Acute orofacial infections

Table 39-1 presents quantifiable data from 12 clinical studies from 1976-1996 on the microbiology of acute orofacial infections. The average number of isolates per case was 3.6, with a maximum of 12. The data in Table 39-1 indicate that acute orofacial infections are polymicrobial, dominated by anaerobes, and often contaminated by various microorganisms, particularly from the pharynx, sinuses, and gastrointestinal tract.

TABLE 39-1 Microorganisms Associated with Acute Orofacial Abscesses Based on 2339 Isolates in 12 Studies from 1976-1996

Each of the following species is less than 1% of total but together constitute 11.3% of all isolates: Acinetobacter; Aggregatibacter actinomycetemcomitans; Arachnia; Citrobacter; Corynebacterium; Eikenella corrodens; Clostridium; Enterobacter; Escherichia coli; group A, B, C, D, and G streptococci; Haemophilus influenzae; Klebsiella pneumoniae; Lactobacillus; Neisseria; Propionibacterium acnes; Serratia; and spirochetes (most likely contaminants).

VGS, Viridans group streptococci.

* Most studies list as Bacteroides.

Substantial commonality exists in the microbial cause of acute orofacial cellulitis, pulpal infections, periodontal abscesses, periimplantitis, pericoronitis, acute necrotizing gingivitis, osteomyelitis, and their serious extensions (e.g., Ludwig’s angina, mediastinal infections). These entities differ primarily in quantitative rather than qualitative microbiologic characteristics. Rapidly spreading infections often have a VGS component because streptococci possess various “spreading factors” (e.g., hyaluronidase, streptokinase, streptodornase) that promote rapid movement by fascial planes. Staphylococci rarely move except in blood, whereas gram-negative oral anaerobes may move in tissue but rarely in blood to cause metastatic infections elsewhere; streptococci move easily in blood and tissue.

Metastatic infections from Porphyromonas gingivalis, Prevotella intermedia, and Prevotella nigrescens and other anaerobic periodontal pathogens apparently are very rare,^68,83 whereas respiratory tract infections may commonly precede pericoronitis. Staphylococci isolated from facial cellulitis are most likely contaminants because these organisms are not a normal component of the subgingival flora residing primarily on oral mucosal surfaces. They can be a major factor in the cause of oral mucositis. Anterior nares carriage of Staphylococcus aureus occurs permanently in 20% and intermittently in 60% of the population.⁵³ Subgingival staphylococci may appear because of selection by local or systemic antibiotic therapy.²³ Retropharyngeal abscesses seem to have the same microbial cause as facial cellulitis.

Pulpal and periapical pathogens

It may be artificial to separate acute orofacial infections from the microbiologic features of pulpal and periapical lesions because acute facial cellulitis is most often a sequela to dentition-derived infections. Yet this separation is often made in the literature, and at times it is difficult to determine precisely what type of infection is being studied, making a review of both of these entities necessary.

Numerous studies have attempted to determine the significance and quantity of microbial pathogens responsible for pulpal and periapical infections. Some studies maintain that certain microorganisms work synergistically to initiate orofacial infections, whereas others have concluded that each pulpal infection has its own distinct flora. More recent studies have isolated a high prevalence of black-pigmented anaerobes (e.g., P. nigrescens, P. intermedia, P. gingivalis, and Porphyromonas endodontalis); however, this may reflect better anaerobic isolation technique, rather than a shift in pathogenic flora. The percent of obligate anaerobes isolated varies with the particular study from 21% to 80%, possibly reflecting the skill in taking the culture. These infections are polymicrobial, with the number of species isolated varying from 1 to 33, with 5 to 7 species commonly reported as an average. Achieving a general consensus of the major pathogenic microorganisms responsible for pulpal/periapical infections is hampered by methodologic difficulties, including small sample sizes, lack of randomization or use of consecutive case series, varying expertise in culturing, presence or absence of dental caries or periodontal disease, and bacterial contamination of cultures. The major exception is VGS, which is prominent in periodontal health and acute orofacial infections.

