Penicillin and semisynthetic penicillins in dermatology

Penicillin and Semisynthetic Penicillins in Dermatology Miroslava Kadurina, MD, Georgeta Bocheva, MD and Stojan Tonev, MD, PhD enicillins are one of most important antibiotics groups. They are extremely effective and still widely used. Moreover, they are the drugs of choice for a large number of infectious diseases. Penicillins belong to the ␤-lactam group, which also include cephalosporins, monobactams, and carbapenems. ␤-lactam antibiotics have fourmembered ring structure. P HISTORY The era of modern microbial chemotherapy stems from Paul Erlich’s work a century ago. In 1928, Alexander Fleming isolated penicillin from a sample of the mold Penicillinium notatum in his laboratory at St. Mary’s Hospital in London. This antibacterial substance was named penicillin by Fleming. It was not introduced into clinical practice until 1941, when Florey, Chain, and their colleagues had been successful in extracting enough penicillin.1-4 The first clinical trials were conducted in 1942 at Yale University and the Mayo Clinic with excellent results. Since 1957, after the 6-aminopenicillinic acid’s isolation, the development of numerous semisynthetic penicillins has continued. CHEMISTRY The basic structure of penicillin includes a nucleus (6-aminopenicillanic acid, 6-APA) and side chain (R) (see Fig 1). The penicillin nucleus consists of thiazolidine ring (A) linked to a ␤-lactam ring (B) and it is a requirement for biologic activity of these molecules. The side chain determines many of the antibacterial and pharmacologic characteristics of penicillins. In the natural penicillin (penicillin G), the R is benzyl; in the semisynthetic penicillins, other groups are used. Penicillin G (benzylpenicillin) has the greatest antimicrobial activity within all natural penicillins. Reprinted with permission from Clinics in Dermatology (2003;21:12-23). Copyright 2003, Elsevier Inc. Dis Mon 2004;50:291-314. 0011-5029/$ – see front matter doi:10.1016/j.disamonth.2004.05.004 DM, June 2004 291 FIG 1. Two- (a) and three (b)-dimensional structures of penicillin nucleus. A, thiazolidine ring; B, ␤-lactam ring. Sites of penicillinase action: circled 1, amidase; circled 2, ␤-lactamase. Side chain (R): 1-penicillin G; 2-penicillin V; 3-methicillin; 4-izoxasolyl penicillins; 5-nafcillin; 6-aminopenicillins; 7-carbenicillins; 8-ticarcillin. Penicillin can interact with amines, such as procaine, and benzathine to form salts with low solubility. These salts are given by intramuscular (IM) injection, and the penicillin releases slowly and gives prolonged levels of drug. 6-Aminopenicillanic acid was obtained from cultures of Penicillinium chrysogenum. Now it is produced with the aid of an amidase from P. chrysogenum. The amidase splits the peptide linkage, by which the side chain of penicillin is joined to 6-aminopenicillanic acid (see Fig 1) and makes the development of the semisynthetic penicillins possible. 292 DM, June 2004 The type of the side chain (eg, adding an amino, a carboxyl group etc.) markedly changes the activity against bacteria and pharmacologic characteristics of each particular semisynthetic penicillins.5 R also controls a susceptibility of the molecule to the penicillinases, produced of most Staphylococcus aureus and some other bacteria, which hydrolyze the ␤-lactam ring and inactivate penicillins.6 The specific activity of penicillin G is defined in international units. One milligram of pure penicillin G sodium thus equals 1667 U. The dosage and antibacterial potency of the semisynthetic penicillins are expressed in terms of weight. MECHANISMS OF ACTION All ␤-lactam antibiotics share general mechanisms of antibacterial action. These mechanisms involve: (1) attachment to specific penicillin-binding proteins (PBPs)7-9; (2) inhibition of the bacterial cell wall peptidoglycan synthesis10; and (3) inactivation of an inhibitor of the autolytic enzymes in the cell wall, which initiate bacterial cell lysis and death.11 The relationship between inhibition of PBP’s activity and activation of autolysins is unclear. Some organisms have defective autolytic enzymes and are inhibited but not lysed—they are referred to as tolerant.11,12 The PBPs vary in their affinities for different ␤-lactam antibiotics. RESISTANCE Resistance to penicillin may be due to different causes. The production of ␤-lactamases, which inactivate some penicillins by breaking the ␤-lactam ring (over 90% of S. aureus, some Haemophilus influenzae and Neisseria gonorrhoeae, most Gram-negative enteric rods). It is suggested that there are three classes ␤-lactamases. Classes A and C include serine enzymes, and class B includes metalloproteins. The ␤-lactame compounds, clavulanic acid and sulbactam, act as strong inhibitors of class A but not of classes B or C ␤-lactamases. Approximately 50 different types of ␤-lactamases are known. Their production is genetically controlled. The information for staphylococcal penicillinase is encoded in a plasmid, ␤-lactamases of Gram-negative bacteria are encoded either in chromosomes or plasmids, and they may be constitutive or inducible. The plasmids can be transferred from one bacterium to another by conjugation.13,14 Other penicillins (eg, nafcillin) and cephalosporins are ␤-lactamase resistant because the ␤-lactam ring is protected by parts of the side chain. Such penicillins are active against ␤-lactamaseproducing microorganisms. Resistance to penicillin also may be caused by the