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Penicillin and semisynthetic penicillins in dermatology

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Penicillin and
Semisynthetic Penicillins in Dermatology
MIROSLAVA KADURINA, MD
GEORGETA BOCHEVA, MD
STOJAN TONEV, MD, PhD

P
enicillins are one of most important antibiotics salts are given by intramuscular (IM) injection, and the
groups. They are extremely effective and still penicillin releases slowly and gives prolonged levels of
widely used. Moreover, they are the drugs of drug.
choice for a large number of infectious diseases. Peni- 6-Aminopenicillanic acid was obtained from cultures
cillins belong to the ␤-lactam group, which also include of Penicillinium chrysogenum. Now it is produced with
cephalosporins, monobactams, and carbapenems. ␤-lac- the aid of an amidase from P. chrysogenum. The amidase
tam antibiotics have four-membered ring structure. splits the peptide linkage, by which the side chain of
penicillin is joined to 6-aminopenicillanic acid (see Fig
History 1) and makes the development of the semisynthetic
penicillins possible.
The era of modern microbial chemotherapy stems from
The type of the side chain (eg, adding an amino, a
Paul Erlich’s work a century ago. In 1928, Alexander
carboxyl group etc.) markedly changes the activity
Fleming isolated penicillin from a sample of the mold
against bacteria and pharmacologic characteristics of
Penicillinium notatum in his laboratory at St. Mary’s
each particular semisynthetic penicillins.5 R also con-
Hospital in London. This antibacterial substance was
trols a susceptibility of the molecule to the penicilli-
named penicillin by Fleming. It was not introduced into
nases, produced of most Staphylococcus aureus and some
clinical practice until 1941, when Florey, Chain, and
other bacteria, which hydrolyze the ␤-lactam ring and
their colleagues had been successful in extracting
inactivate penicillins.6
enough penicillin.1– 4 The first clinical trials were con-
The specific activity of penicillin G is defined in
ducted in 1942 at Yale University and the Mayo Clinic
international units. One milligram of pure penicillin G
with excellent results. Since 1957, after the 6-aminopeni-
sodium thus equals 1667 U. The dosage and antibacte-
cillinic acid’s isolation, the development of numerous
rial potency of the semisynthetic penicillins are ex-
semisynthetic penicillins has continued.
pressed in terms of weight.
Chemistry
Mechanisms of Action
The basic structure of penicillin includes a nucleus (6-
All ␤-lactam antibiotics share general mechanisms of
aminopenicillanic acid, 6-APA) and side chain (R) (see
antibacterial action. These mechanisms involve: (1) at-
Fig 1). The penicillin nucleus consists of thiazolidine
tachment to specific penicillin-binding proteins
ring (A) linked to a ␤-lactam ring (B) and it is a require-
(PBPs)7–9; (2) inhibition of the bacterial cell wall pepti-
ment for biologic activity of these molecules. The side
doglycan synthesis10; and (3) inactivation of an inhibi-
chain determines many of the antibacterial and phar-
tor of the autolytic enzymes in the cell wall, which
macologic characteristics of penicillins. In the natural
initiate bacterial cell lysis and death.11
penicillin (penicillin G), the R is benzyl; in the semisyn-
The relationship between inhibition of PBP’s activity
thetic penicillins, other groups are used. Penicillin G
and activation of autolysins is unclear. Some organisms
(benzylpenicillin) has the greatest antimicrobial activity
have defective autolytic enzymes and are inhibited but
within all natural penicillins.
not lysed—they are referred to as tolerant.11,12 The PBPs
Penicillin can interact with amines, such as procaine,
vary in their affinities for different ␤-lactam antibiotics.
and benzathine to form salts with low solubility. These

Resistance
From the Clinic of Dermatology and Venereology, Military Academy of
Medicine, Sofia, Bulgaria. Resistance to penicillin may be due to different causes.
Address correspondence to Miroslava Kadurina, MD, Clinic of Derma- The production of ␤-lactamases, which inactivate some
tology and Venereology, Military Academy of Medicine, 3 G. Sofiiski Street,
1606 Sofia, Bulgaria. penicillins by breaking the ␤-lactam ring (over 90% of S.
E-mail address: [email protected] aureus, some Haemophilus influenzae and Neisseria gonor-

© 2003 by Elsevier Science Inc. All rights reserved. 0738-081X/03/$–see front matter
360 Park Avenue South, New York, NY 10010 doi:10.1016/S0738-081X(02)00329-2
Clinics in Dermatology Y 2003;21:12-23 PENICILLIN AND SEMISYNTHETIC PENICILLINS 13

Figure 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.