Commonly isolated microorganisms associated with pulpal/periapical lesions seem to be VGS, other streptococci (β-hemolytic, β-hemolytic, group D), Fusobacterium, Peptostreptococcus micros, Lactobacilli, Actinomyces, Porphyromonas, Prevotella, Veillonella, Eubacterium, and Bacteroides forsythus. Other microorganisms found less commonly or rarely include Propionibacterium acnes, Candida albicans, Enterococcus, staphylococci, Pseudomonas aeruginosa, Enterobacter aerogenes, Serratia marcescens, Eikenella corrodens, S. pneumoniae, Corynebacterium, Capnocytophaga, Selenomonas, and Wolinella (Box 39-1). A significant portion of these may be contaminants.

Periodontal abscesses

An acute periodontal abscess is characterized as a lesion of periodontal breakdown located within the gingival wall of the periodontal pocket and manifested as a localized accumulation of purulence.⁴⁰ An acute periodontal abscess may result from an exacerbation of local periodontitis pathology, after periodontal debridement procedures, or from the lodgment of a foreign object in the periodontal pocket (e.g., popcorn husks, dental floss, calculus).⁴⁰ The microbial cause of a periodontal abscess is similar to that of adult periodontitis, and the flora is commonly indistinguishable from the microflora of the subgingival plaque in adult periodontitis.⁴⁰ The predominant microflora are P. gingivalis (55% to 100% of isolates), P. intermedia (25% to 100% of isolates), Fusobacterium nucleatum (44% to 65% of isolates), Aggregatibacter actinomycetemcomitans (25% of isolates), Campylobacter rectum (80% of isolates), Prevotella melaninogenicus (22% of isolates), and Treponema denticola (71% of isolates)⁴⁰; other organisms include P. micros and B. forsythus.⁴⁰ It has been estimated that 74% may be anaerobes and 67% may be gram-negative rods, with streptococci significant only at the base of the abscess.⁷³

The principal and sometimes only therapy of periodontal abscess is incision and drainage through the external tissue and compression of the soft tissue wall.⁴⁰ Curettage or root planing is not usually required unless a reasonable chance exists to eliminate the periodontal pocket.⁴⁰ The abscess tends to become fistulous readily and rarely results in metastasis or acute orofacial cellulitis, possibly because VGS have been replaced by periodontal pathogens that do not spread by fascial planes as do streptococci. On fistulization, the lesion is self-limiting, as opposed to dentoalveolar abscesses of pulpal origin, which may readily end in cellulitis.

Periodontal abscess often can be treated simply with incision and drainage without antibiotics because it is rarely associated with fever, malaise, lymphadenopathy, and other signs of systemic involvement; periodontal abscess may necessitate antibiotic therapy only if the signs and symptoms of systemic involvement or cellulitis are present, or incision and drainage cannot be performed.^40,60,80 This is in contrast to antibiotic therapy of pulpal/periapical infection, which should be more aggressive because there is a much greater tendency to spread into the fascial planes. If antibiotic therapy of a periodontal abscess is indicated, the situation is classic for short-term, high-dose therapy, as opposed to commonly longer therapy for dentoalveolar abscess.^60,81 Periodontal pathogens rarely, if ever, metastasize to the heart or other organs and tissues.^82,83

Acute necrotizing ulcerative gingivitis

The microbiology of acute necrotizing ulcerative gingivitis (trench mouth, Vincent’s infection) is characterized primarily by Treponema, Fusobacterium, Selenomonas, and P. intermedia and secondarily by Veillonella, Neisseria, Capnocytophaga, E. corrodens, Bacteroides, Actinomyces, and gram-positive cocci.⁶⁵

Pericoronitis

The microbial flora of pericoronitis are a complex mixture of organisms resembling that of periodontitis and gingivitis,⁵⁸ often with a high concentration of VGS. Common microorganisms found in 40% or more of samples include Stomatococcus, Rothia dentocariosa, Actinomyces naeslundii, Actinomyces israelii, Prevotella, Neisseria, Haemophilus, P. micros, Capnocytophaga, Corynebacterium, Bifidobacteria, and treponemes.⁵⁸ Other, less common isolates include coagulase-negative staphylococci (CoNS), lactobacilli, Veillonella, Fusobacterium, and Porphyromonas.⁵⁸

