Info

Decreased uptake Altered target

Aminoglycoside resistance in a variety of gram-negative bacteria

Enterococcal resistance to streptomycin (may also be mediated by enzymatic modifications)

Quinolones (e.g., ciprofloxacin, ofloxacin, levofloxacln, norfloxacin, lomefloxacin)

Decreased uptake Altered target

Alterations in the outer membrane diminishes uptake of drug and/or activation of an "efflux" pump that removes quinolones before Intracellular concentration sufficient for inhibiting DNA metabolism can be achieved

Changes In the DNA gyrase subunits decrease ability of quinolones to bind this enzyme and interfere with DNA processes

Gram-negative and staphylococcal (efflux mechanism only) resistance to various quinolones fHJinjyrf'ii.'lilJlTVli^" "MfffcHi ii : ■ <f-i't(Tli.,|"Jlll-£ll^' "H:. rn

Gram-negative and gram-positive resistance to various quinolones

Macrolides (e.g., erythromycin, azithromycin, clarithromycin)

Efflux

Altered target

Pumps drug out of cell before target binding

Enzymatic alteration of ribosomal target reduces drug binding

Various streptococci and staphylococci Various streptococci and staphylococci

11-10). Beta-lactamases also vary in their spectrum of substrates, that is, not all beta-lactams are susceptible to hydrolysis by every beta-lactamase. For example, staphylococcal beta-lactamase can readily hydrolyze penicillin and penicillin derivatives, such as ampi-cillin, mezlocillin, and piperacillin, but this enzyme cannot effectively hydrolyze many cephalosporins or imipenem.

  • f P-lactamase -j_.Unable to
  • I bind PBPs

Figure 11-9 Mode of beta-iactamase enzyme activity. By cleaving the beta-lactam ring, the molecule can no longer bind to penicillin-binding proteins (PBPs) and is no longer able to inhibit cell wall synthesis. (Modified from Salyers AA, Whitt DD, editors; Bacterial pathogenesis: a molecular approach, Washington, DC, 1994, ASM Press.)

Various molecular alterations in the beta-lactam structure have been developed to protect the beta-lactam ring against enzymatic hydrolysis. This development has resulted in the production of more effective antibiotics in this class. For example, methidllin and closely related agents oxacillin and nafcillin are molecular derivatives of penicillin that by the nature of their structure are riot susceptible to staphylococcal beta-lactamases. These agents are the mainstay of antistaphylococcal therapy. Similar strategies have been applied to develop penicillins and cephalosporins that are more resistant to the variety of beta-lactamases produced by gram-negative bacilli. Even with this strategy, it is important to note that among common gram-negative bacilli (e.g„ Enterobacteriaceae, P. aeruginosa, and Acinetobacter spp.), the list of molecular types and numbers of beta-lactamases continues to emerge and diverge, thus challenging the effectiveness of currently available beta-lactam agents.

Another therapeutic strategy has been to combine two different beta-lactam drugs. One of the beta-lactams (the beta-lactamase inhibitor) avidly and irreversibly binds to the beta-lactamase and renders the enzyme incapable of hydrolysis, while the second beta-lactarn, which is susceptible to beta-lactamase activity, exerts its antibacterial activity. Examples of beta-lactam/beta-lactamase inhibitor combinations include ampicillin/sulbactam, amoxicillin/clavulanic add, and piperacillin/ tazobactam.

Altered targets also play a key role in clinically relevant beta-lactam resistance (see Table 11-3). By this pathway the organism changes, or acquires from another organism, genes that encode altered cell Wall-synthesizing enzymes (i.e., PBPs). These "new* PBPs continue their function even in the presence of a beta-lactam antibiotic, usually because the beta-lactam lacks suffident affinity for the altered PBP. This is the mechanism by which staphylococd are resistant to methicillin and all other beta-lactams (e.g., cephalosporins and imipenem). Therefore, strains that exhibit this mechanism of resistance must be challenged with a non-beta-lactam agent, such as vancomycin, that acts on the cell wall. Changes in PBPs are also responsible for ampidllin resistance in Enterococcus faedum and in the widespread beta-lactam resistance observed in 5. pneumoniae and viridans streptococd, organisms that to date have not been known to produce beta-lactamase.

