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Antibacterial agents, their mechanism of action, spectrum of antibacterial activity, patterns of antibiotic resistance, and current clinical use are presented in this chapter. Fig. 292.1 summarizes the main sites of antibacterial agent activity. Chapter 289 provides the principles regarding the selection of agents based on the characteristics of the patient and co-morbidities, site(s) of infection, likely pathogen(s) and antibiotic susceptibilities, antibiotic tissue exposure, and consideration of the benefits versus the risks of antimicrobial therapy. Specific chapters throughout the book offer more detailed discussions of types of infections and pathogens. Chapter 290 provides an in-depth discussion of mechanisms of antibiotic resistance and laboratory methods for detection. Chapter 291 illustrates the pharmacokinetic-pharmacodynamic bases of optimal antibiotic therapy and recommended antibacterial drug dosing for children with normal and impaired kidney function (Appendix 291.1). In this chapter, Table 292.1 provides the spectrum of activity of each antibiotic, and Appendix 292.1 provides dosages of antibacterial agents in neonates.
I. Cell Wall−Active Agents | ||
Class | Name | Spectrum Of Activity a |
Penicillins | ||
Natural penicillins | Penicillin G Penicillin V Benzathine penicillin G Procaine penicillin G Benzathine–procaine–penicillin G combinations |
Gram-positive Actinomyces Bacillus anthracis Listeria monocytogenes Streptococci
|
Gram-negative Borrelia burgdorferi Eikenella corrodens Leptospira spp. Neisseria meningitidis Neisseria gonorrhoeae Pasteurella multocida Spirillum minus Streptobacillus moniliformis Treponema pallidum |
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Anaerobes Bacteroides and Prevotella spp. (non-β-lactamase−producing strains) Fusobacterium spp. Veillonella spp. Clostridium spp. Cutibacterium (formerly Propionibacterium ) spp. Eubacterium spp. Peptococcus spp. Peptostreptococcus spp. |
||
Penicillinase-stable penicillins | Oxacillin Nafcillin Dicloxacillin |
Gram-positive Streptococci as above for penicillins Staphylococcus aureus (except MRSA) |
Aminopenicillins | Ampicillin Amoxicillin |
Gram-positive L. monocytogenes Streptococci and Enterococci as above for penicillins |
Gram-negative Escherichia coli Haemophilus influenzae N. meningitidis |
||
Anaerobes As above for penicillins | ||
Amoxicillin–clavulanate | Adds activity to amoxicillin: S. aureus (except MRSA) H. influenzae, β-lactamase–producing strains Moraxella catarrhalis (β-lactamase–producing strains) E. coli (some β-lactamase–producing strains) |
|
Anaerobes As above for penicillins, but adds: Bacteroides and Prevotella spp., β-lactamase–producing strains |
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Ampicillin–sulbactam | Adds activity to ampicillin: S. aureus (except MRSA) E. coli (some β-lactamase−producing strains) Klebsiella spp. Proteus mirabilis Proteus vulgaris Providencia rettgeri Providencia stuartii Morganella morganii |
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Anaerobes | ||
As above for penicillins, but adds: Bacteroides and Prevotella spp. (β-lactamase−producing strains) |
||
Extended spectrum penicillins | Piperacillin b | Gram-positive Streptococci and Enterococci as above for penicillins |
Gram-negative E. coli H. influenzae P. mirabilis P. vulgaris M. morganii Pseudomonas aeruginosa P. rettgeri Enterobacter species |
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Anaerobes Bacteroides and Prevotella spp. (non-β-lactamase−producing strains) Fusobacterium spp. Veillonella spp. Clostridium spp. Eubacterium spp. Peptococcus spp. Peptostreptococcus spp. |
||
Piperacillin–tazobactam | As above, but adds: β-lactamase–producing strains of S. aureus (except MRSA) H. influenzae E. coli (except AmpC- or KPC-producing strains) Klebsiella spp. (except KPC-producing strains) Serratia marcescens, Citrobacter spp. and Enterobacter spp. (except AmpC-producing strains) |
|
Anaerobes Bacteroides and Prevotella spp. (including β-lactamase−producing strains) Fusobacterium spp. Veillonella spp. Clostridium spp. Eubacterium spp. Peptococcus spp. Peptostreptococcus spp. |
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Cephalosporins | ||
First generation | Cefazolin Cephalexin Cefadroxil |
Gram-positive Streptococci
S. aureus (except MRSA) |
Gram-negative E. coli P. mirabilis | ||
Second generation | Cefuroxime Cefaclor Cefoxitin (a cephamycin) Cefotetan (a cephamycin) Cefprozil |
Gram-positive Streptococci
S. aureus (except MRSA) |
Gram-negative E. coli (except ESBL- and KPC-producing strains) H. influenzae (including β-lactamase–producing strains) Klebsiella spp. (except ESBL- and KPC-producing strains) M. catarrhali s N. gonorrhoeae N. meningitidis P. mirabilis P. rettgeri Salmonella spp. Shigella spp. |
||
Anaerobes Bacteroides and Prevotella spp. (non-β-lactamase–producing strains, except for cefoxitin, and to a lesser extent, cefotetan and cefamycins, which do cover β-lactamase–producing strains) Fusobacterium spp. Veillonella spp. Eubacterium spp. Peptococcus spp. Peptostreptococcus spp. |
||
Third generation | Cefdinir Cefixime Cefotaxime Ceftriaxone Ceftazidime Cefpodoxime Cefdinir |
Gram-positive Streptococci
S. aureus (except MRSA) |
Gram-negative Citrobacter spp. Enterobacter spp. E. coli H. influenzae (including β-lactamase–producing strains) Klebsiella spp. M. morganii N. gonorrhoeae (including β-lactamase–producing strains) N. meningitidis P. mirabilis P. vulgaris P. rettgeri P. stuartii S. marcescens For ceftazidime: P. aeruginosa |
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Anaerobes Bacteroides and Prevotella spp. (non-β-lactamase–producing strains) Fusobacterium spp. Eubacterium spp. Peptococcus spp. |
||
Ceftazidime–avibactam | Adds activity to ceftazidime to include many ESBL-, KPC-, and Oxa-48–producing E. coli and Klebsiella, and strains of Enterobacter, Serratia, Citrobacter and indole-positive Proteus that constitutively produce AmpC β-lactamase | |
Ceftolozane b –tazobactam | Adds activity to ceftolozane (enhanced Pseudomonas activity beyond ceftazidime) to include many ESBL-producing E. coli and Klebsiella, but not KPC-producing strains | |
Fourth generation | Cefepime | Gram-positive Streptococci
S. aureus (except MRSA) |
Gram-negative As above for third generation cephalosporins, but adds P. aeruginosa | ||