occurrence of modified penicillin-binding sites. Some bacteria (eg, staphylococci) may DM, June 2004 293 be insusceptible to the action of ␤-lactamase-resistant penicillins, such as methicillin.15 The tolerant organisms (eg, certain staphylococci, streptococci, Listeria) are inhibited but not killed because the autolytic cell wall enzymes are not activated. Another reason may be that the organisms that lack cell walls (Mycoplasma, L-forms) or are metabolically inactive are resistant to penicillin because they do not synthesize peptidoglycans. Finally, resistance can occur as a result of a reduction in the permeability of the outer membrane and a decreased in the ability of the drug to penetrate to the target site. This occurs with Gram-negative organisms, which have an outer membrane that limits the penetration of hydrophilic antibiotics.16 TYPES OF PENICILLIN AND THEIR BACTERIAL SUSCEPTIBILITY The first penicillins are the naturally occurring benzylpenicillin and its congeners. Because of their susceptibility to bacterial ␤-lactamases, various semisynthetic penicillinase-resistant penicillins have been produced using different side chains. Semisynthetic penicillins include ␤-lactamase-resistant penicillins (isoxazolylpenicillins, methicillin, nafcillin), broad-spectrum penicillins (aminopenicillins), and extended-spectrum penicillins with antipseudomonal activity (carboxypenicillins and ureidopenicillins).17-19 Penicillins are classified according to their preparation—natural and semisynthetic penicillins (see Table 1). In each of these groups, they can be further classified by chemical structure. For clinical use, it is more convenient to classify the penicillins into three groups based of their antibacterial spectra. These groups are narrow spectrum, ␤-lactamase sensitive; broad-spectrum, ␤-lactamase sensitive; and ␤-lactamase resistant.19 Narrow-Spectrum, ␤-Lactamase-Sensitive Penicillins (Penicillin G and Penicillin V) Penicillin G is the drug of choice for infections caused by pneumococci, streptococci, meningococci, non-␤-lactamase-producing staphylococci, and gonococci, Treponema pallidum (exquisitely sensitive), and many other spirochetes, clostridia, Bacteroides (except Bacteroides fragilis). Borrelia burgdorferi, the organism responsible for Lyme disease, also is sensitive. Although most of Corynebacterium diphtheriae and Bacillus anthracis are susceptible to penicillin G, some are highly resistant. 294 DM, June 2004 TABLE 1. Types of penicillin Penicillin Groups Drugs Natural penicillins and congeners Benzylpenicillin (penicillinG), Phenoxymethylpenicillin (penicillin V) Semisynthetic penicillins ␤-lactamase-resistant penicillins Isoxazolyl penicillins Other Cloxacillin, oxacillin, dicloxacillin, methicillin Nafcillin Aminopenicillins Carboxypenicillins Ureidopenicillins Amidinopenicillins Methoxypenicillins Ampicillin, amoxicillin, bacampicillin Carbenicillin, ticarcillin Azlocillin, mezlocillin, piperacillin Mecillinam Temocillin Protected penicillins (combined with ␤-lactamase inhibitors) Amoxicillin-clavulanic acid (Augmentin姞) Ticarcillin-clavulanic acid (Timentim姞) Ampicillin-sulbactam (Unasyn姞) Piperacillin-tazobactam (Zosyn姞) Penicillin G inhibits Actinomyces israeli, Listeria monocytogenes, Pasteurella multocida, among others. Many strains of N. gonorrhoeae have developed resistance to penicillin, and this drug is no longer a drug of choice for gonorrhea. This antibiotic has narrow spectra because it is not active against enteric Gram-negative organisms. The oral formulation in this group is penicillin V. It is less potent than penicillin G and is indicated only in minor infectious (eg, streptococcal sinusitis, otitis, or pharyngitis), particularly in children, or for prophylaxis.19-22 Broad-Spectrum, ␤-lactamase-Sensitive Penicillins (Ampicillin, Amoxicillin, Carbenicillin, Ticarcillin, Piperacillin, Mezlocillin, Azlocillin) These antibiotics (Table 1) have greater activity than penicillin G against Gram-negative bacteria, but they are inactivated by ␤-lactamases. Aminopenicillins (ampicillin and amoxicillin) have the same spectrum and activity. These drugs are given PO to treat common urinary tract infections with enteric Gram-negative bacteria or infections of the respiratory tract (sinusitis, otitis, bronchitis). Ampicillin is ineffective against Enterobacter, Pseudomonas, and indole-positive Proteus infections.19 Carboxypenicillins (carbenicillin and ticarcillin) have more activity against Pseudomonas and Proteus organisms but their activity against DM, June 2004 295 Gram-positive organisms decrease. However, in serious Pseudomonas infections, they should be used in combination with aminoglycosides. The newer ureidopenicillins (azlocillin, mezlocillin, and piperacillin), which are Ampicillin derivatives and have similar activity against streptococcal species, have even greater activity against Pseudomonas, Klebsiella and other Gram-negative microorganisms.19-21 These ␤-lactamase-sensitive antibiotics can be made resistant combined with ␤-lactamase inhibitors, such as clavulanic acid, sulbactam, or tazobactam. ␤-lactamase inhibitors are most active against plasmidencoded ␤-lactamases. Clavulanic acid is produced by Streptomyces clavuligerus and it is a “suicide” inhibitor (irreversible binder) of ␤-lactamases.23 ␤-Lactamase-Resistant Penicillins (Cloxacillin, Oxacillin, Dicloxacillin, Methicillin, Nafcillin) This group of antibiotics is highly active against the ␤-lactamase (penicillinase)- producing staphylococci (eg, S. aureus) but compared with penicillin G, they have less potent activity against the other Gram-positive microorganisms. They are totally inactive against Gramnegative enteric bacteria. Some strains of S. aureus have PBPs with lower affinity for penicillins and can develop resistance. The term methicillinresistance designated staphylococci resistant only to methicillin, but now this term is used to demonstrate staphylococcal resistance to all ␤-lactam antibiotics. Methicillin is rarely used now because of serious nephrotoxicity.15,18-22 PHARMACOKINETICS The absorption of different penicillin preparations after oral application differs depending on their acid stability in the stomach and their adsorption and/or binding onto food. To minimize the binding to foods, oral penicillins should be given at least 1 hour before or after eating. Unabsorbed penicillin is destroyed by bacteria in the colon.19 Penicillin V, ampicillin, amoxicillin, cloxacillin, dicloxacillin, and oxacillin are well absorbed because of their acid stability. Oxacillin is least well absorbed compared to cloxacillin and dicloxacillin. These drugs are highly bound to plasma albumin (⬎90%). Amoxicillin is better absorbed after oral application than ampicillin and is not influenced by food.19,21 Penicillin G, methicillin, nafcillin, carbenicillin, ticarcillin, and piperacillin are poorly absorbed because they are not acid stable and are hydrolyzed in the stomach. Therefore, these penicillins are administrated 296 DM, June 2004 parenterally. Because of the irritation and local pain produced by IM injection of large doses, intravenous (IV) application is often preferred.19,21 The penicillins are widely distributed in body fluids (joint fluid, pleural fluid, pericardial fluid, and bile) and tissues after absorption. They pass also across the placenta (eg, for syphilis treatment in the pregnancy). However, only low concentrations of them are found in prostatic secretions, intraocular fluid, and brain tissue. They do not enter living phagocytic cells to a significant extent. Being lipid insoluble, the penicillins do not cross the blood-brain barrier (less than 1% of plasma concentration) when the meninges are normal. When the meninges are inflamed, the penicillins may reach therapeutically effective concentration in the cerebrospinal fluid (CSF). About 5-10% of serum concentration with penicillin G, ampicillin, carbenicillin, and ticarcillin attains in the CSF during treatment for meningitis. In meningitis, high levels of penicillins in the CSF are caused by increased permeability of meninges, inhibition of the normal active transport of penicillin out of the CSF,24 and some bindings of penicillin to CSF proteins. Another penicillins (methicillin, cloxacillin, nafcillin) penetrate the CSF poorly. The elimination of most free penicillins is mainly renal, they are excreted by glomerular filtration (10%) and renal tubular secretion (90%), to about 1.8 g/h in adults. The short serum half-life of penicillin G (less than 1 hour) is one of the main problems in the clinical use, which can be overcome with a slow-release procaine penicillin and benzathine penicillin. In renal failure, the half-life of penicillin G increases to about 10 hours. Nafcillin, oxacillin, and the ureidopenicillins have significant excretion (about 80%) into the biliary tract and only 20% by tubular secretion. These drugs are recommended to use for patients with renal failure. Probenecid can partially block tubular secretion and achieve higher systemic and CSF levels of penicillin.24 Penicillin is also excreted into sputum and milk (3-15% of serum concentration). The presence of antibiotics (eg, penicillin) in the milk of cows treated for mastitis presents a big problem in human allergy. CLINICAL USES The penicillins are frequently prescribed class antibiotics.—Penicillin V and Penicillin G. General Indications These drugs are used for treatment of large number of mild to severe infections. DM, June 2004 297 Streptococcal Infections. As mentioned previously, penicillin V is given PO for mild infections, such as pharyngitis (including Scarlet fever), sinusitis, and otitis caused by S. pyogenes (group A ␤-hemolytic streptococcus). Parenteral therapy for streptococcal pharyngitis is preferred when there is potential for rheumatic fever. Severe infections, such as pneumonia, arthritis, meningitis, and endocarditis caused by S. pyogenes should be treated with penicillin G. Penicillin G is also widely used to treat streptococcal endocarditis caused by S. viridans (penicillin-sensitive viridans group). This bacterial endocarditis is associated with several skin findings (eg, petechiae, subungual splinter hemorrhages, Janeway’s macules, Osler’s nodes) and optimally treated with two antibiotics, penicillin G IV in combination with aminoglycosides. Some physicians prefer a 4-week course of treatment using penicillin G alone.25 Pneumococcal Infections. Penicillin G is the drug of choice for pneumococcal pneumonia and meningitis (caused by sensitive strains of S. pneumoniae). Penicillin-resistant pneumococci are becoming more common, especially in the pediatric population. When there is penicillin resistance caused by pneumococci, the drugs used are vancomycin or a third-generation cephalosporin. Infections with Anaerobes. The majority of anaerobic infections— periodontal and pulmonary infections, lung abscess,26, brain abscess, caused by mixtures