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Omp F and Omp C are the two main porins, with Omp F being most permeable to beta-lactam agents. Some mutants which lack Omp F porins can be resistant to beta-lactams due to decreased and slower penetration through the remaining porins (Omp C) and subsequent increased beta-lactamase degradation (66).

Binding to the PBP is necessary for the penicillin to exert its antibacterial effect. There are natural differences in the affinity for penicillin to a PBP. For instance, the affinity of the Enterococcal PBP to the antistaphylococcal penicillins is very low versus a high affinity to penicillin G or buy amoxicillin 250mg ampicillin. This accounts for the resistance seen in the case of oxacillin and Enterococcus.

Mutations can occur which can result in changes in susceptibility of an organism, which is “normally” susceptible to a particular penicillin, usually by producing PBPs with a decreased affinity to the penicillin. An alteration in PBP2 byВ Staphylococcus В to PBP2a results in methicillin resistance, as PBP2a exhibits a decreased affinity for methicillin and most other beta-lactam agents (102). WithВ Staphylococcus aureus В (241) this type of production of PBPs with decreased affinity for the penicillin is inducible by exposure to the agent, resulting amoxil 500 price in decreased susceptibility to low concentrations of the drug.

An important example of bacteria that can develop such mutations that confer resistance isВ Streptococcus pneumoniae В that is penicillin-resistant.

The resistance mutation is genetically coded with "mosaics" that are made up of native pneumococcal DNA and DNA that is presumably from another streptococcal species, such as viridans streptococci, more amoxicillin 500 for uti resistant to penicillin (93,127). The genes that appear to be most affected are PBP 2b and 2x.

The current interpretive MIC breakpoints for penicillin as determined by the National Committee for Clinical Laboratory Standards (NCCLS) are 48 hours is an indication for repeat desensitization (210).

Cross-Reactivity with Other Beta-Lactams and Related Compounds.

There is a concern over the potential for allergy to other beta-lactam compounds, such as cephalosporins, aztreonam, and the carbapenems, in patients allergic to penicillin.

Estimates of cross-reactivity with cephalosporins range from 2-10% (182,В 195), though there is data to suggest that the incidence is much lower (6). No major or minor determinants exist with cephalosporins, which could account for the low cross-reaction potential.

Cross reaction with the carbapenems may also occur, however the monobactams (aztreonam) appear the have a low propensity for eliciting an immune response and have not shown a cross-reaction with penicillin antibodies when testedВ in vitro В (1). The bulky side chain, rather than the beta-lactam ring may be the site of immunologic reactivity.

TheВ in vitro В studies (1,В 201) also demonstrated that cross-reaction between aztreonam and ceftazidime occurred, which is expected since the two compounds have identical side chains. Though the risk of cross-reactivity appears to be low, in patients with a history of severe allergy it may be prudent to avoid the use of cephalosporins as good therapeutic alternatives are available.

The potential for a cross-reaction with penicillamine has also been explored, as penicillamine is a metabolite of penicillin degradation. A study examined 40 patients with a positive history of penicillin allergy. Sixteen patients skin tested positive for sensitivity to penicillin only and 1 patient had a positive penicillamine skin test (21). This data suggests that the incidence of cross-reaction is low, but that penicillamine should be administered with caution to these patients. The penicillins are associated with several adverse effects.

These adverse effects will be discussed according to body system affected.

Perhaps the most common adverse reaction to orally administered penicillins is gastrointestinal effects.

Diarrhea can occur in up to 20% and 5% of patients receiving oral ampicillin and amoxicillin, respectively. The incidence may be increased to up to 40% in children.

Other effects, such as nausea, vomiting, and epigastric distress may also occur. Diarrhea has also been reported in patients receiving intravenous penicillins (approximately 3%).

Antibiotic-associated pseudomembranous colitis caused byВ Clostridium difficile , may occur during or immediately after therapy with a penicillin due to changes in normal bowel flora from the broad spectrum coverage and overgrowth of this organism. WhileВ Clostridium difficile В is “sensitive” to ampicillin and amoxicillin, it produces spore form, which survives.

In the scenario of diarrhea associated with presence ofВ Clostridium difficile В and depending upon the severity of illness, appropriate treatment with metronidazole or oral vancomycin should be considered. Rash may occur with administration of any penicillin.

Patients are over twice as likely to develop a rash while receiving ampicillin or amoxicillin (5-10%) versus the other penicillins (2%) (138).

The ampicillin rash is maculopapular and is often self-limited. Patients who have infectious mononucleosis, cytomegalovirus infection, chronic lymphocytic leukemia, or are on concurrent allopurinol are at increased risk of development of such a rash. Neutropenia can occur with administration of any penicillin at an estimated incidence of 3-8%.