Anaerobes Bacteroides and Prevotella spp. (non-β-lactamase–producing strains) Fusobacterium spp. Veillonella spp. Eubacterium spp. Peptococcus spp. |
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Fifth generation | Ceftaroline Ceftobiprole |
As above for third generation cephalosporins but adds MRSA . Ceftobiprole has in vitro activity against E. faecalis |
Catechol cephalosporins | Cefiderocol | Gram-negative |
Acinetobacter baumanniiCitrobacter freundii Citrobacter koseri Enterobacter cloacae E. coli Klebsiella aerogenes Klebsiella oxytoca Klebsiella pneumoniae M. morganii P. mirabilis P. vulgaris P. rettgeri P. aeruginosa S. marcescensStenotrophomonas maltophilia |
||
Carbapenems | Imipenem (with cilastatin) Meropenem Ertapenem Doripenem |
Gram-positive Streptococci
E. faecalis |
Gram-negative Acinetobacter spp. Citrobacter spp. (including AmpC–producing strains) Enterobacter spp. (including AmpC–producing strains) E. coli (including ESBL–producing and AmpC–producing strains) Gardnerella vaginalis H. influenzae Klebsiella spp. (including ESBL–producing and AmpC–producing strains) M. morganii (including AmpC–producing strains) P. vulgaris P. rettgeri P. aeruginosa (except for ertapenem) Serratia spp. (including AmpC–producing strains) |
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Anaerobes Bifidobacterium spp. Clostridium spp. Eubacterium spp. Peptococcus spp. Peptostreptococcus spp. Cutibacterium spp. Bacteroides and Prevotella spp. (including β-lactamase–producing strains) Fusobacterium spp. |
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Monobactams | Aztreonam (used both as antibiotic and as a metallo–β-lactamase inhibitor) | Gram-negative |
Non ESBL- or non-ampC–producing strains: Citrobacter spp. Enterobacter spp. E. coli H. influenzae (including β-lactamase–producing strains) Klebsiella spp. P. mirabilis P. aeruginosa Serratia spp. |
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Glycopeptides | Vancomycin Telavancin Dalbavancin Oritavancin |
Gram-positive Streptococci
E. faecalis b |
Anaerobes Clostridioides difficile | ||
Phosphoric Acid | Fosfomycin | Gram-positive E. faecalis E. faecium S. aureus (including MRSA) S. epidermidis Gram-negative E. coli Citrobacter diversus C. freundii Enterobacter spp. Klebsiella spp. P. mirabilis P. vulgaris S. marcescens |
II. Cell Membrane-Active Agents | ||
Class | Name | Spectrum of Activity a |
Lipopeptides | Daptomycin | S. aureus (including MRSA and VRSA) E. faecalis (vancomycin-susceptible and vancomycin-resistant strains) E. faecium (vancomycin-susceptible and vancomycin-resistant strains) Streptococci
|
Polymyxins | Colistin | Enterobacter aerogenes E. coli K. pneumoniae P. aeruginosa Actinobacter spp. Citrobacter spp. Haemophilus spp. Salmonella spp. Shigella spp. |
III. Ribosome-Active Agents | ||
Class | Name | Spectrum of Activity a |
Macrolides | Erythromycin | Gram-positive Corynebacterium diphtheriae Corynebacterium minutissimum L. monocytogenes S. aureus S. pneumoniae Streptococcus pyogenes |
Gram-negative Bordetella pertussis Legionella pneumophila N. gonorrhoeae |
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Other pathogens Chlamydia trachomatis Entamoeba histolytica Mycoplasma pneumoniae T. pallidum Ureaplasma urealyticum |
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Clarithromycin | Gram-positive S. aureus S. pneumoniae S. pyogenes |
|
Gram-negative H. influenzae M. catarrhalis Helicobacter pylori |
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Other pathogens M. pneumoniae Chlamydophila pneumoniae Mycobacterium avium complex |
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Azalides | Azithromycin | Gram-positive S. aureus Streptococci
B. pertussis |
Gram-negative H. influenzae Haemophilus ducreyi M. catarrhalis N. gonorrhoeae |
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Other pathogens C. pneumoniae C. trachomatis L. pneumophila M. pneumoniae U. urealyticum |
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Ketolides | Telithromycin | Gram-positive S. aureus Streptococci
|
Gram-negative H. influenzae M. catarrhalis |
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Other pathogens B. pertussis M. pneumoniae L. pneumophila C. pneumoniae |
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Tetracyclines | Tetracycline Minocycline Doxycycline Eravacycline Omadacycline |
Gram-positive Actinomyces spp. B. anthracis E. faecalis b E. faecium b L. monocytogenes Nocardia spp . S. aureus (including MRSA)
|
Gram-negative Acinetobacter spp. Bartonella bacilliformis Borrelia recurrentis Brucella spp. Campylobacter spp. C. freundii C. koseri E. coli Francisella tularensis H. ducreyi H. influenzae Klebsiella spp. Klebsiella granulomatis M. catarrhalis N. meningitidis N. gonorrhoeae Shigella spp. Vibrio cholerae Yersinia pestis |
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Anaerobes Bacteroides fragilis (for eravacycline) Clostridium spp. Cutibacterium acnes Fusobacterium fusiforme |
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Other pathogens Balantidium coli Entamoeba spp. Plasmodium falciparum Chlamydophila psittaci C. trachomatis M. pneumoniae Rickettsia spp . Ureaplasma spp . T. pallidum |
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Glycylcyclines | Tigecycline | Gram-positive Streptococci
E. faecalis |
Gram-negative A. baumannii Aeromonas hydrophila C. freundii C. koseri E. cloacae E. aerogenes E. coli K. oxytoca K. pneumoniae P. multocida S. marcescens S. maltophilia Bacteroides spp. |
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Other pathogens | ||
C. trachomatis M. pneumoniae Ureaplasma spp. Mycobacterium abscessus Mycobacterium chelonae Mycobacterium fortuitum |
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Lincosamides | Clindamycin | Gram-positive Streptococci
|
Anaerobes B. fragilis Prevotella melaninogenica Fusobacterium spp. Peptococcus spp. Peptostreptococcus spp. Actinomyces spp. C. perfringens Cutibacterium spp. |
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Aminoglycosides | Streptomycin | Gram-negative Brucella spp. Francisella spp. |
Other pathogens Mycobacterium tuberculosis |
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Gentamicin Tobramycin Amikacin |
Gram-positive S. aureus |
|
Gram-negative E. coli Enterobacter spp. Klebsiella spp. Serratia spp. Citrobacter spp. M. morganii Acinetobacter spp. Providencia spp. P. mirabilis P. vulgaris P. aeruginosa |
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Paromomycin | E. histolytica Dientamoeba fragilis Cryptosporidium spp. |