of microorganisms are susceptible to penicillin G (except Bacteroides fragilis— up to 75% resistance). Meningococcal Infections. Patients with meningococcal meningitis and/or meningococcemia caused by Gram-negative N. meningitidis should be treated with high doses of penicillin G IV. Penicillin G does not eliminate the meningococcal carrier state and is ineffective for prophylaxis.27-29 Penicillin in Dermatology From an historical point of view, brilliant therapeutic results after penicillin administration in serious cases have elevated the use of penicillin over other drugs. Penicillin may be used in the treatment of pemphigus, dermatitis herpetiformis, lupus vulgaris, psoriasis vulgaris, lichen planus, cold urticaria, etc.30 At the present time, penicillin is used as an antiinfectious drug in dermatology, but sometimes it is used its nonspecific action. Erysipelas. Aqueous penicillin G has many indications, but its main use in dermatology is treatment of erysipelas. Penicillin G remains the therapeutic reference for erysipelas. Most of the cases with erysipelas are 298 DM, June 2004 caused by S. pyogenes (group A ␤-hemolytic streptococcus), but occasionally other streptococci are identified. At particular risk for infection are young patients, elderly patients (especially with diabetes), and immunocompromised patients. The main local factors are tinea pedis, venous or lymphatic stasis, and a history of saphenous phlebectomy or lymphadenectomy. The prevention of the recurrence is correct treatment of the disease (usually erysipelas recur when the treatment is stopped), treatment of venous and lymphatic stasis, and/or wounds. The early stages of erysipelas are frequently treated with oral or IM penicillin.31-35 For prophylaxis, selected patients are given depot penicillins (eg, benzathine penicillin G—1,2 million units monthly) for several months.36,37 Other Skin and Soft-Tissue Infections Caused by S. Pyogenes. Infections successfully treated with penicillin G or V are perianal streptococcal dermatitis; ecthyma; impetigo (more frequently caused by S. aureus); cellulitis; and necrotizing fasciitis (streptococcal gangrene).34,35,38 The choice of preparation and duration of the therapy depend on the patient’s medical status and background. Scarlet Fever. Scarlet fever is streptococcal infection manifested by pharyngitis, fever, glossitis, and a diffuse exanthem. It is a disease of childhood, caused by group A ␤-hemolytic streptococcus-producing pyrogenic (previously called erythrogenic) exotoxin. As mentioned above, S. pyogenes is particularly sensitive to penicillin. The recommended therapy is oral penicillin V for 10 days or a single injection of benzathine penicillin G.39 Erysipeloid. The causative agent of this disease, Erysipelothrix rhusiopathiae, is sensitive to penicillin. Oral penicillin V is effective for local infection. Patients with signs of endocarditis should be treated with penicillin G IV. The therapy should be continued for 4 to 6 weeks.40,41 Anthrax. Penicillin G has been the traditional agent of choice in the treatment of all clinical forms of anthrax. The type of anthrax depends on the way the spores or organisms enter in the patient. Cutaneous anthrax is most common form. Some patients, particularly the immunosuppressed, may develop complications such as edema and anthrax sepsis. Usually, cutaneous anthrax responds well to IM injections of penicillin G in the beginning, followed by oral medication (penicillin V, amoxicillin).42,43 More severe form of anthrax44 (eg, sepsis, pulmonary anthrax) should be treated IV with penicillin G. Penicillins (penicillin G, amoxicillin) are given also for prophylactic therapy of anthrax to asymptomatic patients, especially pregnant women and children, exposed to B. anthracis; however, strains of B. anthracis resistant to penicillins have been reported. DM, June 2004 299 Lyme Disease. The first stage of the disease is manifested with cutaneous findings: Erythema chronicum migrans, which is usually solitary lesion. Although tetracyclines are the preferable group of choice for early stage, penicillin V also is effective, especially in the treatment of children with solitary erythema migrans.45-48 Because B. burgdorferi can cross the placenta, there is a risk of fetal involvement. Pregnant women should be treated with penicillin G or ceftriaxone to prevent fetal death, spontaneous abortions, and congenital malformations.49 Patients with neuroborreliosis or cardiovascular involvement are best treated with crystalline penicillin G IV for 14 to 30 days, depending on disease severity,50,51 or third-generation cephalosporins. The antibiotic therapy may be complicated with Jarisch-Herxheimer reaction because of endotoxins release.52 Actinomycosis. Actinomycosis is caused by Actinomyces israelii, which is part of normal oral mucosa, but occasionally is found in the intestinal flora. The main predisposing factors for the disease are dental problems, broken bones, and trauma. All forms of actinomycosis are well treated with penicillin. The usual recommended regimen is penicillin G IV for at least 6 weeks. Some physicians continue therapy with oral penicillin V for several months. The treatment is much easier after surgical excision of the lesion.39 Listeriosis. L. monocytogenes produces a variety of clinical findings. It may develop localized cutaneous lesions on the side of contact. Penicillin G or ampicillin are the drugs of choice in the treatment of listeriosis. If