rhoeae, most Gram-negative enteric rods). It is suggested action of ␤-lactamase-resistant penicillins, such as
that there are three classes ␤-lactamases. Classes A and methicillin.15 The tolerant organisms (eg, certain staph-
C include serine enzymes, and class B includes metal- ylococci, streptococci, Listeria) are inhibited but not
loproteins. The ␤-lactame compounds, clavulanic acid killed because the autolytic cell wall enzymes are not
and sulbactam, act as strong inhibitors of class A but activated.
not of classes B or C ␤-lactamases. Approximately 50 Another reason may be that the organisms that lack
different types of ␤-lactamases are known. Their pro- cell walls (Mycoplasma, L-forms) or are metabolically
duction is genetically controlled. The information for inactive are resistant to penicillin because they do not
staphylococcal penicillinase is encoded in a plasmid, synthesize peptidoglycans.
␤-lactamases of Gram-negative bacteria are encoded Finally, resistance can occur as a result of a reduction
either in chromosomes or plasmids, and they may be in the permeability of the outer membrane and a de-
constitutive or inducible. The plasmids can be trans- creased in the ability of the drug to penetrate to the
ferred from one bacterium to another by conjuga- target site. This occurs with Gram-negative organisms,
tion.13,14 Other penicillins (eg, nafcillin) and cephalo- which have an outer membrane that limits the penetra-
sporins are ␤-lactamase resistant because the ␤-lactam tion of hydrophilic antibiotics.16
ring is protected by parts of the side chain. Such peni-
cillins are active against ␤-lactamase-producing micro-
Types of Penicillin and Their
organisms.
Bacterial Susceptibility
Resistance to penicillin also may be caused by the
occurrence of modified penicillin-binding sites. Some The first penicillins are the naturally occurring ben-
bacteria (eg, staphylococci) may be insusceptible to the zylpenicillin and its congeners. Because of their suscep-
14 KADURINA ET AL. Clinics in Dermatology Y 2003;21:12-23

Table 1. Types of penicillin The oral formulation in this group is penicillin V. It is

Penicillin Groups Drugs less potent than penicillin G and is indicated only in
minor infectious (eg, streptococcal sinusitis, otitis, or
Natural penicillins and Benzylpenicillin (penicillinG),
congeners Phenoxymethylpenicillin (penicillin V)
pharyngitis), particularly in children, or for prophylax-
is.19 –22
Semisynthetic penicillins
␤-lactamase-resistant Broad-Spectrum, ␤-lactamase-Sensitive Penicillins
penicillins
Isoxazolyl Cloxacillin, oxacillin, dicloxacillin,
(Ampicillin, Amoxicillin, Carbenicillin, Ticarcillin,
penicillins methicillin Piperacillin, Mezlocillin, Azlocillin)
Other Nafcillin
These antibiotics (Table 1) have greater activity than
Aminopenicillins Ampicillin, amoxicillin, bacampicillin penicillin G against Gram-negative bacteria, but they
Carboxypenicillins Carbenicillin, ticarcillin
are inactivated by ␤-lactamases.
Ureidopenicillins Azlocillin, mezlocillin, piperacillin
Amidinopenicillins Mecillinam Aminopenicillins (ampicillin and amoxicillin) have
Methoxypenicillins Temocillin the same spectrum and activity. These drugs are given
Protected penicillins Amoxicillin–clavulanic acid (Augmentin威)
PO to treat common urinary tract infections with enteric
(combined with ␤- Ticarcillin–clavulanic acid (Timentim威) Gram-negative bacteria or infections of the respiratory
lactamase inhibitors) Ampicillin–sulbactam (Unasyn威) tract (sinusitis, otitis, bronchitis). Ampicillin is ineffec-
Piperacillin–tazobactam (Zosyn威) tive against Enterobacter, Pseudomonas, and indole-posi-
tive Proteus infections.19
Carboxypenicillins (carbenicillin and ticarcillin) have
tibility to bacterial ␤-lactamases, various semisynthetic more activity against Pseudomonas and Proteus organ-
penicillinase-resistant penicillins have been produced isms but their activity against Gram-positive organisms
using different side chains. Semisynthetic penicillins decrease. However, in serious Pseudomonas infections,
include ␤-lactamase-resistant penicillins (isox- they should be used in combination with aminoglyco-
azolylpenicillins, methicillin, nafcillin), broad-spectrum sides.
penicillins (aminopenicillins), and extended-spectrum The newer ureidopenicillins (azlocillin, mezlocillin,
penicillins with antipseudomonal activity (car- and piperacillin), which are Ampicillin derivatives and
boxypenicillins and ureidopenicillins).17–19 have similar activity against streptococcal species, have
Penicillins are classified according to their prepara- even greater activity against Pseudomonas, Klebsiella and
tion—natural and semisynthetic penicillins (see Table other Gram-negative microorganisms.19 –21
1). In each of these groups, they can be further classified These ␤-lactamase-sensitive antibiotics can be made
by chemical structure. resistant combined with ␤-lactamase inhibitors, such as
For clinical use, it is more convenient to classify the clavulanic acid, sulbactam, or tazobactam. ␤-lactamase
penicillins into three groups based of their antibacterial inhibitors are most active against plasmid-encoded
spectra. These groups are narrow spectrum, ␤-lacta-
␤-lactamases.
mase sensitive; broad-spectrum, ␤-lactamase sensitive;
Clavulanic acid is produced by Streptomyces clavulig-
and ␤-lactamase resistant.19
erus and it is a “suicide” inhibitor (irreversible binder)
Narrow-Spectrum, ␤-Lactamase-Sensitive Penicillins of ␤-lactamases.23
(Penicillin G and Penicillin V)
␤-Lactamase-Resistant Penicillins (Cloxacillin,
Penicillin G is the drug of choice for infections caused Oxacillin, Dicloxacillin, Methicillin, Nafcillin)
by pneumococci, streptococci, meningococci, non-␤-lac-
tamase-producing staphylococci, and gonococci, Trepo- This group of antibiotics is highly active against the
nema pallidum (exquisitely sensitive), and many other ␤-lactamase (penicillinase)- producing staphylococci
spirochetes, clostridia, Bacteroides (except Bacteroides fra- (eg, S. aureus) but compared with penicillin G, they
gilis). Borrelia burgdorferi, the organism responsible for have less potent activity against the other Gram-posi-
Lyme disease, also is sensitive. Although most of tive microorganisms. They are totally inactive against
Corynebacterium diphtheriae and Bacillus anthracis are Gram-negative enteric bacteria. Some strains of S. au-
susceptible to penicillin G, some are highly resistant. reus have PBPs with lower affinity for penicillins and
Penicillin G inhibits Actinomyces israeli, Listeria monocy- can develop resistance. The term methicillin-resistance
togenes, Pasteurella multocida, among others. Many designated staphylococci resistant only to methicillin,
strains of N. gonorrhoeae have developed resistance to but now this term is used to demonstrate staphylococ-
penicillin, and this drug is no longer a drug of choice for cal resistance to all ␤-lactam antibiotics. Methicillin is
gonorrhea. This antibiotic has narrow spectra because it rarely used now because of serious nephrotoxici-
is not active against enteric Gram-negative organisms. ty.15,18 –22
Clinics in Dermatology Y 2003;21:12-23 PENICILLIN AND SEMISYNTHETIC PENICILLINS 15