|
Oxazolidinones | Linezolid Tedizolid |
Gram-positive Streptococci
S. aureus (including MRSA strains) |
Streptogramins | Quinupristin–dalfopristin b | Gram-positive Streptococci groups A and B S. aureus E. faecium |
Pleuromutilins | Lefamulin | Gram-positive Streptococci
S. aureus (including MRSA) |
Gram-negative H. influenzae Haemophilus parainfluenzaeM. catarrhalis |
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Other pathogens M. pneumoniaeC. pneumoniaeL. pneumophila |
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IV. Nucleic Acid−Active Antibiotics | ||
Class | Name | Spectrum of Activity a |
Rifamycins | Rifampin | Gram-positive S. aureus |
Gram-negative N. meningitidis H. influenzae |
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Other pathogens M. tuberculosis M. avium complex |
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Rifabutin | M. tuberculosis | |
Rifapentine | M. avium complex | |
Rifaximin | Susceptible at concentrations achieved within the gastrointestinal lumen:
|
|
Quinolones | Nalidixic acid | Gram-negative E. coli Enterobacter spp. M. morganii P. mirabilis P. vulgaris P. rettgeri |
Fluoroquinolones | Ciprofloxacin | Gram-positive B. anthracis E. faecalis S. pyogenes S. pneumoniae S. aureus |
Gram-negative Aeromonas spp. Acinetobacter spp. Campylobacter jejuni C. diversus C. freundii E. cloacae E. coli H. influenzae H. parainfluenzae K. pneumoniae M. catarrhalis M. morganii N. gonorrhoeae b P. multocida P. mirabilis P. vulgaris P. rettgeri P. stuartii P. aeruginosa Salmonella spp. S. marcescens Shigella spp. Vibrio spp. Yersinia enterocolitica Y. pestis |
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Other pathogens L. pneumophila |
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Levofloxacin Moxifloxacin Delafloxacin |
Gram-positive B. anthracis Streptococci
E. faecalis |
|
Gram-negative Acinetobacter spp. Citrobacter spp. E. coli Enterobacter spp. H. influenzae Klebsiella spp. M. catarrhalis M. morganii Proteus spp. Providencia spp. P. aeruginosa Pseudomonas fluorescens S. marcescens Y. pestis |
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Anaerobes C. perfringens |
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Other pathogens L. pneumophila M. pneumoniae C. pneumoniae |
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NitroimIdazoles | Metronidazole Tinidazole |
Anaerobes Clostridium spp. Eubacterium spp. G. vaginalis Peptococcus spp. Peptostreptococcus spp. Prevotella spp. B. fragilis Fusobacterium spp. |
Other pathogens E. histolytica Giardia Trichomonas |
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Nitrofurans | Nitrofurantoin | Gram-positive E. faecalis S. aureus (including MRSA) S. epidermidis Staphylococcus saprophyticus Streptococci
Gram-negative |
Sulfonamides | Sulfamethoxazole b –trimethoprim | Gram-positive S. aureus (including MRSA) S. pneumoniae c |
Gram-negative Acinetobacter spp. Citrobacter spp . E. coli Enterobacter spp. H. influenzae Klebsiella spp. M. morganii P. mirabilis P. vulgaris Salmonella spp. Serratia spp. Shigella spp. S. maltophilia Vibrio cholera Y. enterocolitica |
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Other pathogens Cyclospora spp . Cystoisospora spp. Pneumocystis jirovecii |
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Sulfadiazine–pyrimethamine b | Toxoplasma gondii Plasmodium spp. |
a A majority of strains of the bacteria listed are susceptible; however, some organisms with the group may be less susceptible or resistant. Local antibiograms should be used in conjunction with this table.
The structure, function, and biosynthesis of the bacterial cell envelope is remarkably complicated. New discoveries continue to enhance our understanding of the envelope’s role in the pathogenesis and treatment of bacterial infection. The gram-negative envelope consists of an inner (cytoplasmic) and outer lipid bilayer membrane, each separated by a thin cell wall made of peptidoglycan (PG). Lipopolysaccharides (LPS) are present in the outer lipid leaflet of the outer gram-negative membrane. Gram-positive bacteria have only an inner membrane surrounded by a thicker PG cell wall fortified with phosphodiester-linked glycopolymers called teichoic acids ( Fig. 292.2 ). Cell wall construction involves several steps, from the synthesis of precursors within the bacterial cytoplasm to the intricate construction of a lattice-like PG structure around the organism that maintains cell shape and osmotic integrity. , Many of these steps, and others in cell envelope structural biosynthesis and assembly, have been exploited as targets of currently available antibacterial agents and provide potential targets for ongoing anti-bacterial research.
Fig. 292.3 illustrates the steps and components involved in PG synthesis. The PG building block monomer, Lipid II, is synthesized in the cytoplasm and consists of a N -acetylmuramic acid (MurNAc) and N -acetylglucosamine (GlcNAc) disaccharide backbone with both a pentapeptide stem and a phospholipid (undecaprenyl C55 diphosphate) bound to MurNAc. The antibacterial agent fosfomycin inhibits the transferase enzyme MurA responsible for the initial step in Lipid II synthesis. Lipid II is subsequently transferred through the cell membrane to undergo further modifications by membrane bound enzymes responsible for polymerizing PG. Historically, these enzymes were identified by their penicillin binding affinity and became known as penicillin-binding proteins or PBPs. Those with glycosyltransferase activity elongate the polysaccharide chain while those with transpeptidase activity crosslink the peptide stems, ultimately creating the PG polymer either outside the cell membrane in gram-positive organisms or between the inner plasma membrane and outer membrane within the cell wall in gram-negative organisms. Some enzymes have carboxypeptidase activity that cleave the crosslinked peptides to maintain cell shape. , Vancomycin and related glycopeptide antibiotics interfere with PG polymerization by hydrogen-binding to the terminal d -alanine, d -alanine residues of the MurNAc attached pentapeptide. The β-lactam class of antibiotics structurally mimic the terminal d -alanine, d -alanine residues and bind covalently to the transpeptidase active serine site ( Fig. 292.4A ), causing inactivity. The structure of enzymes that are responsible for PG polymerization vary somewhat between bacteria. Fortunately, the active sites of these enzymes tend to be conserved.