the disease is complicated with endocarditis, the duration of the treatment should be no less than a month.53 Fusospirochetal gingivostomatitis. Fusospirochetal gingivostomatitis is readily treatable with penicillin. For simple infections, penicillin V is administered. Gas Gangrene. Gas gangrene is caused by Clostridium perfringens. The treatment of the disease includes high-dose penicillin G IV and adequate debridement of the infected areas. Leptospirosis (Weil disease). The causative agent of this disease is spirochete, or Leptospira interrogans, which is sensitive to penicillin and tetracycline. In Weil disease a variety of cutaneous findings can develop, as well as multisystem involvement. In clinical practice, penicillin G is widely used to treat leptospirosis.54 Nonspecific Action of Penicillin G Scleroderma. Clinical and histologic investigations suggest some success inf using penicillin G and D-penicillamine (DPA) to treat dermal 300 DM, June 2004 fibrosis in patients suffering from circumscribed and systemic sclerosis55-57 however, there is little knowledge about the mechanism of the antifibrotic action of penicillin G and DPA. DPA is formed from penicillin by hydrolytic breakdown and returns the collagen synthesis to normal by a direct inhibition of the crosslink reaction of collagen and indirectly by an inhibition of ␤-galactosidase.58 This enzyme plays an important role in the pathogenesis of localized and generalized scleroderma. Penicillin G and DPA activate also collagenase, leading to degradation of collagen. The rapid improvement in localized scleroderma after high-dose penicillin G therapy can purportedly be related with the role of B. burgdorferi in the development of the disease.59 Because of the relationship between idiopathic atrophoderma of Pasini and Pierini60 and linear atrophoderma of Moulin,61 treatment with penicillin could be possible. Scleroderma Adultorum Buschke. Among children and young women, scleredema may follow or associate with a streptococcal infection. Even in the absence of a documented infection, high doses of penicillin G have been given with positive results.62,63 Pityriasis Rubra Pilaris. Penicillin could be a possible therapeutic agent for the treatment of Pityriasis rubra pilaris.64-66 Venereal and Nonvenereal Treponematoses Penicillin was introduced for syphilis therapy by Mahoney et al.67 in 1943. After more than 50 years of use, there is no evidence of T. pallidum resistance to penicillin. Many other antibiotics have been tested for treatment of syphilis, but the treatment of choice is still parenteral penicillin G. It can be used in its aqueous crystalline form or as an IM depot injection. The choice of regimen depends on the stage of the disease.68,69 The recommended therapy for neurosyphilis is aqueous crystalline penicillin G IV. When the patient is allergic to penicillin, then an alternative is tetracyclines and macrolides, although this is not a valid option for syphilotherapy in pregnancy. The mother should be desensitized and treated with penicillin. In the HIV era, the patient with HIV/AIDS occasionally has a loss of seroreactivity, as well as a false-positive reaction. HIV patients should always be treated with penicillin. The majority (70-90%) of patients with secondary syphilis develop the Jarish-Herxheimer reaction, although it can occur with any stage. Several hours after the first injection of penicillin, fever, chills, myalgias, headache, tachycardia, and often hypotension may develop. The syphilitic DM, June 2004 301 cutaneous lesions may become more prominent, edematous and shiny in color. In case of cardiovascular and neurosyphilis, the Jarish-Herxheimer reaction is more severe. This reaction is thought to be caused by the release of endotoxin from killed spirochetes.70 Aspirin can control the fever and other symptoms, and therapy with penicillin should not be discontinued. Nonvenereal treponematoses—yaws, pinta and endemic syphilis—are caused also by treponemes and have many clinical, serologic and therapeutic similarities with syphilis, but they are not usually sexual transmitted. Gonorrhea Because of the increasing incidence of penicillinase-producing N. gonorrhoeae, penicillins are no longer the therapy of choice for gonorrhea. Semisynthetic Penicillins: The Aminopenicillins (Ampicillin and Amoxicillin) General Indications. Penicillinase-resistant penicillins are the agents of choice for staphylococcal pneumonia, osteomyelitis, endocarditis, and septicemia.18,21 Upper respiratory infections (sinusitis, otitis media, acute exacerbation of chronic bronchitis, epiglositis) are successfully treated with aminopenicillins.19 Gram-negative urinary tract infections, especially uncomplicated enterococcal infections, are treated effectively with Ampicillin. Meningitis. Acute bacterial meningitis in children is most frequently caused by H. influenzae, S. pneumoniae, or N. meningitidis. The combination of Ampicillin plus a third generation cephalosporins is a rational regimen for empiric treatment of suspected bacterial meningitis.21 Salmonella Infections. In typhoid and paratyphoid fevers, ampicillin is an alternative drug. Helicobacter Infections. H. pylori is responsible for most cases of chronic atrophic gastritis, as well as gastric and duodenal ulcers. This pathogen is suspected as a possible cause of chronic urticaria and rosacea. Amoxicillin is included in the complex therapy for the eradication of H. pylori.71 Antipseudomonal