13- Lactam susceptibility

Antibiotics used for empirical treatment of community-acquired intraabdominal infections should be active against empiric gram-negative aerobic and facultative bacilli and /5-lactam-susceptible gram-positive cocci. 

In addition to variable chemical stabiUty the carbapenems are susceptible to P-lactam cleavage by a dehydropeptidase en2yme (DHP-I) located on the bmsh borders of the kidney (53). Clinically, MK 0787 (18) is used with an inhibitor of this en2yme, cil a sta tin [78852-98-9] (MK 0791) (34), 16 26 2 5 dramatic effect not only on the urinary recovery of the drug, but also reduces any nephrotoxic potential (52) (see Enzyme... 

Certain penicillins and penam derivatives have the ability to inhibit the /3-lactamase enzyme, and can provide a variable degree of protection to susceptible /3-lactam antibiotics... 

The 3-lactam antibiotics are cell-wall inhibitors toward susceptible bacteria. To survive in a hostile environment with ionic strengths often quite different from the interior of the cell, bacteria have evolved a rigid, quite complex cell wall. 

Vancomycin is bactericidal to most susceptible bacteria at concentrations near its minimum inhibitory concentration (MIC) and is an inhibitor of bacterial cell wall peptidoglycan synthesis, although at a site different from that of j3-lactam antibiotics (Chapter 9). 

A second mechanism of resistance involves alterations in PBPs which affect binding of /3-lactams. These changes have been found to occur by multiple substitutions through recombination rather than point mutations. Acquired penicillin resistance in Strep, pneumoniae is because of such gene mosaics which code for an altered yet functional PBP with reduced affinity for penicillin. Sections of the susceptible PBP gene have been replaced by other DNA sequences, presumably via transformation. 

Once the organism has been identified and sensitivities are known, drug selection should be adjusted to reflect the susceptibilities of the organism. Streptococcal, staphylococcal, and enterococcal species sensitive to P-lactam antibiotics should be treated with continuous IP dosing to increase efficacy and minimize resistance.49 Peritonitis caused by S. aureus or P. aeruginosa are often associated with catheter-related... 

Development of resistance to P -lactam antibiotics, including penicillins and cephalosporins, has significantly impacted the management of bacterial meningitis. Approximately 17% of United States pneumococcal CSF isolates are resistant to penicillin, and 3.5% of CSF isolates are resistant to cephalosporins.26 The Clinical and Laboratory Standards Institute (CLSI) has set a lower ceftriaxone susceptibility breakpoint for pneumococcal CSF isolates (1 mg/L) than for isolates from non-CNS sites (2 mg/L). Increasing pneumococcal resistance to penicillin G... 

Patients with PVE caused by penicillin-susceptible strains of viridans streptococci require treatment for 6 weeks with penicillin G or ceftriaxone with or without gentamicin during the initial 2 weeks of therapy. However, if the organism demonstrates less susceptibility to penicillin (MIC greater than 0.12 mcg/mL), a combination therapy with penicillin G or ceftriaxone plus gentamicin should be given for the entire 6 weeks. Vancomycin remains the primary alternative if the patient is allergic to (l-lactams (e.g., penicillins, cephalosporins, etc.). 

For penicillin-allergic (nonanaphylactoid type) patients cefazolin 6 g/24 hours IV in 3 equally divided doses 6 IB Consider skin testing for oxacillin-susceptible staphylococci and questionable history of immediate-type hypersensitivity to penicillin cephalosporins should be avoided in patients with anaphylactoid-type hypersensitivity to P-lactams vancomycin should be used in these cases ... 

Penicillin G 24 million units/24 h IV in four to six equally divided doses may be used in place of nafcillin or oxacillin if strain is penicillin susceptible (minimum inhibitory concentration 0,1 mcg/mL) and does not produce /5-lactamase vancomycin should be used in patients with immediate-type hypersensitivity reactions to beta-lactam antibiotics (see Table 37-3 for dosing guidelines) cefazolin may be substituted for nafcillin or oxacillin in patients with non-immediate-type hypersensitivity reactions to penicillins... 

In the case of /3-lactam antibiotics, the bacterial targets are the so-called PBPs. Modification of PBPs can result in a decreased affinity for /1-lactam antibiotics. In some cases the normal PBPs, through mutation, become less susceptible to acylation and inactivation by /3-lactam antibiotics. So, the target protein is unable to bind the antibiotic effectively, and hence resistance to a particular antibiotic is acquired [5]. Frequently, this difference consists of substitution of a single amino acid in the protein chain. In S. aureus, ac-... 

Beginning in the late 1980s, three -lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) have been used against serine enzymes, usually in combination with penicillins more susceptible to /1-lactamase hydrolysis. This therapeutic strategy has been effective over two decades. The following section provides a brief overview on various classes of -lactam-based inhibitors. 

What about the susceptibility of lactam metabolites to metabolic hydrolysis to yield the corresponding co-amino acid metabolite Little is... 

The quinoline antibiotics are relatively late arrivals on the antibiotic scene. The parent compound of this class of drugs is nalidixic acid. The downside of this molecule is the rapid development of resistance by pathogenic bacteria. A major step forward was the introduction of a single fluorine atom at a key position, to yield new molecules such as ciprofloxacin, ofloxacin, levofloxacin, andmoxifloxacin. Of these, levofloxacin and moxifloxacin have the best combinations of spectrum of action, potency, and pharmacokinetic properties. In time, they are likely to largely replace the current quinoline antibiotic of choice, ciprofloxacin. Since these molecules work by a different mechanism than do the p-lactams, organisms that become resistant to the latter are generally susceptible to the former. 

This selectivity is not achievable by simple chemical hydrolysis, since the strained P-lactam ring is much more susceptible to nucleophilic attack than the unstrained side-chain amide function. Normally, the electron-donating effect from the lone pair of the adjacent nitrogen stabilizes the carbonyl against nucleophilic attack (see Section 7.9.2) this is not possible with the P-lactam ring because of the geometric restrictions (see Box 3.20). 

The range of monomers that can be incorporated into block copolymers by the living anionic route includes not only the carbon-carbon double-bond monomers susceptible to anionic polymerization but also certain cyclic monomers, such as ethylene oxide, propylene sulfide, lactams, lactones, and cyclic siloxanes (Chap. 7). Thus one can synthesize block copolymers involving each of the two types of monomers. Some of these combinations require an appropriate adjustment of the propagating center prior to the addition of the cyclic monomer. For example, carbanions from monomers such as styrene or methyl methacrylate are not sufficiently nucleophilic to polymerize lactones. The block copolymer with a lactone can be synthesized if one adds a small amount of ethylene oxide to the living polystyryl system to convert propagating centers to alkoxide ions prior to adding the lactone monomer. 

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