The β-lactam antibacterials all share the capacity to inhibit the transpeptidase crosslinking of PG in the final steps of formation of the cell wall. Whereas the β-lactam structure itself is consistent across all antibiotics in this class, the ring to which the lactam moiety is fused is variable with relatively small differences in the composition of the ring, allowing for variable activity against the PBPs of both gram-positive and gram-negative bacteria ( Fig. 292.4B ). The addition of chemical “chains” to the ring structures enhances activity against certain organisms, but simultaneously can decrease activity against others. For example, identical side chain modifications on the ceftazidime and aztreonam molecule give these agents enhanced activity against Pseudomonas aeruginosa but reduced activity against gram-positive bacteria. The newer anti-pseudomonal agent ceftolozane contains the same side chain plus additional chains added to the cephem ring that provide greater stability against Pseudomonas-derived cephalosporinase enzymes that can inactivate ceftazidime. Another newer cephalosporin, ceftaroline, possesses activity against methicillin-resistant Staphylococcus aureus (MRSA) due to its unique side chain’s affinity for an allosteric binding site on the organism’s PBP2a enzyme. Binding of ceftaroline to this site induces a conformational change exposing the enzyme’s active site, which is normally geometrically buried and poorly accessible to β-lactams. Differences in β-lactam electrical charges due to their side chains can affect their interaction with gram-negative membrane porins channels. Compounds such as cefepime and ertapenem interact favorably with certain porins due to their charge characteristics and pass through the porin more freely compared with other β-lactam antibiotics such as ampicillin.
In general, the β-lactam antibiotics are bactericidal, with the concentrations required for killing being very close to those required for inhibition of growth. The maximal bactericidal effect occurs on rapidly growing bacteria, while slower growing or those in stationary phase or as sessile organisms in biofilms are phenotypically resistant to this class of antibiotics. , Subinhibitory concentrations of β-lactam antibiotics (and many other antibacterial classes) actually can promote biofilm growth and antibacterial resistance. The size of an inoculum also can affect β-lactam bactericidal activity, at least that of penicillin, with higher density of organisms at a site of infection requiring higher penicillin dosages and suprainhibitory systemic concentrations to achieve adequate killing. , This phenomenon was discovered several decades ago in an animal model by the pathologist Dr. Harry Eagle at the US National Institutes of Health. It is not the same as the “Eagle effect,” a related discovery by the same physician-scientist, which describes a paradoxical increase in bacterial growth when a fixed sized inoculum of organisms is exposed to increased ultra-suprainhibitory concentrations of anti-bacterial drugs, including β-lactams. The human clinical significance of these 2 discoveries continues to be studied and debated.
The penicillins can be divided broadly into four different groups: (1) natural penicillins, (2) penicillinase-stable penicillins, (3) aminopenicillins, and (4) extended-spectrum penicillins.
Natural penicillins are the natural products of Penicillium chrysogenum. Both penicillins and penicillin-resistance mechanisms likely evolved millions of years ago as result of competition for survival between single-cell organisms. Fleming’s observations in the 1920s led to the identification of penicillin and the discovery of the mechanism by which Penicillium killed other bacteria, paving the way for the modern era of antibacterial therapy. The basic structure of penicillin, 6-aminopenicillanic acid, is characteristic of the lactam ring fused to a larger ring structure to create a penam nucleus that is the basic structure of all penicillins ( Fig. 292.4B ). Of the natural penicillins, only penicillin G (crystalline penicillin G also called benzyl-penicillin) and penicillin V (phenoxymethyl-penicillin) are available commercially. The former is administered parenterally and the latter enterally. For intramuscular injection, penicillin G is available in two suspension/repository forms: penicillin G procaine and penicillin G benzathine. Both special intramuscular forms are long acting due to the viscous lecithin-carboxymethylcellulose suspension that forms a compact drug depot and slowly releases penicillin from the site of injection. The procaine and benzathine moieties also have low aqueous solubility and dissolve slowly in muscle tissue. Benzathine has the lower solubility of the two, and hence benzathine-penicillin has the slowest dissolution in muscle and is the longest acting, but also achieves the lowest serum concentrations. The peak serum concentrations of the intramuscular suspension forms of penicillin G are a fraction of that achieved with intravenous administration of crystalline penicillin G. Therefore the only settings in which the intramuscular repository forms of penicillin are effective are those in which the targeted organisms are exquisitely susceptible to penicillin, and infection focus is in tissues with good perfusion (see Chapter 182 ). Intramuscular procaine penicillin has a half-life of approximately 12 hours and achieves peak serum concentration of about 2 μg/mL, compared with intravenous crystalline penicillin G that has a half-life of 30–50 minutes and peak serum concentration of approximately 20 μg/mL. Intramuscular benzathine penicillin G yields serum concentrations of only about 1.5 μg/mL but can remain above 0.2 μg/mL for ≥3 weeks. A combination of procaine and benzathine penicillin in equal amounts 1:1 (benzathine-to-procaine) mixture is also available. Because these intramuscular suspension forms of penicillin are used infrequently, extreme caution must be taken never to administer them intravenously, which can cause tissue necrosis, compartment syndrome, gangrene, and death.
In clinical practice, although active against a wide range of bacteria ( Table 292.1 ), the natural penicillins are used most widely for treatment and prevention of infections caused by streptococci. Pharyngitis, lower respiratory tract infection, skin and skin structure infections, and bloodstream infection (BSI) caused by group A Streptococcus ( Streptococcus pyogenes ) are effectively treated with penicillin. The in vitro susceptibility has remained unchanged over the past several decades, although resistance due to PBP2x mutations has been reported recently and may become more common. Intramuscular injections of benzathine penicillin every 3–4 weeks are effective in the prevention of rheumatic fever because of the prolonged tonsillar tissue concentrations of penicillin G.
Empiric penicillin therapy of infections suspected to be caused by Streptococcus pneumoniae was not uniformly successful given widespread penicillin-resistance during the mid-1990s. With the widespread use of protein-conjugated vaccines, empiric penicillin therapy was more likely to be microbiologically effective by the early 2010s. Certain serotypes of pneumococcus were able to acquire genetic resistance and form stable alterations in the structure of several pneumococcal PBPs, yielding penicillin-nonsusceptible organisms, treatment of which requires use of higher dosages of penicillins or agents from other antibiotic classes. However, if culture results document susceptibility, penicillin represents highly effective therapy. Fortunately, widespread use of protein-conjugated vaccines against the most antibiotic-resistant and virulent serotypes have had a dramatic impact in decreasing both the burden and antibiotic resistance of pneumococcal infections.
Most anaerobes, except for β-lactamase−producing strains of Bacteroides spp. and Prevotella spp., are highly susceptible to penicillin G. However, because of the common isolation of Bacteroides fragilis among the anaerobes present in intra-abdominal infections and Prevotella melaninogenica among the organisms causing sinus-related and deep head and neck space infections, including brain abscesses, agents active against β-lactamase−producing anaerobes are preferred to treat infections at these sites.
Penicillin G continues to play a role in the treatment of infections caused by other α- and β-hemolytic streptococci, most of which remain susceptible. For life-threatening infections such as bacterial endocarditis, susceptibility testing should be performed to ensure that the organisms do not exhibit penicillin tolerance, which may decrease treatment success using single-drug therapy at standard dosages.