Periimplantitis

The microbial causes of chronic periodontitis, refractory periodontitis, and periimplantitis (an inflammatory process of the tissues surrounding an osseointegrated implant resulting in loss of supporting bone) are remarkably similar, differing primarily in the quantitative and not qualitative isolation of the predominant species: B. forsythus, F. nucleatum, P. gingivalis, P. intermedia, P. nigrescens, C. rectum, and treponemes (spirochetes).⁶² Healthy dentulous or implant periodontium usually exhibits fewer of the above-mentioned organisms and is dominated by VGS, Actinomyces, Veillonella, E. corrodens, and Capnocytophaga.⁵⁷

Periimplantitis results from a shift in periodontal flora with facultative anaerobic streptococci (VGS) and nonmotile rods replaced by gram-negative anaerobic bacilli and spirochetes, similar to what occurs in periodontitis.^57,62 The issue of whether implant success is compromised in patients with periodontitis (treated or untreated) is controversial, but it seems reasonable to postulate that the gingival sulcus in patients with periodontitis is a reservoir for periodontal microbial pathogens.⁸⁴ Host resistance and factors that reduce immunity (stress) are as likely a complicating factor in periimplantitis as they are in aggressive periodontitis.

Osteomyelitis

Osteomyelitis is an infectious inflammatory process resulting in bone destruction. There are several clinical descriptions of osteomyelitis as follows: (1) secondary to a contiguous infection, (2) secondary to vascular deficiency and diabetic foot infection, (3) in association with an infected prosthesis (e.g., dental implant, prosthetic joint), (4) hematogenous, (5) chronic, and (6) acute.^21,59 Osteomyelitis, resulting from local spread from a contiguous contaminated or infectious source, commonly follows trauma, bone surgery, or joint replacement. Approximately 15% of diabetics develop foot pathology requiring amputation with contributing factors of bone and soft tissue ischemia and peripheral motor, sensory, and autonomic neuropathy. The amount of osteomyelitis associated with various bone implants is increasing; this includes dental implants.^21,59 Spread of bacteria to bone via the hematogenous route is particularly common in prepubertal children and immunocompromised elderly patients. Chronic osteomyelitis is a long-standing infection of months to years in duration characterized by persistent microorganism, low-grade inflammation, sequestrum formation, and fistulous tracts. Acute osteomyelitis evolves over a few days or weeks.

The treatment of osteomyelitis usually involves antibiotic therapy and surgery. Because of the multiplicity of etiologic organisms, it seems imperative to get a culture and sensitivity test as soon as possible to initiate the most appropriate antibiotic therapy.⁴⁵ The disease may have a polymicrobial etiology with an average of 3.9 microbes per culture. The microbial cause of oral osteomyelitis varies to some extent with the anatomic site. The most common microorganisms in orofacial osteomyelitis include streptococci, lactobacilli, Eubacterium, Klebsiella pneumoniae, S. aureus, Acinetobacter baumanii, and P. aeruginosa.²¹

Deep neck space infections

Deep neck space infections arise most commonly from upper airway infections (47.5% to 53.2%) and odontogenic infections (28.8% to 30.5%).^10,46 The spaces involved include the sublingual, submylohyoid (submental, submandibular), lateral pharyngeal (parapharyngeal, peripharyngeal, pterygopharyngeal, retropharyngeal), and masseter spaces (masseter, pterygotemporal, parotid, peritonsillar).⁸⁷ These infections include Lemierre’s syndrome (suppurative thrombophlebitis of the internal jugular vein from septic emboli) and Ludwig’s angina. Deep neck infections seem to be more common in patients with diabetes mellitus⁴⁷ and patients with low socioeconomic status and with poor oral hygiene.³

The microbiology of deep neck space infections is primarily that of commensal microorganisms that for some reason travel quickly through the fascial planes, which likely have acquired virulence genes they do not normally possess. These organisms include VGS, S. aureus, Peptostreptococcus, K. pneumoniae, and oral anaerobes (Porphyromonas, Prevotella, and Fusobacterium species).⁹

There are no data to support pretreatment or postsurgical antibiotic prophylaxis to prevent deep neck space infections (see Chapter 49). For unknown reasons, these normally commensal and harmless bacteria become very aggressive and spread rapidly to the submandibular regions. These infections are often polymicrobial, making antibiotic treatment alone very difficult, and most must be treated by incision and drainage.

