting of a thiazolidine ring, an attached b-lactam ring, and a side chain [6]. Manipulations of the side chain have altered b-lactamase susceptibility, antibacterial spectrum, and pharmacokinetic properties. Other groups of antibacterial agents that contain the b-lactam ring include cephalosporins, carbapenems, and monobactams. In actively dividing bacteria, the b-lactams inhibit enzymes (transpeptidase, carboxypeptidase, and endopeptidase) located beneath the cell wall that are termed the "penicillin-binding proteins.'' This inhibition prevents the development of normal peptidogly-can structure, because these enzymes are involved in creating the cross-linkage between the peptide chains. Various bacteria differ in the permeability of their cell walls to antibiotics and the type and concentration of penicillin-binding proteins. Subsequent activation of the endogenous autolytic system of bacteria by b-lactams initiates cell lysis and death [7].

Penicillins

The penicillin family of antibiotics remains an important part of today's antimicrobial armamentarium. Penicillins are bactericidal against most susceptible bacteria (an important exception is Enterococcus spp) and have an excellent safety profile. The initial introduction of aqueous penicillin G for treatment of streptococcal and staphylococcal infections in 1941 to 1944 was followed by the emergence of penicillinase-producing Staphylococcus aureus. This finding prompted the development of penicillinase-resistant penicillins (methicillin, oxacillin, and nafcillin), in which an acyl side chain prevents disruption of the b-lactam ring by penicillinase. The aminopenicil-lins (ampicillin, amoxicillin, and bacampicillin) were developed because of the need for antibiotics with activity against gram-negative bacteria. Amino-penicillins initially were effective against Escherichia coli, Proteus mirabilis, Shigella spp, Salmonella spp, Hemophilus spp, and Neisseria spp. Carboxy-penicillins (carbenicillin and ticarcillin) and ureidopenicillins (mezlocillin, azlocillin, and piperacillin) offer additional activity that includes Enterobac-teriaceae, such as Klebsiella spp and Enterobacter spp, and Pseudomonas aeruginosa. Many gram-negative bacteria, including Enterobacteriaceae and Hemophilus influenzae, are now resistant to penicillins because of b-lactamase production. b-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) inhibit the non-group 1 b-lactamases of resistant bacteria. They are available as combinations of amoxicillin-clavulanate, ampicillin-sulbactam, ticarcillin-clavulanate, and piperacillin-tazobactam. The current penicillin group of drugs is ineffective against gram-negative bacteria that produce other types of b-lactamases, including extended-spectrum b-lactamases.

Cephalosporins

This large family of broad-spectrum b-lactam agents was introduced for clinical use in the 1960s [8]. They are bactericidal, with favorable pharmacokinetic profiles and low rates of drug-associated toxicity. In general, firstgeneration cephalosporins (cefazolin, cephalexin) are most active against aerobic, gram-positive cocci, including methicillin-susceptible S aureus. Second-generation cephalosporins are more active against selected gramnegative organisms, such as Klebsiella spp, E coli, and Proteus spp. Cefoxitin and cefotetan (technically cephamycins) are active against anaerobic bacteria as well. Third-generation cephalosporins are the most active against gram-negative aerobic organisms. From this group, ceftazidime and, to a lesser extent, cefoperazone are active against P aeruginosa. Cefepime, classified as a fourth-generation cephalosporin, has an extended spectrum of activity against both gram-positive and gram-negative organisms, including P aeruginosa.

Carbapenems

Carbapenems are a class of b-lactam antibiotics with a broad spectrum of activity against aerobic and anaerobic gram-positive and gram-negative organisms [9]. Imipenem in combination with cilastatin became available in 1985 and meropenem in 1996. With the exception of enterococci, carbapenems are bactericidal against susceptible bacteria. The spectrum of activity of carbapenems includes streptococci, methicillin-susceptible staph-ylococci, Neisseria spp, Haemophilus spp, anaerobes, and aerobic gramnegative pathogens, including P aeruginosa. Stenotrophonomas maltophilia is typically resistant to carbapenems. Imipenem is more active against gram-positive cocci in vitro, and meropenem has better in vitro activity against gram-negative bacilli. A third carbopenem, ertapenem, has become available recently; however, it does not have activity against P aeruginosa or enterococci.