Although the susceptibility of Enterococcus faecalis to penicillin remains adequate, effects are bacteriostatic and susceptibility mean inhibitory concentration (MIC) cutoffs are higher than for the β-hemolytic streptococci, necessitating higher doses and combination with an aminoglycoside to achieve bactericidal effects (see Chapter 180 ). Most nosocomial strains of Enterococcus faecium, and rarely some of E. faecalis, exhibit high levels of resistance due to expression of PBP5 and PBP4, respectively, which have low affinity for the penicillins.
Penicillin G is effective therapy for other infections, including diphtheria, naturally occurring anthrax, actinomycosis, leptospirosis, and syphilis.
This class of semisynthetic penicillins, represented today by the isoxazolyl penicillins dicloxacillin and oxacillin, and the naphthalene penicillin nafcillin, was created to meet the challenge of the development of penicillin-resistant S. aureus. The bulky side chains prevent the staphylococcal β-lactamases from binding to and hydrolyzing the lactam ring of the molecule. However, these antibiotics are resistant only to staphylococcal penicillinases, and not to the β-lactamases of gram-negative organisms. They are not effective against MRSA because they cannot bind to PBP2a. These penicillins are also much less susceptible to the inoculum effect compared with penicillin G.
In clinical practice, these antibiotics are only used to treat infections caused by methicillin-susceptible S. aureus (MSSA). They are available in both parenteral and oral formulations. With the emergence of community-associated (CA)-MRSA, their longstanding role in the empiric therapy of presumed staphylococcal infections is compromised. For MSSA, however, these semisynthetic penicillins are safe and highly effective.
The aminopenicillin class of semisynthetic penicillins, represented by ampicillin and amoxicillin, contains an amino substitution in the side chain of the penam nucleus. This provides a polar charge on the molecule that allows activity against gram-negative pathogens, including Escherichia coli and Haemophilus influenzae ( Table 292.1 ). However, aminopenicillins are not capable of binding to PBP2a of MRSA, nor are they stable to staphylococcal penicillinases, or the hundreds of different β-lactamases produced by gram-negative pathogens (see Chapter 290 ). Their activity against other gram-positive organisms, such as group A and group B Streptococcus spp., is excellent. Like penicillin, activity against most enterococci is decreased compared with group A and group B Streptococcus , but higher dosages are usually effective at achieving exposures required for inhibition of susceptible enterococci.
As a means of enhancing the activity of the aminopenicillins against β-lactamase-producing pathogens, the concurrent use of a second agent that binds irreversibly to β-lactamase has led to a useful group of drugs. These concurrently used agents, called β-lactamase inhibitors (BLI), have little antibiotic activity on their own because they have been selected for avid binding characteristics to specific β-lactamases, rather than to PBPs. However, there is variability in the binding affinity of each BLI to the β-lactamases of different organisms. Currently in the US, clavulanate ( Fig. 292.4B ) is paired with amoxicillin in an oral formulation and ampicillin is paired with sulbactam in an intravenous formulation ( Table 292.1 ).
The clinical uses of ampicillin and amoxicillin are extensive. The enhanced activity against E. coli and other gram-negative enteric bacilli compared with penicillin G permits ampicillin and amoxicillin to be used for the treatment of some urinary tract infections (UTIs) and gastrointestinal infections. The excellent activity against β-lactamase−negative strains of H. influenzae allows ampicillin and amoxicillin to be used in the treatment of upper and lower respiratory tract infections. Ampicillin is one of the most bactericidal agents when used together with gentamicin for susceptible strains of Enterococcus. Unfortunately, the development of ampicillin resistance in E. coli, Shigella, Salmonella, and H. influenzae has limited the usefulness of aminopenicillins against these pathogens. However, the addition of clavulanate to amoxicillin allows activity against β-lactamase−producing strains of H. influenzae and Moraxella catarrhalis as well as MSSA. This combination increases the clinical usefulness of amoxicillin in the treatment of community-associated upper and lower respiratory tract infections (e.g., acute otitis media, sinusitis, and pneumonia) in addition to skin and skin structure infections. Clavulanate alone has little effect on ampicillin-resistant E. coli . The addition of sulbactam to ampicillin allows activity against many β-lactamase−producing organisms, including methicillin-susceptible staphylococci, many enteric gram-negative bacilli (not E. coli typically), and B. fragilis. Ampicillin-sulbactam can be used for treatment of complicated pneumonia, many skin and skin structure infections, and some intra-abdominal infections, which is not possible with ampicillin alone.
Extended-spectrum semisynthetic penicillins are designed to increase activity against gram-negative pathogens, including Klebsiella, Enterobacter, and, for some agents, Pseudomonas ( Table 292.1 ). The two major classes are the carboxypenicillins, represented by ticarcillin and carbenicillin, and the acylureidopenicillins, represented by piperacillin. Only piperacillin is currently available in the US, and only in combination with the BLI tazobactam. Although the spectrum of activity of these penicillin antibiotics has been enhanced beyond the aminopenicillins, they remain susceptible to hydrolysis by many β-lactamases, including those of MSSA. Similar to the aminopenicillins, activity of these drugs has been enhanced by pairing them with BLIs.
The clinical uses of piperacillin-tazobactam (PIP-TAZO) reflects its broad activity against gram-negative enteric bacilli and P. aeruginosa. Many organisms, including MSSA, B. fragilis, P. melaninogenica, and many gram-negative enteric bacilli ( E. coli and Klebsiella spp.) are susceptible to this combination ( Table 292.1 ). This allows for successful therapy for many skin and skin structure infections, intra-abdominal infections, and many gram-positive and gram-negative hospital-associated infections, such as wound infections, UTIs, and pneumonia. The extended-spectrum penicillins also retain good activity against ampicillin-susceptible strains of Enterococcus. Tazobactam adds little to antimicrobial activity of piperacillin against P. aeruginosa, and empiric treatment of Pseudomonas infection with PIP-TAZO may be enhanced by the addition of another agent (e.g., an aminoglycoside) due to declining susceptibility rates to PIP-TAZO, resulting from the presence of many mechanisms of resistance, including inducible ß-lactamase production (see also Chapter 155, Chapter 290 ).
Cephalosporins, like the penicillins, are derived from β-lactam antibiotics found in nature. Cephalosporin C, the precursor molecule for cephalosporins used in humans, was originally isolated from the fungus Cephalosporium acremonium . Similar, related compounds (cefamycins) were later discovered from Streptomyces spp., the natural source of many antibacterial agents. Successive modifications of the cephem ring structure have resulted in “generations” of cephalosporin antibiotics. There is no official scientific designation of generations; rather, the description of enhanced activity of the second generation over the first was created as a marketing tool. However, the ability to distinguish the relative activity of the large number of cephalosporin antibiotics by generation is useful ( Table 292.1 ).