Ludwig’s angina

As first described by Ludwig in 1836, Ludwig’s angina is characterized by a massive bilateral edema of the mouth floor with pathognomonic elevation of the tongue against the palate and posterior pharyngeal wall along with glottic edema, resulting in potentially life-threatening airway obstruction—hence the vernacular terms morbus strangulatoris, angina maligne, and garotillo (“hangman’s noose”). Ludwig’s angina involves the connective tissues, fascia, and muscle and spreads by fascial planes through the submandibular, sublingual, and submental spaces and potentially on to the pharynx, retropharyngeal region, and mediastinum.⁷⁷ Approximately 70% to 80% of cases are of odontogenic origin, with 99% exhibiting bilateral swelling in the neck; 95%, an elevated tongue; 89%, fever; and 51%, trismus.⁷⁷ In 71 patients in whom cultures were obtained, 35% of species were VGS, 28% were “other” streptococci, 14% were staphylococci, and 27% were Porphyromonas and Prevotella and other anaerobes, with a few isolates of P. aeruginosa, K. pneumoniae, H. influenzae, S. pneumoniae, and Escherichia coli.⁷⁰ The heavy preponderance of streptococci emphasizes the ability of these organisms to move through tissue rapidly.

Mediastinal infections

Rarely, oral microorganisms may traverse anatomic pathways to locate in the mediastinum. The microbial flora is typically diverse, with the single predominant organisms being VGS, followed by Porphyromonas, Prevotella, Fusobacterium, and staphylococci. Rare isolates included E. coli, P. aeruginosa, Clostridium perfringens, Enterobacter, Enterococcus, H. influenzae, K. pneumoniae, and Proteus vulgaris.

Necrotizing fasciitis

Necrotizing fasciitis is a rare but often fatal infection involving the superficial fascial layers of the neck, extremities, abdomen, and perineum.³⁶ It was first described by Hippocrates and has also been known as streptococcal, hospital, or galloping gangrene. Most recently, the lay press has labeled it the “flesh-eating disease.” The term necrotizing fasciitis was first employed in 1952.³⁶

The most common cause of head and neck necrotizing fasciitis is dental infection (odontogenic origin) with 9% of all cases located in the head and neck region.³⁸ In a review of 125 literature cases, it was found that (1) the male/female ratio was 3 : 1; (2) the origin of the infection was 66 in the mandible, 11 in the maxilla, and 48 nondelineated; (3) periapical infection was the most common cause; and (4) 70 of 125 patients had systemic complications (e.g., alcoholism, hypertension, liver cirrhosis, acquired immunodeficiency syndrome [AIDS], intravenous drug abuse, and renal insufficiency). Despite aggressive therapy, the mortality rate was 19.2%.¹⁰³ In other scenarios, death may occur within hours, and the mortality rate may be 50%.

Cervicofacial actinomycosis

The most common organisms causing actinomycosis are A. israelii, A. naeslundii, Actinomyces odontolyticus, and Actinomyces viscosus. Cervicofacial actinomycosis commonly appears in one of two distinct patterns: (1) a chronic, slowly progressive mass evolving into multiple abscesses and fistulas or (2) an acute fluctuant suppurative pyogenic mass. Involved sites in the head and neck include the tongue, larynx, hypopharynx, mandible, cheek, scalp, paranasal sinuses, palate, and parotid gland. The characteristic sulfur granule is a small colony of intertwined actinomycoses filaments grossly resembling a granule of sulfur. It is likely also to be associated with A. actinomycetemcomitans, E. corrodens, Fusobacterium species, S. aureus, streptococci, and enterococci. Actinomyces species are usually susceptible to penicillin G or penicillin V and may require surgical removal.

Penicillins

Penicillin is a generic term for a group of antibiotics that share the β-lactam ring nucleus, similar adverse drug reactions, and similar mechanism of action, but differ in their antibacterial spectrum, pharmacokinetics, and resistance to β-lactamase enzymes.