Monobactams

The only available monobactam, aztreonam, is a synthetic compound with a b-lactam ring that is activated by its sulfonic acid group [9]. Because of the lack of affinity for the penicillin-binding proteins of gram-positive and anaerobic bacteria, the antibacterial spectrum of aztreonam is limited to aerobic gram-negative bacilli, similar to that of aminoglycosides. However, it is not nephrotoxic and is only weakly immunogenic. Therefore, aztreo-nam, in susceptible bacteria, is a useful nonnephrotoxic alternative to the aminoglycosides and may be used with caution in patients with significant penicillin hypersensitivity reactions.

The aminoglycosides

The first aminoglycoside, streptomycin, was introduced in 1942 for treatment of tuberculosis [10]. It was followed by the availability of neomycin, which has formidable toxicity and is not useful for systemic therapy. Kana-mycin, isolated in 1957, was the aminoglycoside of choice until gentamicin became available in 1963. Gentamicin provided a breakthrough in the therapy for infections caused by aerobic gram-negative bacilli, including P aeruginosa. Tobramycin, amikacin, and netilmicin became available in 1968, 1972, and 1975, respectively. Dibekacin, sisomicin, and isepamicin are not available in the United States.

The aminoglycosides bind irreversibly to the 30S bacterial ribosomes and inhibit protein synthesis. The irreversible binding may explain the bactericidal effect of aminoglycosides as compared with other inhibitors of protein synthesis. Low pH and anaerobic conditions inhibit an energy- and oxygen-dependent transport mechanism, which is an essential prelude to the binding of aminoglycosides to ribosomes. When such conditions exist within a focus of infection (such as purulence, abscess formation), the activity of aminogly-cosides is limited. The uptake of aminoglycosides is facilitated in the presence of inhibitors of cell-wall synthesis (ie, b-lactams and glycopep-tides). Aminoglycosides demonstrate concentration-dependent killing and a prolonged postantibiotic effect. The postantibiotic effect leads to continued bacterial killing even after serum concentrations fall below the minimum inhibitory concentrations. Aminoglycosides are useful in the treatment of infections caused by aerobic gram-negative bacilli (including P aeruginosa), particularly in combination with ß-lactams. Most institutions have noted little change in the patterns of aminoglycoside resistance among gramnegative bacilli, despite alarming increases in aminoglycoside-resistant enterococci. Amikacin may be active against gentamicin-resistant gramnegative bacilli and is useful in the treatment of infections caused by Nocardia and nontuberculous mycobacteria. Streptomycin is an important agent for the treatment of infections due to multidrug-resistant Mycobacterium tuberculosis and may be useful in the treatment of some gentamicin-resistant enter-ococccal infections.

The macrolides and ketolides

The prototype macrolide, erythromycin derived from Streptomyces eryth-rus, became available in the 1950s [11]. Macrolides inhibit RNA-dependent protein synthesis by reversibly binding to the 50S ribosomal subunit of susceptible organisms. They inhibit bacterial growth by inducing dissociation of peptidyl transfer RNA from the ribosome during the elongation phase. In general macrolides are bacteriostatic, although bactericidal activity may occur under certain conditions or against specific micro-organisms. Erythromycin is active against streptococci, including group A ß-hemolytic streptococci and Streptococcus pneumoniae, methicillin-susceptible staphylo-cocci, Treponema pallidum, Ureaplasma urealyticum, Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia spp, some strains of Rickettsia, Neisseria meningitidis, Neisseria gonorrhoeae, Bordetella pertussis, and Campylobacter jejuni. The two new macrolides, clarithromycin and azithromy-cin, are more stable, have a longer half-life, and are better tolerated than erythromycin. The new macrolides have a broader antimicrobial spectrum than erythromycin against Mycobacterium avium complex, other nontuber-culous mycobacteria, H influenzae, and Chlamydia trachomatis.