In general, the first-generation cephalosporins, represented by parenteral cefazolin and by enteral cephalexin, are active against gram-positive pathogens, group A Streptococcus and MSSA, which has led to their use for skin and skin structure infections and surgical prophylaxis, as well as for systemic infections caused by these organisms. Although cefazolin is better tolerated than the anti-staphylococcal penicillinase-stable penicillins (e.g., oxacillin), it is somewhat less active in vitro against MSSA and may not be as effective in the treatment of serious infections such as endocarditis. This may be due to a high inoculum effect related to cefazolin’s greater vulnerability to anti-staphylococcal β-lactamases. , , However, retrospective and non-randomized prospective studies of treatment of MSSA BSI in adults signal that cefazolin and anti-staphylococcal penicillins are equivalently effective, even when a high inoculum focus is present. More prospective randomized trials in adults and children are needed to determine the best MSSA treatment (see also Chapter 115 ).
The first generation cephalosporins are active against many strains of E. coli, allowing treatment of urinary tract and intestinal infections. However, increasing resistance has limited the usefulness of these agents in the treatment of both community-associated and hospital-associated infections. Like most cephalosporins, the first-generation agents lack activity against all enterococci due to intrinsic production of PBP5, and possibly other PBPs, to which cephalosporins are unable to bind.
The second generation cephalosporins have enhanced activity against gram-negative pathogens and enhanced stability against β-lactamases compared with first-generation agents ( Table 292.1 ). Increased spectrum of activity includes many enteric gram-negative bacilli and β-lactamase−producing strains of H. influenzae. The activity of second-generation agents against MSSA is decreased, although not sufficiently to lead to clinical failures in treatment of mild to moderate staphylococcal infections. This broad spectrum of activity allows for single-drug therapy of streptococcal, H. influenzae, and some staphylococcal infections in children. However, because of poor penetration of the first- and second-generation cephalosporins into cerebrospinal fluid (CSF), their routine use for the treatment of BSI caused by S. pneumoniae and H. influenzae type B that can commonly cause central nervous system (CNS) disease is not appropriate. Within the second generation of agents, all of which share the cephem ring structure ( Fig. 292.4B ), are both true cephalosporins and the cephamycins (cefoxitin and cefotetan). The cephamycins were originally isolated from Streptomyces cattleya and contain an additional side chain that enhances stability to β-lactamases, providing improved activity against β-lactamase-containing strains of B. fragilis. Given reasonable activity against gram-positive organisms (except enterococci), gram-negative enteric bacilli, and anaerobes, these cephamycin antibiotics are more effective in the treatment of intra-abdominal infections than cephalosporins.
Oral second-generation agents have been used widely for the treatment of upper and lower respiratory tract infections in children. However, with higher rates of penicillin resistance in S. pneumoniae caused by mutations that alter the structure of PBP drug targets, treatment failures of infections caused by penicillin-nonsusceptible strains of pneumococcus using the oral second-generation cephalosporins occurs; high-dose amoxicillin therapy is superior.
The third generation cephalosporins have further enhanced gram-negative activity, more stable to common β-lactamases produced by Gram-negative bacilli which extends to P. aeruginosa for ceftazidime, but at the expense of a further decrease in activity against MSSA. As with other cephalosporins, they lack activity against enterococci. Enhanced activity against enteric gram-negative bacilli has led to successful therapy of UTIs and many nosocomial infections caused by multi-drug resistant (MDR) gram-negative pathogens. However, therapy of infections caused by Enterobacter, Serratia, and Citrobacter spp., which can produce chromosomally mediated (inducible) AmpC β-lactamases, can fail. Failure is likely due to the selection of organisms at the site of infection that constitutively hyperproduce these enzymes, based on alterations in β-lactamase gene regulation, thus conferring resistance to third-generation agents. In general, the third generation cephalosporins also are hydrolyzed by extended-spectrum β-lactamases (ESBLs) produced most commonly by E. coli and Klebsiella spp. (see Chapter 290 ). The combination of ceftazidime with avibactam, a novel BLI with activity against ESBL, Klebsiella pneumoniae carbapenemase (KPC), OXA-48 carbapenemase, and ampC β-lactamase, is safe and effective against these β-lactamase producing pathogens, as demonstrated for gram-negative pathogens present in young infants and children with complicated intra-abdominal and complicated UTIs. , Although it is highly active against B. fragilis , ceftazidime-avibactam has limited activity against other Bacteroides spp. and many other anaerobic pathogens. It should therefore be given with metronidazole to treat intra-abdominal infection. Because of its broad-spectrum of β-lactam aseresistance, ceftazidime-avibactam represents a newer option for the treatment of gram-negative bacterial infections. However, avibactam and all other clinically available BLI inhibitors do not inhibit the Class B metallo- β-lactamases (MBL), which can hydrolyze all β-lactam antibiotics (including carbapenems) except monobactams. Ceftazidime-avibactam would therefore not be effective monotherapy for an MBL-expressing pathogen. Nor is it effective against ceftazidime-resistant P. aeruginosa enabled by MexAB-OprM or other efflux pump expression, a common resistance mechanism for this pathogen (see Chapter 290 ). Ceftolozane-tazobactam is a drug that pairs the BLI tazobactam with a newer cephalosporin ceftolozane that was created by modifying the ceftazidime molecule with a unique R2 chain, giving it more intrinsic binding activity against Pseudomonas , including some ceftazidime-resistant strains. The result is an agent with much better activity against P. aeruginosa, including Amp-C producing and efflux pump expressing carbapenem-resistant isolates, very good but slightly weaker in vitro coverage of ESBL-producing gram-negative bacteria than ceftazidime-avibactam, but no coverage of the Klebsiella producing OXA-48 carbapenemases due to the weaker inhibition by tazobactam compared with avibactam. ,
The activity of the third-generation agents is superb against virtually all strains of H. influenzae. These agents, in general, achieve CSF concentrations that are effective for treatment of bacterial meningitis caused by all 3 major pediatric pathogens: H. influenzae type b , S. pneumoniae, and Neisseria meningitidis. Of note, certain penicillin-resistant strains of S. pneumoniae have decreased susceptibility to third-generation cephalosporins and have been associated with clinical and microbiologic failure of treatment for CNS infection. , The most active of the third-generation cephalosporins against S. pneumoniae, ceftriaxone, has not been associated with treatment failure of respiratory tract infections caused by penicillin-resistant strains when appropriate dosing regimens are used. None of the third-generation agents should be considered optimum for the treatment of infections caused by MSSA because other cephalosporins and penicillinase-stable penicillins are more active against this pathogen.