Penicillins. Antipseudomonal penicillins, such as carboxypenicillins and ureidopenicillins, are used exclusively for pseudomonas infections of the urinary tract, lung and blood, and infections after burns. Protected Penicillins. The amoxicillin-clavulanic acid combination is used for treatment of otitis media in children, and sinusitis, bacterial 302 DM, June 2004 exacerbation of bronchitis, and lower respiratory tract infections in adults. The Ticarcillin-clavulanate and piperacillin-tazobactam are effective in treating IA and gynecologic infections and osteomyelitis when mixed bacteria are present. Semisynthetic Penicillins in Dermatology The penicillinase-resistant penicillins (cloxacillin, oxacillin, dicloxacillin, and nafcillin) are considered as the agents of choice for most staphylococcal skin and soft-tissue infections. Nafcillin is highly resistant to penicillinase and is more effective than others against staphylococcal skin infections. Toxin-Mediated Staphylococcal Disease. Most staphylococci (esp. S. aureus) produce a variety of toxins, including cytotoxins and leukocytolytic toxins, which cause serious diseases. Many of these toxins serve as superantigens and activate polyclonal T cells, leading to cytokine release, especially of tumor necrosis factor-␣ and interleukins-1 and -6. Toxic shock syndrome is life-threatening multisystem disease with skin involvement caused by the staphylococcal exotoxin toxic shock syndrome toxin-1. The S. aureus enterotoxin causes staphylococcal food poisoning.39 Impetigo. Impetigo is superficial skin infection, usually appearing among children. It is commonly caused by S. aureus as a result of the production of two exotoxins, exfoliatin A and B. A variant of bullous impetigo is seen in newborns (impetigo neonatorum). The therapy should consider with the age of patient. Staphylococcal Scalded Skin Syndrome. The disease usually involves infants or children up to 5years of age. Staphylococcal scalded skin syndrome is manifested with widespread superficial skin loss and fever. After application of penicillinase-resistant penicillins, replacement of fluids and temperature control, there is a surprising improvement.72 Folliculitis. There are many different forms of folliculitis with different causes. Bacterial agent of folliculitis is usually S. aureus. Antistaphylococcal therapy with penicillinase-resistant penicillins is recommended for such folliculitis. Furuncle and Carbuncle. Furuncles and carbuncles are also staphylococcal infection, improved after therapy with these type penicillins. Cellulitis. Cellulitis should be treated with penicillinase-resistant penicillins, because S. aureus is the major pathogen. Antipseudomonal Penicillins. Antipseudomonal penicillins do not play a role in dermatologic therapy. DM, June 2004 303 Protected Penicillins. Protected penicillins are suitable, especially for polymicrobial-caused skin infections or gonorrhea. They are effective particularly in the treatment of diabetic foot ulcers, infected decubitus ulcers, and burn wounds.73 Gonorrhea For patients without resistance to penicillin the oral application of amoxicillin (3 g) ⫹ probenecid (1 g) or ampicillin (3.5 g) ⫹ probenecid is recommended. The combination of procaine penicillin G injected into two sites with probenecid (1 g) is also efficacious. If there is a resistance to penicillin, the recommended treatment for gonococcal urethritis, arthritis, and disseminated gonococcal infections with skin lesions is ceftriaxone IM or IV.29 Chlamydial Infections Amoxicillin is equally efficacious compared with azithromycin in the treatment of cervical Chlamydia trachomatis during pregnancy.74 DOSAGE Penicillins can be administered by the oral, IM, or IV route. Dosages vary widely depending on the infecting pathogen, the type of infection being treated, and the patient. The average recommended daily doses of the penicillins given PO (penicillin V, ampicillin, cloxacillin, and oxacillin) are 20-30 mg/kg, usually divided into four equal doses. The approximate daily dose given parenterally is between 50 and 200 mg/kg (50-100 mg/kg for children) for ampicillin, cloxacillin, methicillin, nafcillin, and oxacillin; 300 mg/kg for ticarcillin; 400-500 mg/kg for carbenicillin, and 100,000-200,000 IU/kg for aqueous benzylpenicillin (1 UI ⫽ 0.6 ␮g).19,75 The parenteral penicillins are usually administered in four to six equal doses per day. The depot-penicillin G preparations (procaine and benzathine) are prescribed as a single daily, weekly, or monthly dose. The approximate dose for these long-acting penicillins is 1.2-2.4 million units. These doses are average and must be adjusted for renal insufficiency.75 CONTRADICTIONS The majority of patients who give a history of allergy to penicillins should be treated with different type of antimicrobials. In the unusual instance where treatment with penicillin is essential, skin tests should be 304 DM, June 2004 placed.76 If the infection is life-treating only with penicillin (eg, bacterial endocarditis) desensitization is recommended, although it is a potentially dangerous procedure in itself. About 10% of patients sensitive to penicillins who are given cephalosporins will exhibit cross-drug sensitivity and develop eruption. It is recommended that patients with a history of immediate or accelerated reactions to penicillin (type I—IgE mediated— or severe type IV delayed hypersensitivity reactions) not be treated with cephalosporins. It is suggested that