Chemistry and classification

Penicillin is a cyclic dipeptide consisting of two amino acids (d-valine, l-lysine), a particular molecular configuration unknown in higher life forms (Figure 39-1). The synthesis in 1958 of the basic structure of penicillins (6-aminopenicillanic acid) allowed for its manipulation by the addition of various side chains to the β-lactam and thiazolidine rings. Different salts (Na⁺, K⁺, procaine, benzathine) were also created for pharmacokinetic purposes. On the basis of these modifications, penicillins can be divided into four groups: penicillin G and its congeners, β-lactamase–resistant (stable) penicillins, extended-spectrum penicillins, and extended-spectrum penicillins with β-lactamase inhibitors (Table 39-2).

FIGURE 39-1 Biosynthesis and hydrolysis of penicillins (isomeric conversion of l-valine and d-valine during conjugation). A, β-Lactam ring. B, Thiazolidine ring.

TABLE 39-2 Structures and Characteristics of Penicillin Derivatives

Acid-stable penicillins are resistant to breakdown in stomach acid, indicating their usefulness as oral drugs. Penicillin V, amoxicillin, and cloxacillin are examples. Other examples of orally useful drugs are listed in Table 39-2. Penicillinase-resistant penicillins are resistant to some β-lactamases. Bacteria, particularly staphylococci, develop resistance to penicillins chiefly through the elaboration of β-lactamase enzymes (penicillinases) that inactivate the penicillins by cleavage of the 6-aminopenicillanic acid nucleus to yield penicilloic acid derivatives. The production of staphylococcal penicillinase is encoded in a plasmid and may be transferred to other bacteria. Methicillin was the first semisynthetic derivative to be introduced that was stable in the presence of β-lactamase. Subsequently, nafcillin and three isoxazolyl derivatives (oxacillin, cloxacillin, and dicloxacillin) were marketed. The structural formulas for these semisynthetic derivatives are shown in Table 39-2.

Extended-spectrum penicillins are represented by two groups of penicillin derivatives. One group includes ampicillin, the first extended-spectrum penicillin to be introduced; amoxicillin, a close congener of ampicillin; and bacampicillin, a drug that is rapidly hydrolyzed in vivo to yield ampicillin (which accounts for its pharmacologic and toxicologic effects). The second group contains carbenicillin, the first penicillin to exhibit activity against Pseudomonas and indole-positive Proteus species, and ticarcillin, mezlocillin, and piperacillin, drugs with improved activity against P. aeruginosa.⁷⁵ The molecular structures of these agents are depicted in Table 39-2. Carbenicillin for injection is no longer available in the United States, but carbenicillin indanyl, the oral form, is still used.

Absorption, fate, and excretion

Table 39-3 lists important pharmacokinetic properties of oral penicillins.^13,72 Penicillin G (benzylpenicillin) is rarely used orally because of its poor gastric absorption rate. If it is prescribed orally, it should be given at doses four to five times greater than drugs used parenterally. Penicillin V and amoxicillin are well absorbed orally, with amoxicillin considerably superior in its half-life and peak serum concentrations. Better oral absorption argues for the use of amoxicillin over penicillin V, but both drugs are effective in microorganism-sensitive orofacial infections and are equally inactive against VGS with altered PBPs.

TABLE 39-3 Pharmacokinetics of Various Oral Penicillins

Procaine penicillin G and benzathine penicillin G are repository forms prepared for intramuscular injection with slow release from the injection site (Figure 39-2). The free non–protein-bound serum concentrations of penicillins are 0.9 µg/mL for penicillin G, 0.8 µg/mL for penicillin V, 0.45 µg/mL for dicloxacillin, and 6.2 µg/mL for amoxicillin.¹³ The route of excretion is primarily by the kidneys, with limited liver metabolism.¹³

FIGURE 39-2 Comparative plasma concentrations of penicillin G obtained from soluble versus repository intramuscular (IM) dosage forms.

β-Lactam antibiotics produce time-dependent killing of bacteria, and frequent dosing is required to maintain relatively constant blood levels with as little fluctuation as possible.¹⁰¹ The killing power of β-lactams is maximum at three to four times the MIC of susceptible microorganisms.¹⁰¹ The prime determinant of the efficacy of β-lactams is the length of time the concentration of the drug in the infected area is greater than the MIC of the infecting organism.¹⁰¹

To be maximally effective, the serum and tissue concentrations of β-lactams should be greater than the MIC for 50% to 70% of the dosing interval.²² The current package insert recommends dosing intervals of 6 hours for penicillin V and first-generation oral cephalosporins. Some drugs have very short half-lives (30 to 45 minutes),³³ and consequently 6-hour dosing intervals may result in very low serum levels in the last 2 or 3 hours. Continuous intravenous penicillin is receiving greater attention as a way to circumvent this problem.