Among the third-generation agents, ceftriaxone has a prolonged serum half-life compared with others, permitting its once-daily use for treatment of exquisitely susceptible organisms. The infrequent dosing and the ability to use either intramuscular or intravenous routes of administration have permitted outpatient therapy of serious, invasive infections at a point when the child’s clinical condition is stable. The use of ceftriaxone for treating MSSA skin infections is discouraged, despite this being an FDA approved indication. Very high ceftriaxone protein binding (>95%) and relatively high ceftriaxone MICs limit the amount of free ceftriaxone available to adequately eradicate MSSA, particularly in high-density infections and undrained abscesses.
The fourth-generation cephalosporin, cefepime, maintains activity against P. aeruginosa and displays enhanced stability to the AmpC chromosomal β-lactamases of Enterobacter, Serratia, and Citrobacter spp. due to the pyrrolidinium moiety on the R2 side chain ( Fig. 292.4B ) while retaining significant (but not optimal) activity against MSSA ( Table 292.1 ). This broad activity permits empiric therapy of neutropenic children with fever and permits treatment of a wide variety of nosocomial gram-negative infections. However, lack of activity against B. fragilis and against Enterococcus limits the ability to treat intra-abdominal infections with cefepime alone.
The fifth-generation cephalosporins, ceftaroline and ceftobiprole, combine the gram-negative and gram-positive activity of the third-generation cephalosporins with in vitro and clinically demonstrable activity against MRSA. These agents have been designed to bind to and inactivate PBP2a, the PBP responsible for β-lactam resistance in MRSA and coagulase-negative staphylococci, and to PBP2x in Pneumococcus, providing clinically relevant activity against MRSA and penicillin-resistant pneumococci superior to all other currently available β-lactam agents. Ceftaroline’s two-step mechanism of overcoming PBP2a resistance was described earlier. Ceftobiprole’s mechanism is different, only requiring one step to directly inhibit the PBP2a enzyme at the active site through multiple hydrogen bonds as opposed to covalent binding at the PBP active site like all other β-lactams. Ceftobiprole is also unique among cephalosporins for its activity against ampicillin-susceptible E. faecalis . However, ceftobiprole and ceftaroline are not adequately active against Pseudomona or Bacteroides and are not stable to ESBLs or carbapenemases. Ceftaroline was the first anti-MRSA fifth generation cephalosporin to be approved in the US for neonates, infants, and children, and currently is the only fifth-generation cephalosporin available in the US. Approval for ceftaroline was based on studies for skin infections and community-acquired pneumonia, as well as late-onset neonatal sepsis. Therapy should be effective for any infection caused by susceptible pathogens, including those caused by MRSA or penicillin-resistant pneumococci, although no prospective data are available for CNS infections treated with ceftaroline. MRSA resistance to ceftaroline has been reported in patients treated with repeated courses for pulmonary exacerbations of cystic fibrosis.
Cefiderocol is a new cephalosporin designed to treat multidrug resistant gram-negative bacteria that is under investigation in children. This compound is structurally similar to both ceftazidime and cefepime, with an additional chlorocatechol moiety on the end of the R2 side chain ( Fig. 292.4B ). This key moiety chelates iron giving the drug “siderophore” properties, capable of being efficiently transported into the bacteria cloaked as iron nutrition, hitching a ride on the cellular active iron transport system. This delivery mechanism allows cefiderocol to overcome porin entry barriers and efflux pump effects, while the structure itself is also resistant to most β-lactamases including MBLs. However, cefiderocol lacks any substantial Gram-positive activity. Cefiderocol currently represents the broadest of all the carbapenemase-resistant gram-negative antibacterial agents ( Table 292.1 ).
Carbapenems, also naturally occurring, were initially isolated from S. cattleya , with the β-lactam moiety contained within a carbapenem nucleus ( Fig. 292.4B ). Carbapenems demonstrate the broadest spectrum of activity (gram-positive and gram-negative activity against both aerobes, facultative and anaerobic organisms) of all the β-lactam antibiotics and currently include imipenem, meropenem, and ertapenem. Carbapenems are active against both gram-positive pathogens, including MSSA (but not MRSA), and streptococci with moderate activity against ampicillin-susceptible enterococci (imipenem is more active against gram-positives than meropenem and ertapenem), and gram-negative pathogens (including P. aeruginosa for imipenem, meropenem, but not ertapenem), with enhanced stability against both the chromosomal ampC β-lactamases of Enterobacter, Serratia, and Citrobacter spp. and the ESBLs of E. coli and Klebsiella ( Table 292.1 ). They are all also highly active against anaerobic organisms, including β-lactamase−producing strains of Bacteroides and Prevotella. Carbapenems are used primarily for infections that require coverage for gram-positive and gram-negative bacteria that includes both aerobes and anaerobes. Common examples for single-antibiotic therapy include intraabdominal infections such as appendicitis and deep head and neck space infections. In addition, the broad spectrum of activity is important for hospital-acquired infections caused by resistant organisms, and for infections in immunocompromised hosts. Imipenem is paired with cilastatin, a renal dehydropeptidase inhibitor that inhibits the destruction of imipenem by renal tubular enzymes, providing both an increase in the serum half-life of imipenem and a decrease in the renal toxicity of the compound. Imipenem use was associated with unexpected seizures in an open, noncomparative clinical trial in children with meningitis, probably attributable to competitive inhibition of the inhibitory CNS neural pathways. Therefore meropenem, which does not produce clinically detectable CNS side effects, is the preferred carbapenem agent for treatment of CNS infections, including meningitis, brain abscess, epidural abscess, and subdural empyema. Meropenem is also the preferred and best-studied carbapenem in neonates with intra-abdominal infections or with septicemia due to ESBL producing gram-negative bacteria. , In addition to the infections already mentioned, data support clinical and microbiologic efficacy of the carbapenems in children with pneumonia, complicated UTIs, intra-abdominal infections, wound infections, bone and joint infections, and skin and skin structure infections. , Imipenem and meropenem are also appropriate as single-drug empiric therapy of fever and neutropenia in immunocompromised children. Ertapenem has the most prolonged serum half-life of the carbapenems and requires only once-daily dosing in older children (≥13 years of age) and once- or twice-a-day dosing in younger children, although it should not be used for meningitis or other pediatric CNS infections due to lack of data. Carbapenems provide the best activity of all β-lactam agents against pathogens harboring either chromosomally mediated ampC β-lactamases or ESBLs. Use of such broad-spectrum agents must be weighed against the risk for promoting resistance and profoundly altering normal flora. Recent emergence of carbapenemase-producing Klebsiella and other carbapenem-resistant Enterobacteriaceae (CRE) have limited the usefulness of these broad-spectrum agents in certain regions of the world. In response to these threats, 3 BLI combination drugs have been developed: ceftazidime-avibactam, imipenem-cilastatin-relebactam, and meropenem-vaborbactam. These are effective against CRE due to KPC and other Class A carbapenemases and to AmpC β-lactamase. However, vaborbactam is not active against Oxa-48 carbapenemase (see ceftazidime-avibactam above, and Chapter 290 ). Interestingly, ceftazidime-avibactam and imipenem-cilastatin-relebactam restore susceptibility to some strains of carbapenem-resistant P aeruginosa , whereas meropenem-vaborbactam may not based on multiple evolving mechanisms of resistance with penetration of drugs through the cell envelope, efflux pumps, and the presence of multiple lactamases, each with different affinities for the β-lactam structure, each with different degrees of inhibition by the BLI.