Pharmacokinetics Probenecid can partially block tubular secretion and

achieve higher systemic and CSF levels of penicillin.24
The absorption of different penicillin preparations after
Penicillin is also excreted into sputum and milk (3–
oral application differs depending on their acid stability
15% of serum concentration). The presence of antibiot-
in the stomach and their adsorption and/or binding
ics (eg, penicillin) in the milk of cows treated for mas-
onto food. To minimize the binding to foods, oral pen-
titis presents a big problem in human allergy.
icillins should be given at least 1 hour before or after
eating. Unabsorbed penicillin is destroyed by bacteria
in the colon.19 Clinical Uses
Penicillin V, ampicillin, amoxicillin, cloxacillin, di- The penicillins are frequently prescribed class antibiot-
cloxacillin, and oxacillin are well absorbed because of ics.—Penicillin V and Penicillin G.
their acid stability. Oxacillin is least well absorbed com-
pared to cloxacillin and dicloxacillin. These drugs are General Indications
highly bound to plasma albumin (⬎90%). Amoxicillin is These drugs are used for treatment of large number of
better absorbed after oral application than ampicillin mild to severe infections.
and is not influenced by food.19,21
Penicillin G, methicillin, nafcillin, carbenicillin, ticar- Streptococcal Infections
cillin, and piperacillin are poorly absorbed because they As mentioned previously, penicillin V is given PO for
are not acid stable and are hydrolyzed in the stomach. mild infections, such as pharyngitis (including Scarlet
Therefore, these penicillins are administrated parenter- fever), sinusitis, and otitis caused by S. pyogenes (group
ally. Because of the irritation and local pain produced A ␤-hemolytic streptococcus). Parenteral therapy for
by IM injection of large doses, intravenous (IV) appli- streptococcal pharyngitis is preferred when there is
cation is often preferred.19,21 potential for rheumatic fever. Severe infections, such as
The penicillins are widely distributed in body fluids pneumonia, arthritis, meningitis, and endocarditis
(joint fluid, pleural fluid, pericardial fluid, and bile) and caused by S. pyogenes should be treated with penicillin
tissues after absorption. They pass also across the pla- G.
centa (eg, for syphilis treatment in the pregnancy). Penicillin G is also widely used to treat streptococcal
However, only low concentrations of them are found in endocarditis caused by S. viridans (penicillin-sensitive
prostatic secretions, intraocular fluid, and brain tissue. viridans group). This bacterial endocarditis is associ-
They do not enter living phagocytic cells to a significant ated with several skin findings (eg, petechiae, subun-
extent. Being lipid insoluble, the penicillins do not cross gual splinter hemorrhages, Janeway’s macules, Osler’s
the blood– brain barrier (less than 1% of plasma concen- nodes) and optimally treated with two antibiotics, pen-
tration) when the meninges are normal. When the me- icillin G IV in combination with aminoglycosides. Some
ninges are inflamed, the penicillins may reach thera- physicians prefer a 4-week course of treatment using
peutically effective concentration in the cerebrospinal penicillin G alone.25
fluid (CSF). About 5–10% of serum concentration with Pneumococcal Infections
penicillin G, ampicillin, carbenicillin, and ticarcillin at- Penicillin G is the drug of choice for pneumococcal
tains in the CSF during treatment for meningitis. In pneumonia and meningitis (caused by sensitive strains
meningitis, high levels of penicillins in the CSF are of S. pneumoniae). Penicillin-resistant pneumococci are
caused by increased permeability of meninges, inhibi- becoming more common, especially in the pediatric
tion of the normal active transport of penicillin out of population. When there is penicillin resistance caused
the CSF,24 and some bindings of penicillin to CSF pro- by pneumococci, the drugs used are vancomycin or a
teins. Another penicillins (methicillin, cloxacillin, naf- third-generation cephalosporin.
cillin) penetrate the CSF poorly.
The elimination of most free penicillins is mainly Infections with Anaerobes
renal, they are excreted by glomerular filtration (10%) The majority of anaerobic infections—periodontal and
pulmonary infections, lung abscess,26, brain abscess,
and renal tubular secretion (90%), to about 1.8 g/h in
caused by mixtures of microorganisms are susceptible
adults. The short serum half-life of penicillin G (less
to penicillin G (except Bacteroides fragilis— up to 75%
than 1 hour) is one of the main problems in the clinical
resistance).
use, which can be overcome with a slow-release pro-
caine penicillin and benzathine penicillin. In renal fail- Meningococcal Infections
ure, the half-life of penicillin G increases to about 10 Patients with meningococcal meningitis and/or menin-
hours. Nafcillin, oxacillin, and the ureidopenicillins gococcemia caused by Gram-negative N. meningitidis
have significant excretion (about 80%) into the biliary should be treated with high doses of penicillin G IV.
tract and only 20% by tubular secretion. These drugs Penicillin G does not eliminate the meningococcal car-
are recommended to use for patients with renal failure. rier state and is ineffective for prophylaxis.27–29
16 KADURINA ET AL. Clinics in Dermatology Y 2003;21:12-23