Ketolides are a new class of macrolides with activity against gram-positive organisms (S pneumoniae and Streptococcus pyogenes) that are resistant to macrolides [12]. The ketolides have a higher (10- to 100-fold) affinity for the ribosome binding site (domain V) than does erythromycin. In addition, they bind to domain II of the 23SrRNA, do not induce methylase production, and resist active drug efflux. Because of these attributes, the ketolides are able to overcome both low-level and high-level resistance to macrolides. Telithromycin, a ketolide and a semisynthetic derivative of erythromycin, became available in 2005 for treatment of community-aquired pneumonia, acute exacerbation of chronic bronchitis, and acute sinusitis.

The tetracyclines

Aureomycin, the first tetracycline, was discovered by Duggar in 1948 [13]. After amoxicillin and erythromycins, tetracyclines remain the most widely prescribed antibiotic class in the world. Tetracycline, oxytetracycline, doxycycline, minocycline, and demeclocycline are available in the United States. The low cost, reduced toxicity, and superior pharmacokinetic properties of doxycycline make it the agent of choice among tetracyclines. Tetra-cyclines inhibit protein synthesis by reversible binding to the 30S ribosome and by blocking the attachment of transfer RNA to an acceptor site on the messenger RNA ribosomal complex. These agents are generally bacterio-static against a wide array of aerobic and anaerobic bacteria, including many Rickettsiae, Chlamydiae, mycoplasmas, spirochetes, mycobacteria, and some protozoa. Minocycline and doxycycline have excellent in vitro inhibitory activity against staphylococci, including methicillin-resistant S aureus, Staphylococcus epidermidis, and Mycobacterium spp, including M marinum, M fortuitum, and M chelonei. In contrast to other tetracyclines, the dose of doxycycline and minocycline does not need to be adjusted in patients who have renal dysfunction. Both are eliminated through the hepatobiliary and gastrointestinal tracts.

The lincosamides

Lincomycin was first isolated from Streptomyces lincolnesis in 1962. Clin-damycin, a derivative of lincomycin with better absorption and improved antibacterial activity, was introduced in 1966 [14]. The lincosamides inhibit bacterial protein synthesis by reversible binding to the 50S ribosomal subunit. The macrolides and chloramphenicol also act at this site and can be antagonistic to each other and to lincosamides. Clindamycin facilitates op-sonization, phagocytosis, and intracellular killing of bacteria. It has also been found to interfere with biofilm formation associated with device-related infection and chronic infections like osteomyelitis. Clindamycin is active against anaerobic gram-positive and gram-negative organisms, with the exception of Clostridium difficile and Fusobacterium varium. Aerobic gram-positive organisms except enterococci are also susceptible to clinda-mycin. All aerobic gram-negative organisms should be considered resistant to clindamycin. Clindamycin-susceptible organisms that are resistant to erythromycin can rapidly become resistant to clindamycin because of the macrolide-lincosamide-streptogramin cross-resistance mechanism.

Trimethoprim-sulfamethoxazole

The combination of trimethoprim (TMP) with sulfamethoxazole (SMX) was widely used before it became available in the United States in 1974 [15]. SMX, like all sulfonamides, is a structural analogue of p-aminobenzoic acid (PABA), which bacteria use to initiate the synthesis of folic acid. Bacterial dihydropteroate synthetase is the enzyme involved in incorporating PABA into dihydrofolic acid and is competitively inhibited by SMX. Dihydrofolate reductase then converts dihydrofolic acid to tetrahydrofolic acid, the meta-bolically active cofactor for synthesis of purines, thymidine, and DNA. TMP competitively binds to dihydrofolate reductase. By virtue of sequential inhibition of two enzymes in the synthesis of folic acid, TMP-SMX acts syn-ergistically and has bactericidal activity against many aerobic gram-positive and gram-negative bacteria involved in community-acquired infections. Some nosocomial pathogens, such as Stenotrophomonas maltophilia, Burkholderia cepacia, and Serratia marcescens, are also susceptible to TMP-SMX. It is active against Nocardia asteroides, Listeria monocytogenes, Pneumocystis jirovecii, Isospora belli, and cyclospora. TMP-SMX is one of the most widely used antimicrobial agents in the world. However, increasing bacterial resistance and occasional severe adverse effects are diminishing the usefulness of this cost-effective antimicrobial agent combination.