Monobactams have a unique β-lactam structure and are a naturally occurring antibiotic isolated from Chromobacterium spp. In contrast to penicillins, cephalosporins, and carbapenems, monobactams are not fused to an adjacent ring. Aztreonam, the only available agent in this class, has been modified chemically with a side chain identical to ceftazidime ( Fig. 292.2 ) and demonstrates gram-negative and anti-pseudomonal activity comparable with ceftazidime, but also without significant gram-positive or anaerobic activity. Clinical use in pediatrics is limited primarily to treatment of community-acquired infections in which enteric gram-negative organisms are suspected, or proven pathogens and aminoglycosides are not adequate or appropriate therapy. The aztreonam monobactam ring is naturally resistant to the broad spectrum MBLs. Unfortunately, organisms that express MBLs usually express other β-lactamase enzymes (ESBLs and carbapenemases), against which aztreonam (like ceftazidime) is not resistant. ,
Aztreonam is also available in an inhalation form that can also be given to children with cystic fibrosis who are 7 years or older for the treatment of P. aeruginosa lower respiratory tract infection.
Glycopeptides interfere with cell wall formation in the steps that create the glycan chains before cross-linking the chains in the formation of PG ( Fig. 292.3 ). Glycopeptides have a large, complex structure that consists of a heptapeptide core cross-linked with various aromatic amino acid-derived sidechains and glycosylated with disaccharides. Strong hydrogen bonds occur between the antibiotic and the terminal d -alanine, d -alanine dipeptide of the pentapeptide side chains of the MurNAc subunits of the glycan chain. When bound, the glycopeptides sterically prevent the transglycosylation steps required for lengthening the glycan chain. Glycopeptide antibiotics are active primarily against gram-positive organisms, in which the cell wall construction occurs outside the cell membrane ( Fig. 292.2 ). The negatively charged LPS on gram-negative cell outer membranes provide a repulsion barrier to the diffusion of the polar hydrophilic glycopeptides into the cell. The glycopeptides are also too large to be transported through gram-negative membrane porin channels. Hence, these agents are only active against gram-positive organisms, including the anaerobic genera Clostridia , Peptostreptococcus , and Propionibacterium . Their large size and polarity prevent adequate enteral or intramuscular absorption for therapy of systemic infection by these routes and must be given intravenously. The glycopeptides currently available in the US are vancomycin, and the semisynthetic lipoglycopeptides (LGPs) dalbavancin, oritavancin, and telavancin. All are bactericidal.
Vancomycin is a natural product, originally isolated from Amycolatopsis orientalis in 1956 (formerly Streptomyces orientalis) . Originally developed to treat staphylococcal infections, vancomycin was rarely used following the availability of the penicillinase-stable penicillins, which were tolerated better. However, since the first appearance of healthcare-associated MRSA 4 decades ago, vancomycin has played an important role in the treatment of nosocomial S. aureus and coagulase-negative staphylococcal (CoNS) infections. With current prevalence of CA-MRSA, vancomycin now is used routinely for empiric therapy of serious suspected staphylococcal infections. , Decreased bactericidal activity and clinical efficacy of vancomycin compared with the penicillinase-stable penicillins for treatment of MSSA, as well as greater toxicity, make β-lactams preferred therapy for infections caused by MSSA, and with increasing experience with ceftaroline and ceftobiprole, it is likely that these β-lactams will replace vancomycin for treatment of most MRSA and CoNS infections.
Resistance to vancomycin has developed in two main ways. In Enterococcus spp., vanA -mediated resistance, which alters the PG peptide-binding target, leads to vancomycin-resistant enterococci (VRE), which are completely resistant to vancomycin (see Chapter 290 ). The vanA high-level resistance mechanism has also been detected in S. aureus infecting adults, creating vancomycin-resistant S. aureus (VRSA). A more common resistance mechanism of S. aureus to vancomycin are strains with mutant PG synthesis regulatory proteins that create a disorganized, thickened cell wall that can trap vancomycin before it reaches its target on the outside surface of the cytoplasmic membrane. This produces a heterogeneous population of intermediately susceptible S. aureus strains or hVISA. Under vancomycin pressure, these strains, which are present in every large population of staphylococci, are selected. Some in vitro data suggest that achieving target vancomycin exposures may help prevent the emergence of hVISA (see Chapter 291 ).
Clinical uses of vancomycin include therapy for gram-positive infections in children who are allergic to penicillin, therapy of infections caused by S. pneumoniae that are resistant to penicillin, and therapy of infections caused by MRSA. Treatment of Clostridioides difficile infections with orally administered vancomycin is highly effective but is not first-line therapy due to the emergence of VRE following oral vancomycin therapy. In selected cases of moderate to severe disease or metronidazole failure, vancomycin enterally represents highly effective alternative therapy.
Emerging ways to use vancomycin include combination therapy with anti-staphylococcal β-lactams to treat hVISA and VISA, and by the inhaled route to treat MRSA-related pulmonary exacerbations of cystic fibrosis. ,
A common reaction that can occur within 30–60 minutes of beginning an infusion of vancomycin is the red man syndrome, or vancomycin flushing reaction. Characterized by pruritis, rash, and flushing, this effect is histamine mediated and not immunoglobulin E mediated or immune mediated, is not an allergic reaction, and is distinct from anaphylaxis. The risk of developing the vancomycin flushing side effect increases with dose per kg, infusion concentration, and in children with a history of the side effect. The risk is significantly less in children <2 years of age. This side effect was first recognized in adults receiving rapid infusion (<30 minutes), which would sometimes also cause hypotension. This led to a traditional approach of administering over at least 1–2 hours, although the side effect still can occur at slower rates. For children who develop a flushing reaction, the vancomycin infusion time should be prolonged from baseline. Treating or pretreating with an antihistamine may alleviate some but not all symptoms and permit continuation of therapy with vancomycin.
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