Penicillin in Dermatology Anthrax

Penicillin G has been the traditional agent of choice in
From an historical point of view, brilliant therapeutic
the treatment of all clinical forms of anthrax. The type of
results after penicillin administration in serious cases
anthrax depends on the way the spores or organisms
have elevated the use of penicillin over other drugs.
enter in the patient. Cutaneous anthrax is most common
Penicillin may be used in the treatment of pemphigus,
form. Some patients, particularly the immunosup-
dermatitis herpetiformis, lupus vulgaris, psoriasis vul-
pressed, may develop complications such as edema and
garis, lichen planus, cold urticaria, etc.30 At the present
anthrax sepsis.
time, penicillin is used as an antiinfectious drug in
Usually, cutaneous anthrax responds well to IM in-
dermatology, but sometimes it is used its nonspecific
jections of penicillin G in the beginning, followed by
action.
oral medication (penicillin V, amoxicillin).42,43 More se-
Erysipelas vere form of anthrax44 (eg, sepsis, pulmonary anthrax)
Aqueous penicillin G has many indications, but its main should be treated IV with penicillin G. Penicillins (pen-
use in dermatology is treatment of erysipelas. Penicillin icillin G, amoxicillin) are given also for prophylactic
G remains the therapeutic reference for erysipelas. Most therapy of anthrax to asymptomatic patients, especially
of the cases with erysipelas are caused by S. pyogenes pregnant women and children, exposed to B. anthracis;
(group A ␤-hemolytic streptococcus), but occasionally however, strains of B. anthracis resistant to penicillins
other streptococci are identified. At particular risk for have been reported.
infection are young patients, elderly patients (especially
Lyme Disease
with diabetes), and immunocompromised patients. The
The first stage of the disease is manifested with cuta-
main local factors are tinea pedis, venous or lymphatic
neous findings: Erythema chronicum migrans, which is
stasis, and a history of saphenous phlebectomy or
usually solitary lesion. Although tetracyclines are the
lymphadenectomy. The prevention of the recurrence is
preferable group of choice for early stage, penicillin V
correct treatment of the disease (usually erysipelas re-
also is effective, especially in the treatment of children
cur when the treatment is stopped), treatment of ve-
with solitary erythema migrans.45– 48 Because B. burg-
nous and lymphatic stasis, and/or wounds. The early
dorferi can cross the placenta, there is a risk of fetal
stages of erysipelas are frequently treated with oral or
involvement. Pregnant women should be treated with
IM penicillin.31–35 For prophylaxis, selected patients are
penicillin G or ceftriaxone to prevent fetal death, spon-
given depot penicillins (eg, benzathine penicillin G—1,2
taneous abortions, and congenital malformations.49 Pa-
million units monthly) for several months.36,37
tients with neuroborreliosis or cardiovascular involve-
Other Skin and Soft-Tissue Infections Caused by S. ment are best treated with crystalline penicillin G IV for
Pyogenes 14 to 30 days, depending on disease severity,50,51 or
Infections successfully treated with penicillin G or V are third-generation cephalosporins. The antibiotic therapy
perianal streptococcal dermatitis; ecthyma; impetigo may be complicated with Jarisch-Herxheimer reaction
(more frequently caused by S. aureus); cellulitis; and because of endotoxins release.52
necrotizing fasciitis (streptococcal gangrene).34,35,38 The
Actinomycosis
choice of preparation and duration of the therapy de-
Actinomycosis is caused by Actinomyces israelii, which is
pend on the patient’s medical status and background.
part of normal oral mucosa, but occasionally is found in
Scarlet Fever the intestinal flora. The main predisposing factors for
Scarlet fever is streptococcal infection manifested by the disease are dental problems, broken bones, and
pharyngitis, fever, glossitis, and a diffuse exanthem. It trauma. All forms of actinomycosis are well treated
is a disease of childhood, caused by group A ␤-hemo- with penicillin. The usual recommended regimen is
lytic streptococcus-producing pyrogenic (previously penicillin G IV for at least 6 weeks. Some physicians
called erythrogenic) exotoxin. As mentioned above, S. continue therapy with oral penicillin V for several
pyogenes is particularly sensitive to penicillin. The rec- months. The treatment is much easier after surgical
ommended therapy is oral penicillin V for 10 days or a excision of the lesion.39
single injection of benzathine penicillin G.39
Listeriosis
Erysipeloid L. monocytogenes produces a variety of clinical findings.
The causative agent of this disease, Erysipelothrix rhu- It may develop localized cutaneous lesions on the side
siopathiae, is sensitive to penicillin. Oral penicillin V is of contact. Penicillin G or ampicillin are the drugs of
effective for local infection. Patients with signs of endo- choice in the treatment of listeriosis. If the disease is
carditis should be treated with penicillin G IV. The complicated with endocarditis, the duration of the treat-
therapy should be continued for 4 to 6 weeks.40,41 ment should be no less than a month.53
Clinics in Dermatology Y 2003;21:12-23 PENICILLIN AND SEMISYNTHETIC PENICILLINS 17