Because gram-positive bacteria do not have outer membranes through which beta-lactams must pass before reaching their PBP targets, decreased uptake is not a pathway for beta-lactam resistance among these bacteria. However, diminished uptake can contribute significantly to beta-lactam resistance seen in gram-negative bacteria (see Figure 11-10). Changes in the number or characteristics of the outer membrane porins through which beta-lactams pass contribute to absolute resistance (e.g., P. aeruginosa resistance to imipenem). Additionally, porin changes combined with the presence of certain beta-lactamases in the peri-plasmic space may result in clinically relevant levels of resistance.

Resistance to Glycopeptides

To date, acquired, high-level resistance to vancomycin has been commonly encountered among enterococd, rarely among staphylococd, and not at all among streptococd. The mechanism involves the production of altered cell wall precursors that do not bind vancomydn with suffident avidity to allow inhibition of peptidoglycan synthesizing enzymes. The altered targets are readily incorporated into the cell wall so that synthesis progresses as usual (see Table 11-3). A second mechanism of resistance to glycopeptides, described only among staphylococd to date, results in a lower level of resistance and is thought to be mediated by overproduction of the peptidoglycan layer, resulting in excessive binding of the glyco-peptide molecule and diminished ability for the drug to exert its antibacterial effect.

Vancomydn is the only cell wall-inhibiting agent for use against gram-positive organisms that are resistant to all currently available beta-lactams (e.g., methicillin-resistant staphylococd and ampicillin-resistant enterococd). Therefore, the potential for vancomycin resistance to spread to other gram-positive genera poses a serious threat to public health. Resistance to vancomydn by enzymatic modification or destruction has not been described.

Resistance to Aminoglycosides

Analogous to beta-lactam resistance, aminoglycoside resistance is accomplished by enzymatic, altered target, or decreased uptake pathways (see Table 11-3). Grampositive and gram-negative bacteria produce several

1 Beta-lactamase -Staphylococci -Enterococci

Penicillin-binding proteins (PBP)

Beta-lactams

Murein

  • peptldogiycan layer
  • Cell membrane

2. Altered target -Staphylococci -Pneumococci -Enterococci

Penicillin-binding proteins (PBP)

Beta-lactams

Murein

■ peptldogiycan layer

2. Altered target -Staphylococci -Pneumococci -Enterococci

— Cell membrane

Figure 11-10 Diagrammatic summary of beta-Iactam resistance mechanisms for gram-positive and gram-negative bacteria. A, Among gram-positive bacteria, resistance is mediated by beta-lactamase production and altered PBP targets. B, In gram-negative bacteria, resistance can also be mediated by decreased uptake through the outer membrane porins.

different aminoglycoside-modifying enzymes. Three general types of enzymes catalyze one of the following modifications of an aminoglycoside molecule (see Figure 11-4):

  • Phosphorylation of hydroxyl groups
  • Adenylylation of hydroxyl groups
  • Acetylation of amine groups

Once an aminoglycoside has been modified, its affinity for binding to the 30S ribosomal subunit may be sufficiently diminished or totally lost so protein synthesis is able to continue unabated.

Aminoglycosides enter the gram-negative cell by passing through outer membrane porin channels. Therefore, porin alterations may also contribute to aminoglycoside resistance among these bacteria. Although some mutations that result in altered ribosomal targets have been described, the altered target pathway is thought to be a rare means for bacteria to achieve resistance to most commonly used aminoglycosides.

3. Altered target

Porins

1. Decreased uptake

Outer membrane

Periplasmic space Peptidoglycan layer

Cell membrane

Beta-lactams

Porins

1. Decreased uptake

Outer membrane

Periplasmic space Peptidoglycan layer

Cell membrane

Beta-lactams

3. Altered target

Penicillin-binding proteins (PBP)

Cytoplasm

BOX 11 -3 Bacterial Resistance Mechanisms tor Miscellaneous Antimicrobial Agents

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Bacterial Vaginosis Facts

Bacterial Vaginosis Facts

This fact sheet is designed to provide you with information on Bacterial Vaginosis. Bacterial vaginosis is an abnormal vaginal condition that is characterized by vaginal discharge and results from an overgrowth of atypical bacteria in the vagina.

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