the newer generation of cephalosporins have less allergic cross-reactivity with penicillin molecule than cephalothin.77 SIDE EFFECTS The penicillins have very low toxic effects and are completely safe in pregnancy.78 They have pregnancy risk factor of B according to FDA. Penicillins also have little effect on mammalian cells. However, all penicillins may cause penicillin allergy (they are the most common cause of drug allergy), neuro- and nephrotoxicity, and uncommon hematologic toxicity. Sensitivity to penicillin is a contraindication to exposure any of the semisynthetic analogs. Hypersensitivity reactions are most commonly adverse reactions caused by penicillin, which occur in about 5% of patients. The incidence of hypersensitivity is three to four times higher in atopic than in nonatopic patients. The relationship between atopic symptoms-complex and penicillin allergy is unclear.79 Hypersensitivity reactions may appear in the absence of a previous known drug exposure (eg, in the environment). The most serious of hypersensitivity reactions are anaphylaxis and angioedema that occurs immediately after application (in less than 30 minutes) and are mediated by IgE.79 The incidence of anaphylaxis is about 0.01%. Parenteral administration appears the most likely route inducing anaphylaxis in humans.79-81 It must be known that very small doses of penicillins or even skin testing with these drugs may be followed of fatal episodes of anaphylaxis. The mechanism of these reactions involves the chemical reactivity of the ␤-lactam ring. Penicillins are a classic example of haptens and when they are degraded, the ␤-lactam ring opens and reacts with tissue proteins making them immunogenic. This is the so-called “major determinant” because it is the major reaction leading to protein binding and penicillin allergy. There are “minor antigenic determinants” composed mainly of penicilloic and penillic acids also. Although these determinants refer only to the relative quantity of haptens available and DM, June 2004 305 not to their immunologic importance, a high percentage of immediate reactions (eg, anaphylaxis) is caused by minor determinants. The most serious reactions after administration of penicillin, such as acute anaphylactic shock and angioedema, are fortunately very rarely fatal. The most dramatic clinical picture described anaphylactic shock includes sudden, severe hypotension with collapse; bronchospasm; and abdominal pain, nausea, and vomiting. At the same time, urticaria or angioedema may occur. Angioedema and/or a drug-induce acute urticaria are other important immediate allergic reaction that are characterized clinically by marked swelling of the lips, face and periorbital tissues, genitalia and distal parts of the extremities, and urticarial wheals. The risk of angioedema is swelling of the tongue, larynx, and/or pharynx, which can lead to bronchoconstriction.79-81 Accelerated reactions (occurring within 1-48 hours) are usually manifested by rash and sometimes by fever. Delayed reactions (beginning more than 48 hours after exposure) can present of skin reactions or systemic reactions (such as nephritis or serum sickness). Skin eruption (scarlatiniform, morbilliform, urticarial, vesicular, and bullous eruptions) and fever are the most common manifestations of penicillin allergy. Fever may be the only evidence of hypersensitivity and can reach high levels. Purpuric lesions are uncommon and are mainly the results of a vasculitis. Schönlein-Henoch purpura with renal involvement has been rare complication.82 Exfoliative dermatitis and exudative erythema multiforme of either the erythemopapular or vesiculobullous type also have occurred. Some medications, including aminopenicillins (ampicillin, amoxicillin), may cause severe drug reaction with atypical target lesions, widespread loss of epidermis, and mucosal involvement (in about 90% of patients).83 Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS-TEN overlap are referred to the most severe skin reactions caused by medications. The pathogenesis of these severe skin reactions has not been well defined immunologically. In general, these reactions are held to be cell-mediated cytotoxic responses as the epidermis is infiltrated by activated lymphocytes. It is unclear whether the cytotoxic T cells directly damage the epidermis or release cytokines that stimulate apoptosis.39,84,85 Penicillin is also an agent that causes fixed drug eruption. Clinical and immunologic studies suggest that fixed drug eruption is delayed hypersensitivity reaction, which is also referred to as cell-mediated reaction. Patients frequently give a history of identical lesion(s) occurring at the 306 DM, June 2004 same skin site. The most common sites are palms and soles, glans penis, scrotum, and oral mucosa. Incidences of drug-induced pemphigus (DIP) from penicillin have been described. Even though DIP is suggested to be relate to thiol compounds of the drug, many nonthiol drugs termed “masked” thiols, like penicillin, may also induce pemphigus.86 Penicillins contain sulfur in their molecule, and the sulfur may change metabolically to form active thiol groups. Analyses of the penicillin chemical structure reveal an active amide group in their molecule that may be responsible for induction of the disease, not the sulfur.87,88 Few reports relate penicillin as a possible provocation of generalized pustular psoriasis (von Zumbusch’s type). The penicillin and some semisynthetic penicillins (eg, ampicillin, amoxicillin) may initiate and exacerbate this disease. The mechanism induced pustular psoriasis by the penicillins is unknown.89-91 Serum sickness is a reaction usually appearing after 1 week or more penicillin treatment, and is mediated by IgG antibody. The typical clinical manifestations, including fever, urticarial lesions, lymphadenopathy, polyarthritis, neuritis, serositis and acute glomerulonephritis, is thought to be secondary to circulating antigen-antibody complexes.92 When longacting penicillin preparations are used, clinical findings may be delayed up to three weeks and symptoms may be prolonged several weeks rather than a few days to a week.93 Contact dermatitis is observed occasionally in pharmacists, nurses, and physicians after preparing penicillin solutions. The specific maculo-papular skin eruption is much more common after using of ampicillin or amoxicillin (being about 9%) and is not related to true penicillin hypersensitivity. It may represent a “toxic” rather than a truly allergic reaction.30 Patients with infectious mononucleosis almost always get an ampicillin eruption (more than 90%). The ampicillin eruption is also common among patients with other virus infections (cytomegalovirus), patients with lymphoid malignancies, and patients receiving allopurinol together with ampicillin. The incidence of ampicillin eruption is not a contraindication to treatment with penicillins at a later date.18-22 Acute interstitial nephritis is uncommon, occurring most generally with methicillin exposure. Hematuria, eosinophilia, pyuria, proteinuria, elevation of serum creatinine, and even oliguria have been noted.92,94-96 Hypokalemia may be a side effect of high dose parenteral penicillin therapy because the penicillins act as nonreabsorbable anions. Other hypersensitivity reactions seen occasionally are vasculitis (of the DM, June 2004 307 skin or other organs); Coomb’s test-positive hemolytic anemia (it has been described in patients, receiving massive IV doses of penicillin for 1 week or more.79 Reversible neutropenia is also seen, especially patients taking methicillin, nafcillin, or cloxacillin.97 It is unclear if this is truly hypersensitivity reaction. All penicillins, particularly high doses of carbenicillin and ticarcillin, may cause decreased platelet aggregation by binding to adenosine diphosphate receptors on the platelets. Significant bleeding disorders are infrequent.98,99 Convulsions, twitching, multifocal myoclonus, localized or generalized epileptiform seizures, or other forms of encephalopathy may occur when extremely large doses of penicillin G have been prescribed. These reactions are more likely to occur to patients with renal insufficiency. Many people taking oral penicillins experience nausea, vomiting, and even diarrhea (especially with ampicillin and amoxicillin). These gastrointestinal manifestations are mild and transient and often are related to the dose of the drug. The incidence of diarrhea is higher in children receiving amoxicillin/clavulanic acid.100 Rarely, ampicillin and other penicillins may cause a pseudomembranous colitis. Mild elevation of serum glutamic oxalacetalate transaminase has been reported during therapy with oxacillin and nafcillin. After IM injection of penicillin (especially procaine and benzathine forms), occasionally the medication enters or irritates an artery, causing arteriospasm that leads to distal ischemic necrosis. It is also known as Nicolau syndrome or embolia cutis medicamentosa, which present with hemorrhagic livid lesions progressing to cutaneous necrosis. If an injection damage a nerve, it may cause not only pain but also paralysis and vasoconstriction.101 If after IM injection microcrystals of depot-penicillin enter in venous system, immediate nonallergic reaction can develop known as Hoigné syndrome. Dizziness, tinnitus, headache, hallucinations, sometimes seizures, cough, and angina manifest this reaction.102 Local reactions, such as pain and sterile inflammatory reactions at the site of injection, have been described after penicillin application. As a result of local damage to muscle, serum transaminases and lactic dehydrogenase can be elevated. Some persons receiving penicillin IV also have developed phlebitis or thrombophlebitis. Finally, the literature mentions a few cases of postinflammatory elastolysis (cutis laxa) after penicillin therapy.103,104 308 DM, June 2004 DRUG INTERACTIONS Penicillins bind to aminoglycoside antibiotics and inactivate them both in vitro and in vivo. Therefore, penicillins and aminoglycosides should not be mixed in IV infusions and should be given separately in time.105 Penicillins and bacteriostatic drugs are often antagonistic in vitro. The only in vivo example of this antagonism is the lack of improvement in S. pneumoniae meningitis when is treated with both penicillin and tetracycline. Drugs, which inhibit renal tubular secretion of the penicillins, may cause accumulation with higher and prolonged serum levels. Medications having such an effect include probenecid, phenylbutazone, indomethacin, and sulfinpyrazone. Such an advantage is taken of the interaction with the concurrent use of probenecid and penicillin. This enhances the therapeutic efficacy in the treatment of gonorrhea and of bacterial endocarditis;106 however, concomitant administration of probenecid does not affect the serum concentration of clavulanic acid agents. 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