The glycopeptides

Vancomycin, the first glycopeptide antibiotic, was isolated from Strepto-myces orientalis in the mid-1950s and introduced for clinical use in 1958 [16]. It became an important agent for treatment of infections caused by penicillin-resistant staphylococci and other gram-positive bacteria, which were becoming increasingly prevalent. Early impure preparations of vancomycin were associated with significant nephrotoxicity and ototoxicity. With the availability of b-lactamase-stable penicillins like oxacillin and naficillin, the need for vancomycin use decreased dramatically until the emergence of methicillin-resistant staphylococci in the early 1980s. Vancomycin demonstrated constant activity against all common gram-positive bacteria for more than 3 decades of clinical use. The gradually increasing prevalence of vancomycin resistance in enterococci and the recent emergence of vanco-mycin-intermediately susceptible S aureus and vancomycin-resistant S aureus have created a need for alternatives to vancomycin in the management of serious infections caused by resistant gram-positive organisms [17].

Vancomycin is a bactericidal agent (except against enterococci) that complexes with the D-alanyl D-alanine portion of peptide precursor units at the crucial site of attachment and inhibits peptidoglycan polymerase and transpeptidation reactions. Because vancomycin inhibits the stage of pepti-doglycan synthesis at a site earlier than the site of action of b-lactams, no cross-resistance with b-lactams occurs. Vancomycin also affects the permeability of cytoplasmic membranes and may impair RNA synthesis. The combination of vancomycin and gentamicin is synergistic against S aureus and enterococci. The spectrum of activity of vancomycin is limited to gram-positive organisms, including Staphylococci, Streptococci, Enterococci, Corynebacteria, Bacillus spp, Listeria monocytogenes, anaerobic cocci, Acti-nomyces, and Clostridia. Infrequently encountered gram-positive organisms that are resistant to vancomycin include leuconostoc, Pediococcus, Lactobacillus, and Erysipelothrix.

Teicoplanin, a glycopeptide derived from the fermentation products of Actinoplanes teicnomyceticus, is chemically similar to vancomycin [18]. Teicoplanin is more lipophilic than vancomycin, a property that results in rapid and excellent tissue penetration and intracellular concentration. It is water soluble at physiologic pH, releases slowly from tissues, and has a long elimination half-life. It may be given once a day intramuscularly or intravenously. Although widely used in Europe and Asia for treatment ofgram-positive infections, teicoplanin is still investigational in the United States.

The fluoroquinolones

Fluoroquinolones are synthetic compounds that first became available in the mid-1980s. They have been developed extensively to optimize antibacterial activity against gram-negative and gram-positive bacteria as well to improve pharmacokinetic properties and safety [19]. Topoisomerase (I, II, III, and IV) maintains cellular DNA in an appropriate state of supercoiling in both replicating and nonreplicating regions of the bacterial chromosome. The fluoroquinolones target topoisomerase type II (DNA gyrase) and top-oisomerase type IV. The activity of the quinolones against gram-positive bacteria may primarily be the result of targeting topoisomerase IV and top-oisomerase II, whereas DNA gyrase may be the primary target in gram-negative bacteria. The complexity of the interaction of various fluoroquinolones with different topoisomerases is the basis of differences in the antibacterial spectrum and resistance patterns among fluoroquinolones. The prototype quinolone, nalidixic acid, is considered a first-generation fluoroquinolone. The second-generation fluoroquinolones, such as norfloxacin, ciprofloxacin, and ofloxacin, have predominantly gram-negative activity. Ciprofloxacin remains the most active fluoroquinolone against P aeruginosa. In contrast, the third- and fourth-generation fluoroquinolones, like levofloxacin, gatifloxa-cin, and moxifloxacin, have better activity against gram-positive organisms, particularly S pneumoniae, including penicillin-resistant strains.