Fusospirochetal gingivostomatitis parenteral penicillin G. It can be used in its aqueous

Fusospirochetal gingivostomatitis is readily treatable crystalline form or as an IM depot injection.
with penicillin. For simple infections, penicillin V is The choice of regimen depends on the stage of the
administered. disease.68,69 The recommended therapy for neurosyph-
ilis is aqueous crystalline penicillin G IV. When the
Gas Gangrene
patient is allergic to penicillin, then an alternative is
Gas gangrene is caused by Clostridium perfringens. The
tetracyclines and macrolides, although this is not a
treatment of the disease includes high-dose penicillin G
valid option for syphilotherapy in pregnancy. The
IV and adequate debridement of the infected areas.
mother should be desensitized and treated with peni-
Leptospirosis (Weil disease) cillin. In the HIV era, the patient with HIV/AIDS occa-
The causative agent of this disease is spirochete, or sionally has a loss of seroreactivity, as well as a false-
Leptospira interrogans, which is sensitive to penicillin positive reaction. HIV patients should always be treated
and tetracycline. In Weil disease a variety of cutaneous with penicillin.
findings can develop, as well as multisystem involve- The majority (70 –90%) of patients with secondary
ment. In clinical practice, penicillin G is widely used to syphilis develop the Jarish-Herxheimer reaction, al-
treat leptospirosis.54 though it can occur with any stage. Several hours after
the first injection of penicillin, fever, chills, myalgias,
Nonspecific Action of Penicillin G headache, tachycardia, and often hypotension may de-
Scleroderma velop. The syphilitic cutaneous lesions may become
Clinical and histologic investigations suggest some suc- more prominent, edematous and shiny in color. In case
cess inf using penicillin G and D-penicillamine (DPA) to of cardiovascular and neurosyphilis, the Jarish-Herx-
treat dermal fibrosis in patients suffering from circum- heimer reaction is more severe. This reaction is thought
scribed and systemic sclerosis;55–57 however, there is to be caused by the release of endotoxin from killed
little knowledge about the mechanism of the antifibrotic spirochetes.70 Aspirin can control the fever and other
action of penicillin G and DPA. DPA is formed from symptoms, and therapy with penicillin should not be
penicillin by hydrolytic breakdown and returns the discontinued.
collagen synthesis to normal by a direct inhibition of the Nonvenereal treponematoses—yaws, pinta and en-
crosslink reaction of collagen and indirectly by an inhi- demic syphilis—are caused also by treponemes and
bition of ␤-galactosidase.58 This enzyme plays an im- have many clinical, serologic and therapeutic similari-
portant role in the pathogenesis of localized and gen- ties with syphilis, but they are not usually sexual trans-
eralized scleroderma. Penicillin G and DPA activate mitted.
also collagenase, leading to degradation of collagen.
The rapid improvement in localized scleroderma af- Gonorrhea
ter high-dose penicillin G therapy can purportedly be Because of the increasing incidence of penicillinase-
related with the role of B. burgdorferi in the development producing N. gonorrhoeae, penicillins are no longer the
of the disease.59 therapy of choice for gonorrhea
Because of the relationship between idiopathic atro-
phoderma of Pasini and Pierini60 and linear atropho- Semisynthetic Penicillins: The Aminopenicillins
derma of Moulin,61 treatment with penicillin could be (Ampicillin and Amoxicillin)
possible.
General Indications
Scleroderma Adultorum Buschke Penicillinase-resistant penicillins are the agents of
Among children and young women, scleredema may choice for staphylococcal pneumonia, osteomyelitis, en-
follow or associate with a streptococcal infection. Even docarditis, and septicemia.18,21 Upper respiratory infec-
in the absence of a documented infection, high doses of tions (sinusitis, otitis media, acute exacerbation of
penicillin G have been given with positive results.62,63 chronic bronchitis, epiglositis) are successfully treated
with aminopenicillins.19
Pityriasis Rubra Pilaris
Gram-negative urinary tract infections, especially
Penicillin could be a possible therapeutic agent for the
uncomplicated enterococcal infections, are treated ef-
treatment of Pityriasis rubra pilaris.64 – 66
fectively with Ampicillin.
Venereal and Nonvenereal Treponematoses Meningitis
Penicillin was introduced for syphilis therapy by Ma- Acute bacterial meningitis in children is most fre-
honey et al.67 in 1943. After more than 50 years of use, quently caused by H. influenzae, S. pneumoniae, or N.
there is no evidence of T. pallidum resistance to penicil- meningitidis. The combination of Ampicillin plus a third
lin. Many other antibiotics have been tested for treat- generation cephalosporins is a rational regimen for em-
ment of syphilis, but the treatment of choice is still piric treatment of suspected bacterial meningitis.21
18 KADURINA ET AL. Clinics in Dermatology Y 2003;21:12-23