Risk factors include high doses for a prolonged (> 10 day) period of time (166,В 176) and hepatic impairment (212). The mechanism may be due to immune complex deposition on the neutrophil cell membranes (198). Patients should be monitored for this adverse effect if prolonged treatment courses are used.

Inhibition of platelet aggregation can occur due to alterations in adenosine diphosphate responses, particularly with ticarcillin and carbenicillin. Prolonged bleeding times can result, along with actual bleeding (2,В 4,В 82,В 226). Patients with thrombocytopenia and/or azotemia appear to be at increased risk.

Increased bleeding times were seen in a study of 156 patients receiving ticarcillin (73%), piperacillin (43%), mezlocillin (25%), or cefotaxime (17%).

Though some patients were receiving chemotherapy, which could confound results, the trend remained after those patients were removed from the analysis.

Bleeding occurred in 34%, 17%, and 2% of patients receiving ticarcillin, piperacillin, and mezlocillin, respectively (82). This effect generally reverses upon drug discontinuation. Increased doses and resultant serum concentrations of penicillin G have been associated with encephalopathy, particularly in patients with severe renal impairment (30).

Seizures can also be induced with elevated CSF concentrations of any penicillin (208). Predisposing factors include renal impairment, a history of a seizure disorder, meningitis, or intraventricular antibiotic administration (15).

If neurologic symptoms develop, the dose of penicillin should be reduced or discontinued.

If seizures develop, benzodiazepines may be effective as treatment.

Hypokalemia has been reported with the penicillins (39), possibly due to effects on renal tubules and subsequent potassium loss.

This effect is more common with the carboxypenicillins. Hyperkalemia can result from use of penicillin G potassium, and reports of death have occurred (240).

Hypernatremia may also occur with the carboxypenicillins due amoxicillin clavulanate cost to the increased sodium content in their formulations. Patients with renal impairment should be monitored for potential electrolyte disturbances. Hepatitis or cholestasis can occur with high dose oxacillin and is generally reversible upon drug discontinuation (38). В Intravenous administration of penicillin G, nafcillin, oxacillin, and methicillin can cause thrombophlebitis.

Tissue necrosis can occur with extravasation of nafcillin.

If extravasation occurs, hyaluronidase can be used as a local antidote at the site of injury.

This reaction occurs in patients being treated with a penicillin (usually penicillin G) for a spirochetal infection (usually syphilis, but can include leptospirosis, Lyme disease, and others) and is a result of release of pyrogens from infecting organisms (268). In patients with syphilis, the incidence is 50% in primary syphilis and rises to 75% in patients with secondary syphilis. The reaction usually begins within 2 hours of initiating syphilis treatment and it consists of fever, chills, sweating, tachycardia, hyperventilation, flushing, and myalgia.

The duration is about 1 day and it can be treated with aspirin or prednisone (238).

When procaine penicillin G is used intramuscularly, 0.03 Вµg/mL for at least 7 days (114). If serum concentrations fall to below the MIC for 18-24 hours, spirochetal regrowth will occur (74). There is concern that BPG does not achieve adequate concentrations in the CSF to eradicateВ T.

pallidum , therefore the CNS fleming amoxicillin clavulanic acid would not be treated appropriately (144,В 239).

It may be, however, that the treponemal burden is low early in the disease process in immunocompetent patients and treatment with BPG may be sufficient (114,В 271). Some clinicians may wish to use more aggressive therapy, however. Patients with HIV infection and early syphilis mayВ fail treatmentВ with BPG and develop neurosyphilis (96) therefore these patients should be treated as if they had neurosyphilis, particularly in the later stages of HIV infection.

In patients with neurosyphilis, failure of high-dose penicillin may occur (96). Infants with congenital syphilisВ may be treated with either intravenous penicillin G or PPG.

The data suggests, however that CSF concentrations achieved with intravenous penicillin G are significantly higher than that achieved with PPG (12), therefore intravenous penicillin G may be preferred.

Penicillins are commonly used are treatment forВ skinВ andВ soft tissue infections.

Impetigo is commonly caused by eitherВ group A streptococciВ or Staphylococcus aureus В and can occasionally result in acute glomerulonephritis. BPG (1.2 mu in adults), penicillin VK, or amoxicillin have been used as treatment, but treatment failure may occur if the causative organism isВ Staphylococcus aureus В (62).

Use of a penicillinase-resistant oral penicillin (e.g.

Bullous impetigo, usually caused byВ Staphylococcus aureus , may be treated with an oral penicillinase-resistant penicillin.

Staphylococcal scalded skin syndrome should be treated with an intravenous penicillinase-resistant penicillin. Erysipelas,commonly caused byВ group A streptococci, is a type of superficial cellulitis which may be treated successfully with oral penicillin VK (250-500mg q6h) (27).