The carboxypenicillins, carbenicillin and ticarcillin, were developed to broaden the spectrum of penicillins against Gram-negative pathogens, including P aeruginosa; however, neither agent is available in the USA. The ureidopenicillin piperacillin is also active against many Gram-negative bacilli, such as Klebsiella pneumoniae and P aeruginosa. Piperacillin is available only as a co-formulation with the β-lactamase inhibitor tazobactam. Due to the propensity of P aeruginosa to develop resistance during therapy, an antipseudomonal β-lactam is sometimes used in combination with an aminoglycoside or fluoroquinolone, particularly in infections outside the urinary tract, despite a lack of data supporting combination therapy over single-drug therapy.
Ampicillin, amoxicillin, piperacillin, and, historically, ticarcillin, are available in combination with one of several β-lactamase inhibitors: clavulanic acid, sulbactam, or tazobactam. The addition of a β-lactamase inhibitor extends the activity of these penicillins to include β-lactamase-producing strains of S aureus as well as some β-lactamase-producing Gram-negative bacteria (see Beta-Lactamase Inhibitors).
The penicillins are generally well tolerated, and, unfortunately, this may encourage inappropriate use. Most of the serious adverse effects are due to hypersensitivity. The antigenic determinants are degradation products of penicillins, particularly penicilloic acid and products of alkaline hydrolysis bound to host protein. A history of a penicillin reaction is not reliable. About 5–8% of people claim such a history, but only a small number of these will have a serious reaction when given penicillin. Less than 1% of persons who previously received penicillin without incident will have an allergic reaction when given penicillin. Because of the potential for anaphylaxis, however, penicillin should be administered with caution or a substitute drug given if the person has a history of serious penicillin allergy. Penicillin skin testing may also be used to evaluate Type I hypersensitivity. If skin testing is negative, most patients can safely receive penicillin.
Allergic reactions include anaphylactic shock (very rare—0.05% of recipients); serum sickness–type reactions (now rare—urticaria, fever, joint swelling, angioedema, pruritus, and respiratory compromise occurring 7–12 days after exposure); and a variety of skin rashes. Oral lesions, fever, interstitial nephritis (an autoimmune reaction to a penicillin-protein complex), eosinophilia, hemolytic anemia and other hematologic disturbances, and vasculitis may also occur. Most patients allergic to penicillins can be treated with alternative drugs. However, if necessary (eg, treatment of enterococcal endocarditis or neurosyphilis in a patient with serious penicillin allergy), desensitization can be accomplished with gradually increasing doses of penicillin.