Salmonella Infections fever. After application of penicillinase-resistant peni-

In typhoid and paratyphoid fevers, ampicillin is an cillins, replacement of fluids and temperature control,
alternative drug. there is a surprising improvement.72
Helicobacter Infections Folliculitis
H. pylori is responsible for most cases of chronic atro- There are many different forms of folliculitis with dif-
phic gastritis, as well as gastric and duodenal ulcers. ferent causes. Bacterial agent of folliculitis is usually S.
This pathogen is suspected as a possible cause of aureus. Antistaphylococcal therapy with penicillinase-
chronic urticaria and rosacea. Amoxicillin is included in resistant penicillins is recommended for such folliculi-
the complex therapy for the eradication of H. pylori.71 tis.
Antipseudomonal Penicillins Furuncle and Carbuncle
Antipseudomonal penicillins, such as carboxypenicil- Furuncles and carbuncles are also staphylococcal infec-
lins and ureidopenicillins, are used exclusively for tion, improved after therapy with these type penicillins.
pseudomonas infections of the urinary tract, lung and
Cellulitis
blood, and infections after burns.
Cellulitis should be treated with penicillinase-resistant
Protected Penicillins penicillins, because S. aureus is the major pathogen.
The amoxicillin-clavulanic acid combination is used for
Antipseudomonal Penicillins
treatment of otitis media in children, and sinusitis, bac-
Antipseudomonal penicillins do not play a role in der-
terial exacerbation of bronchitis, and lower respiratory
matologic therapy.
tract infections in adults. The Ticarcillin-clavulanate
and piperacillin-tazobactam are effective in treating IA Protected Penicillins
and gynecologic infections and osteomyelitis when Protected penicillins are suitable, especially for polymi-
mixed bacteria are present. crobial-caused skin infections or gonorrhea. They are
effective particularly in the treatment of diabetic foot
Semisynthetic Penicillins in Dermatology ulcers, infected decubitus ulcers, and burn wounds.73
The penicillinase-resistant penicillins (cloxacillin, ox-
acillin, dicloxacillin, and nafcillin) are considered as the Gonorrhea
agents of choice for most staphylococcal skin and soft- For patients without resistance to penicillin the oral
tissue infections. Nafcillin is highly resistant to penicil- application of amoxicillin (3 g) ⫹ probenecid (1 g) or
linase and is more effective than others against staph- ampicillin (3.5 g) ⫹ probenecid is recommended. The
ylococcal skin infections. combination of procaine penicillin G injected into two
Toxin-Mediated Staphylococcal Disease sites with probenecid (1 g) is also efficacious. If there is
Most staphylococci (esp. S. aureus) produce a variety of a resistance to penicillin, the recommended treatment
toxins, including cytotoxins and leukocytolytic toxins, for gonococcal urethritis, arthritis, and disseminated
which cause serious diseases. Many of these toxins gonococcal infections with skin lesions is ceftriaxone IM
serve as superantigens and activate polyclonal T cells, or IV29
leading to cytokine release, especially of tumor necrosis
factor-␣ and interleukins-1 and -6. Chlamydial Infections
Toxic shock syndrome is life-threatening multisys- Amoxicillin is equally efficacious compared with
tem disease with skin involvement caused by the staph- azithromycin in the treatment of cervical Chlamydia tra-
ylococcal exotoxin toxic shock syndrome toxin-1. The S. chomatis during pregnancy.74
aureus enterotoxin causes staphylococcal food poison-
ing.39
Dosage
Impetigo
Penicillins can be administered by the oral, IM, or IV
Impetigo is superficial skin infection, usually appearing
route. Dosages vary widely depending on the infecting
among children. It is commonly caused by S. aureus as
pathogen, the type of infection being treated, and the
a result of the production of two exotoxins, exfoliatin A
patient.
and B. A variant of bullous impetigo is seen in new-
The average recommended daily doses of the peni-
borns (impetigo neonatorum). The therapy should con-
cillins given PO (penicillin V, ampicillin, cloxacillin,
sider with the age of patient.
and oxacillin) are 20 –30 mg/kg, usually divided into
Staphylococcal Scalded Skin Syndrome four equal doses. The approximate daily dose given
The disease usually involves infants or children up to parenterally is between 50 and 200 mg/kg (50 –100
5years of age. Staphylococcal scalded skin syndrome is mg/kg for children) for ampicillin, cloxacillin, methicil-
manifested with widespread superficial skin loss and lin, nafcillin, and oxacillin; 300 mg/kg for ticarcillin;
Clinics in Dermatology Y 2003;21:12-23 PENICILLIN AND SEMISYNTHETIC PENICILLINS 19

