Resistance p-lactam antibiotics

Bacteria produce chromosomady and R-plasmid (resistance factor) mediated P-lactamases. The plasmid-mediated enzymes can cross interspecific and intergeneric boundaries. This transfer of resistance via plasmid transfer between strains and even species has enhanced the problems of P-lactam antibiotic resistance. Many species previously controded by P-lactam antibiotics are now resistant. The chromosomal P-lactamases are species specific, but can be broadly classified by substrate profile, sensitivity to inhibitors, analytical isoelectric focusing, immunological studies, and molecular weight deterrnination. Individual enzymes may inactivate primarily penicillins, cephalosporins, or both, and the substrate specificity predeterrnines the antibiotic resistance of the producing strain. Some P-lactamases are produced only in the presence of the P-lactam antibiotic (inducible) and others are produced continuously (constitutive). 

More recently the whole picture of antibiotic resistance has become better understood as a very complex phenomenon. Even with P-lactam antibiotics, resistance factors other than the mere production of hydrolytic P-lactamase enzymes are operative. In the late 1960s methicillin-resistant staphylococci began to appear as nosocomial infections. In fact these resistant strains show multiple resistance both to P-lactams as well as to antibiotics with different structures and different mechanisms of action.14... 

The concept of synergistically overcoming p-lactamase resistance by concomitant use of a P-lactam antibiotic resistant to P-lactamase hydrolysis with one sensitive to it is theoretically sound. The expectation is that the sensitive compound would be spared destruction and would add its bacterial effect to that of the resistant compound. Even though in vitro results seemed promising, clinically the synergism achieved was not enough. 

Moreover, 47 shows selective response to the lysates of bacteria (e.g., Escherichia coli) containing different types of P-lactamases. This result provides a simple, low-cost strategy to identify P-lactam antibiotic resistant pathogens and to screen the inhibitors of P-lactamases [86]. 

C QHyN O SNa, as a potentially useful P-lactamase inhibitor capable of potentiating the activity of a number of clinically important P-lactam antibiotics against resistant strains (153). 

The antibacterial effectiveness of penicillins cephalospotins and other P-lactam antibiotics depends upon selective acylation and consequentiy, iaactivation, of transpeptidases involved ia bacterial ceU wall synthesis. This acylating ability is a result of the reactivity of the P-lactam ring (1). Bacteria that are resistant to P-lactam antibiotics often produce enzymes called P-lactamases that inactivate the antibiotics by cataly2ing the hydrolytic opening of the P-lactam ring to give products (2) devoid of antibacterial activity. 

One approach to combating antibiotic resistance caused by P-lactamase is to inhibit the enzyme (see Enzyme inhibition). Effective combinations of enzyme inhibitors with P-lactam antibiotics such as penicillins or cephalosporins, result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, inhibition of P-lactamases alone is not sufficient. Pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. Almost any class of P-lactam is capable of producing P-lactamase inhibitors. Several reviews have been pubUshed on P-lactamase inhibitors, detection, and properties (8—15). 

The total U.S. antibiotic market for 1990 was about 4.73 biUion, 233 million of that was tetracyclines. The development of the semisynthetic P-lactam antibiotics (see Antibiotics, P-LACTAMs) and emergence of resistance to the tetracyclines has steadily diminished the clinical usefulness of tetracyclines. 

P-Lactamases (EC 3.5.2.6) produced by bacteria cleave the P-lactam ring and are responsible for their resistance to P-lactam antibiotics. Lactamases are useful catalysts for the enantioselective hydrolysis of P-lactams and other cyclic amides. P-lactams shown in Figure 6.40 were resolved by whole-cell systems containing an amidase [106]. 

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... 

Of particular note is the combination of amoxicillin and clavulanic acid. The latter is a potent inhibitor of enzymes that degrade amoxicillin and many other p-lactam antibiotics. This combination, marketed as Augmentin, increases the efficacy of amoxicillin against organisms that would be otherwise resistant to it. It is among the most widely used antibiotics in the United States. 

B. Overproduction (A) of PABA is one of the resistance mechanisms of sulfonamides. Changes in the synthesis of DNA gyrases (B) is a well-described mechanism for quinolone resistance. Plasmid-mediated resistance (C) does not occur with quinolones. An active efflux system for transport of drug out of the cell has been described for quinolone resistance, but it is not plasmid mediated. Inhibition of structural blocks (D) in bacterial cell wall synthesis is a basic mechanism of action of p-lactam antibiotics. Inhibition of folic acid synthesis (E) by blocking different steps is the basic mechanism of action of sulfonamides. 

A number of microorganisms have evolved mechanisms to overcome the inhibitory actions of the p-lactam antibiotics. There are four major mechanisms of resistance inactivation of the p-lactam ring, alteration of PBPs, reduction of antibiotic access to PBPs, and elaboration of antibiotic efflux mechanisms. Bacterial resistance may arise from one or more than one of these mechanisms. 

An additional mechanism of antibiotic resistance involves an alteration of PBPs. Resistant bacteria, usually gram-positive organisms, produce PBPs with low affinity for p-lactam antibiotics. The development of mutations of bacterial PBPs is involved in the mechanism for p-lactam resistance in Streptococcus pneumoniae. Enterococcus faecium, and methicillin-resistant S. aureus (MRS A). 

Other P-lactam antibiotics have revolutionized our understanding of the structure-activity relationships in this large group of antibiotics. Thienamycin (9.53), discovered in 1976, is a broad-spectrum antibiotic of high activity. It is lactamase resistant because of its hydroxyethyl side chain but is not absorbed orally as it is highly polar. Unfortunately,... 

Structure-activity correlations in the P-lactam antibiotic field have required drastic re-evaluation in view of the novel structures described above. Apparently, only the intact P-lactam ring is an absolute requirement for activity. The sulfur atom can be replaced (moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unnecessary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase resistance. The amide side chain, so widely varied in the past, is also unnecessary, as shown in the example of thienamycin. There is a considerable literature analyzing the classical structure-activity relationships of the penicillin and cephalosporin groups. 

The transpeptidase activity of PBPs is well characterized, mainly due to its important role in bacterial resistance to P-lactam antibiotics [1-3,15,23-27], The transpeptidase activity can be characterized by its ability to bind to different P-lactams and to hydrolyze analogs of bacterial cell wall stem peptides [1,2,15,28-35], A crystal structure has been described for the transpeptidase domain of the Streptococcus pneumoniae PBP2x protein, a member of class B PBPs [36],... 

II. ROLE OF PBPs IN BACTERIAL RESISTANCE TO P-LACTAM ANTIBIOTICS... 

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