The streptogramins

The first streptogramin antibiotic, pristinamycin, produced by Strepto-myces pristinaespiralis, was developed in France more than 35 years ago. It has been used primarily for the treatment of respiratory and skin structure infections [20]. Quinupristin/dalfopristin (30:70) is a water-soluble derivative of pristinamycin with a selective spectrum of activity against gram-positive organisms. It became available in the United States in 1999 for the treatment of infections caused by vancomycin-resistant Enterococcus faecium and those caused by other gram-positive organisms for which the other available agents are ineffective or not tolerated. The target of quinupristin (streptog-ramin A) and dalfopristin (streptogramin B) is the bacterial ribosome. Dalfopristin blocks an early step of protein synthesis (elongation) and causes a conformational change leading to increased affinity of ribosomes for quinupristin. Quinupristin blocks a subsequent step by inhibiting peptide bond formation, resulting in the release of incomplete protein chains. This sequential dual mechanism of action results in synergy and bactericidal activity against most susceptible organisms except enterococci. The combination is active against E faecium, including Vancomycin resistant Enter-ococcus faecalis (VREF), but not against Enterococcus faecalis, against staphylococci, including methicillin-resistant and vancomycin-resistant strains, against streptococci, including penicillin-resistant S pneumoniae, and against Corynebacteria and Clostridrium perfringens. Other susceptible organisms include Neisseria meningitidis, Moraxella catarrhalis, Legionella pneumophilia, and Mycoplasma pneumoniae [21].

The oxazolidinones

The first oxazolidinone was developed in the late 1970s for control of bacterial and fungal foliage diseases of tomatoes and other plants [22]. A number of the oxazolidinones studied in the 1980s showed an in vitro spectrum of activity against staphylococci, streptococci, enterococci, anaerobes, and M tuberculosis. Because of adverse effects, particularly monomine oxidase inhibition and bone marrow toxicity, they were not further developed for human use. Some also showed acute (lethal) animal toxicity. Further chemical modifications have resulted in safer agents with superior pharmacokinetic properties. Linezolid first became available in the United States in 2000 for treatment of infections caused by vancomycin-resistant enterococci and respiratory and skin structure infections caused by gram-positive bacteria [23]. Linezolid is bacteriostatic against enterococci as well as staphylococci. It inhibits ribosomal protein synthesis by interfering with initiation complex formation. Linezolid is active against most gram-positive cocci, including those resistant to methicillin and vancomycin. It is also active against Legionella spp, Chlamydia pneumoniae, and H influenzae.

The lipopeptides

Daptomycin, a fermentation byproduct of Streptomyces roseosporus, is a naturally occurring cyclic lipopeptide antibiotic [24]. It exhibits a rapid bactericidal activity in a concentration-dependent manner. The spectrum of activity involves a broad range of gram-positive pathogens, including those that are resistant to methicillin, vancomycin, and other currently available agents [25]. The mechanism of action is binding to the cell membrane in a calcium-dependent manner, leading to depolarization of the bacterial membrane potential, which results in termination of bacterial DNA, RNA, and protein synthesis, release of intracellular potassium, and cell death. Daptomycin first became available in the United States in 2004 for the treatment of complicated skin and soft tissue infections [26].

The glycylcyclines

Tigecycline, a derivative of the tetracycline minocycline, is a broad-spectrum glycylcycline antibiotic [27]. It is a bacteriostatic agent, acts by binding to the 30s ribosomal subunit of bacteria, and prevents elongation of peptide chains, which leads to inhibition of protein synthesis. Tigecycline is not affected by the known mechanisms of resistance (efflux and ribosomal) to tetracyclines and has activity against bacterial isolates that are resistant to other antibiotic classes such as b-lactams and fluoroquinolones. These attributes give tigecycline a broad spectrum of activity against vancomycin-resistant enterococci, methicillin-resistant S aureus, and many species of multiresistant aerobic and anaerobic gram-negative bacteria. Its activity against P aeruginosa and Proteus spp is very limited. Tigecycline first became available in the United States in 2005 for the treatment of complicated intraabdominal infections and complicated skin and skin structure infections [28-30].

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