400 –500 mg/kg for carbenicillin, and 100,000 –200,000 penicillins or even skin testing with these drugs may be
IU/kg for aqueous benzylpenicillin (1 UI ⫽ 0.6 ␮g).19,75 followed of fatal episodes of anaphylaxis. The mecha-
The parenteral penicillins are usually administered nism of these reactions involves the chemical reactivity
in four to six equal doses per day. The depot-penicillin of the ␤-lactam ring. Penicillins are a classic example of
G preparations (procaine and benzathine) are pre- haptens and when they are degraded, the ␤-lactam ring
scribed as a single daily, weekly, or monthly dose. The opens and reacts with tissue proteins making them
approximate dose for these long-acting penicillins is immunogenic. This is the so-called “major determi-
1.2–2.4 million units. These doses are average and must nant” because it is the major reaction leading to protein
be adjusted for renal insufficiency.75 binding and penicillin allergy. There are “minor anti-
genic determinants” composed mainly of penicilloic
Contradictions and penillic acids also. Although these determinants
refer only to the relative quantity of haptens available
The majority of patients who give a history of allergy to
and not to their immunologic importance, a high per-
penicillins should be treated with different type of
centage of immediate reactions (eg, anaphylaxis) is
antimicrobials. In the unusual instance where treatment
caused by minor determinants.
with penicillin is essential, skin tests should be placed.76
The most serious reactions after administration of
If the infection is life-treating only with penicillin (eg,
penicillin, such as acute anaphylactic shock and angio-
bacterial endocarditis) desensitization is recommended,
edema, are fortunately very rarely fatal. The most dra-
although it is a potentially dangerous procedure in
matic clinical picture described anaphylactic shock in-
itself.
cludes sudden, severe hypotension with collapse;
About 10% of patients sensitive to penicillins who
bronchospasm; and abdominal pain, nausea, and vom-
are given cephalosporins will exhibit cross-drug sensi-
iting. At the same time, urticaria or angioedema may
tivity and develop eruption. It is recommended that
occur. Angioedema and/or a drug-induce acute urti-
patients with a history of immediate or accelerated
caria are other important immediate allergic reaction
reactions to penicillin (type I—IgE mediated— or severe
that are characterized clinically by marked swelling of
type IV delayed hypersensitivity reactions) not be
the lips, face and periorbital tissues, genitalia and distal
treated with cephalosporins. It is suggested that the
parts of the extremities, and urticarial wheals. The risk
newer generation of cephalosporins have less allergic
of angioedema is swelling of the tongue, larynx, and/or
cross-reactivity with penicillin molecule than cephalo-
pharynx, which can lead to bronchoconstriction.79 – 81
thin.77
Accelerated reactions (occurring within 1– 48 hours) are
usually manifested by rash and sometimes by fever.
Side Effects
Delayed reactions (beginning more than 48 hours after
The penicillins have very low toxic effects and are exposure) can present of skin reactions or systemic
completely safe in pregnancy.78 They have pregnancy reactions (such as nephritis or serum sickness).
risk factor of B according to FDA. Penicillins also have Skin eruption (scarlatiniform, morbilliform, urticar-
little effect on mammalian cells. However, all penicillins ial, vesicular, and bullous eruptions) and fever are the
may cause penicillin allergy (they are the most common most common manifestations of penicillin allergy. Fe-
cause of drug allergy), neuro- and nephrotoxicity, and ver may be the only evidence of hypersensitivity and
uncommon hematologic toxicity. Sensitivity to penicil- can reach high levels. Purpuric lesions are uncommon
lin is a contraindication to exposure any of the semi- and are mainly the results of a vasculitis. Schönlein-
synthetic analogs. Henoch purpura with renal involvement has been rare
Hypersensitivity reactions are most commonly ad- complication.82 Exfoliative dermatitis and exudative er-
verse reactions caused by penicillin, which occur in ythema multiforme of either the erythemopapular or
about 5% of patients. The incidence of hypersensitivity vesiculobullous type also have occurred.
is three to four times higher in atopic than in nonatopic Some medications, including aminopenicillins (am-
patients. The relationship between atopic symptoms- picillin, amoxicillin), may cause severe drug reaction
complex and penicillin allergy is unclear.79 with atypical target lesions, widespread loss of epider-
Hypersensitivity reactions may appear in the ab- mis, and mucosal involvement (in about 90% of pa-
sence of a previous known drug exposure (eg, in the tients).83
environment). The most serious of hypersensitivity re- Stevens-Johnson syndrome (SJS), toxic epidermal
actions are anaphylaxis and angioedema that occurs necrolysis (TEN), and SJS-TEN overlap are referred to
immediately after application (in less than 30 minutes) the most severe skin reactions caused by medications.
and are mediated by IgE.79 The incidence of anaphy- The pathogenesis of these severe skin reactions has not
laxis is about 0.01%. Parenteral administration appears been well defined immunologically. In general, these
the most likely route inducing anaphylaxis in hu- reactions are held to be cell-mediated cytotoxic re-
mans.79 – 81 It must be known that very small doses of sponses as the epidermis is infiltrated by activated lym-
20 KADURINA ET AL. Clinics in Dermatology Y 2003;21:12-23

phocytes. It is unclear whether the cytotoxic T cells eosinophilia, pyuria, proteinuria, elevation of serum
directly damage the epidermis or release cytokines that creatinine, and even oliguria have been noted.92,94 –96
stimulate apoptosis.39,84,85 Hypokalemia may be a side effect of high dose par-
Penicillin is also an agent that causes fixed drug enteral penicillin therapy because the penicillins act as
eruption. Clinical and immunologic studies suggest nonreabsorbable anions.
that fixed drug eruption is delayed hypersensitivity Other hypersensitivity reactions seen occasionally
reaction, which is also referred to as cell-mediated re- are vasculitis (of the skin or other organs); Coomb’s
action. Patients frequently give a history of identical test-positive hemolytic anemia (it has been described in
lesion(s) occurring at the same skin site. The most com- patients, receiving massive IV doses of penicillin for 1
mon sites are palms and soles, glans penis, scrotum, week or more.79
and oral mucosa. Reversible neutropenia is also seen, especially pa-
Incidences of drug-induced pemphigus (DIP) from tients taking methicillin, nafcillin, or cloxacillin.97 It is
penicillin have been described. Even though DIP is unclear if this is truly hypersensitivity reaction.
suggested to be relate to thiol compounds of the drug, All penicillins, particularly high doses of carbenicil-
many nonthiol drugs termed “masked” thiols, like pen- lin and ticarcillin, may cause decreased platelet aggre-
icillin, may also induce pemphigus.86 Penicillins con- gation by binding to adenosine diphosphate receptors
tain sulfur in their molecule, and the sulfur may change on the platelets. Significant bleeding disorders are in-
metabolically to form active thiol groups. Analyses of frequent.98,99
the penicillin chemical structure reveal an active amide Convulsions, twitching, multifocal myoclonus, local-
group in their molecule that may be responsible for ized or generalized epileptiform seizures, or other
induction of the disease, not the sulfur.87,88 forms of encephalopathy may occur when extremely
Few reports relate penicillin as a possible provoca- large doses of penicillin G have been prescribed. These
tion of generalized pustular psoriasis (von Zumbusch’s reactions are more likely to occur to patients with renal
type). The penicillin and some semisynthetic penicillins insufficiency.
(eg, ampicillin, amoxicillin) may initiate and exacerbate Many people taking oral penicillins experience nau-
this disease. The mechanism induced pustular psoriasis sea, vomiting, and even diarrhea (especially with am-
by the penicillins is unknown.89 –91 picillin and amoxicillin). These gastrointestinal mani-
Serum sickness is a reaction usually appearing after festations are mild and transient and often are related to
1 week or more penicillin treatment, and is mediated by the dose of the drug. The incidence of diarrhea is higher
IgG antibody. The typical clinical manifestations, in- in children receiving amoxicillin/clavulanic acid.100
cluding fever, urticarial lesions, lymphadenopathy, Rarely, ampicillin and other penicillins may cause a
polyarthritis, neuritis, serositis and acute glomerulone- pseudomembranous colitis. Mild elevation of serum
phritis, is thought to be secondary to circulating anti- glutamic oxalacetalate transaminase has been reported
gen-antibody complexes.92 When long-acting penicillin during therapy with oxacillin and nafcillin.
preparations are used, clinical findings may be delayed After IM injection of penicillin (especially procaine
up to three weeks and symptoms may be prolonged and benzathine forms), occasionally the medication en-
several weeks rather than a few days to a week.93 ters or irritates an artery, causing arteriospasm that
Contact dermatitis is observed occasionally in phar- leads to distal ischemic necrosis. It is also known as
macists, nurses, and physicians after preparing penicil- Nicolau syndrome or embolia cutis medicamentosa,
lin solutions. which present with hemorrhagic livid lesions progress-
The specific maculo-papular skin eruption is much ing to cutaneous necrosis. If an injection damage a
more common after using of ampicillin or amoxicillin nerve, it may cause not only pain but also paralysis and
(being about 9%) and is not related to true penicillin vasoconstriction.101
hypersensitivity. It may represent a “toxic” rather than If after IM injection microcrystals of depot-penicillin
a truly allergic reaction.30 Patients with infectious enter in venous system, immediate nonallergic reaction
mononucleosis almost always get an ampicillin erup- can develop known as Hoigné syndrome. Dizziness,
tion (more than 90%). The ampicillin eruption is also tinnitus, headache, hallucinations, sometimes seizures,
common among patients with other virus infections cough, and angina manifest this reaction.102
(cytomegalovirus), patients with lymphoid malignan- Local reactions, such as pain and sterile inflamma-
cies, and patients receiving allopurinol together with tory reactions at the site of injection, have been de-
ampicillin. The incidence of ampicillin eruption is not a scribed after penicillin application. As a result of local
contraindication to treatment with penicillins at a later damage to muscle, serum transaminases and lactic de-
date.18 –22 hydrogenase can be elevated.
Acute interstitial nephritis is uncommon, occurring Some persons receiving penicillin IV also have de-
most generally with methicillin exposure. Hematuria, veloped phlebitis or thrombophlebitis. Finally, the lit-
Clinics in Dermatology Y 2003;21:12-23 PENICILLIN AND SEMISYNTHETIC PENICILLINS 21

erature mentions a few cases of postinflammatory elas- 10. Tipper DJ. Antibiotic inhibitors of bacterial cell wall
tolysis (cutis laxa) after penicillin therapy.103,104 biosynthesis. Oxford: Pergamon Press, 1987.
11. Tomasz A. From penicillin-binding proteins to the lysis
and death of bacteria. Rev Infect Dis 1979;1:434 –67.
Drug Interactions 12. Tomasz A, Holtje JV. Murein hydrolases and the lytic
and killing action of penicillin. In: Schlessinger D, editor.
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cillins and aminoglycosides should not be mixed in IV 13. Lindberg F, Normark S. Contribution of chromosomal
infusions and should be given separately in time.105 beta-lactamase to beta-lactam resistance in enterobacte-
Penicillins and bacteriostatic drugs are often antag- ria. Rev Infect Dis 1986;8:292–304.
onistic in vitro. The only in vivo example of this antag- 14. Neu HC. Contribution of beta-lactamases to bacterial
onism is the lack of improvement in S. pneumoniae resistance and mechanisms to inhibit beta-lactamases.
meningitis when is treated with both penicillin and Am J Med 1985;79:2–12.
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