Adverse effects

The adverse effects of penicillins are allergic and nonallergic in nature.

PENICILLIN ALLERGY

Allergic reactions to penicillins are common while allergic fatalities are far less common. Allergy to penicillins ranges from 0.7% to 8% in various studies, with a 0.7% to 4% chance of an allergic reaction (average of 2%) during any given course of penicillin therapy.^49,50 Most allergic manifestations are maculopapular or urticarial skin reactions.

Penicillin may be the most common cause of anaphylactic death in the United States, accounting for 75% of all cases and 400 to 800 annual deaths. These numbers may be low estimates, however. Penicillin-induced anaphylaxis is most common in adults 20 to 49 years old.^49,50 Estimates of severe penicillin anaphylaxis range from 0.004% to 0.015% of individuals exposed and, from the point of view of number of exposures, possibly 1 in 1200 to 1 in 2500 penicillin exposures. The fatality rate from penicillin anaphylaxis by all routes of administration may be 1 in 60,000 patient courses (16 per 1 million),^79,81 but data regarding penicillin allergy are limited.

Eventually, 1% to 10% of the general population exposed to therapeutic penicillin have an allergic reaction, with a higher positive history with increased age. Retrospective studies suggest that the incidence of allergy varies with the route of administration—oral (0.3%), intravenous (2.5%), and intramuscular (5%); the lower incidence by the oral route has been questioned because of limited data.^79,80 With higher oral doses (3.5 g of amoxicillin), the allergy rate may approach that of intramuscular penicillin, indicating that the dose and the route may be a determining factor in penicillin allergy. Fatal anaphylactic reactions after oral penicillin are well documented.^79,81

It is probable that an acute penicillin allergic reaction is less common in children and elderly patients, but fatal reactions may be more likely in elderly patients because of their compromised cardiopulmonary function. Whether certain individuals are predisposed to penicillin allergy remains unsettled. Risk factors for penicillin allergies include multiple allergies to other drugs, particularly other antibiotics (“multiple allergy syndrome”), or atopic disease (asthma, allergic rhinitis, nasal polyps). Several studies indicate a higher rate of penicillin allergy in individuals with a history of other drug allergies, whereas other studies indicate no such increased risk.^79,81 It is possible that individuals with multiple drug allergies or atopy may have more severe penicillin allergic reactions. Allergy to the procaine component of procaine penicillin G has been detected.

In individuals with a positive history of penicillin allergy, 15% to 40% exhibit allergy on re-exposure to penicillin, and individuals with a positive history of penicillin allergy have a four to six times greater likelihood of a subsequent reaction than individuals with a negative history.^79,81 Some patients may retain penicillin-specific IgE antibodies indefinitely, whereas most lose them over time. The serum half-life of penicillin IgE antibodies ranges from 10 to more than 1000 days; the risk of recurrent penicillin allergy is higher in individuals with antibodies with long half-lives or repeated penicillin exposures. Few data are available regarding whether the 60% to 85% not exhibiting allergy on re-exposure reacquire the IgE antibodies to penicillin and then have an allergic reaction to the drug on the next (third) exposure by resensitization. In a study of patients with a positive history of penicillin allergy (25 with urticaria/angioedema, 19 with anaphylaxis, 19 with pruritic skin rash) and a negative skin test for penicillin allergy, none had an allergic reaction to three successive 10-day courses of penicillin.⁹¹ The average length of time from the penicillin allergic reaction to rechallenge was 25 years (range 5 to 50 years), indicating that patients commonly lose their antibodies to penicillin. This study provides no information, however, on patients with a more recent history of penicillin allergy.

Because variable IgE antibody levels to penicillin are common, skin testing for penicillin allergy becomes problematic. The incidence of positive skin tests in individuals with a history of penicillin allergy ranges from 4% to 91% depending on the accuracy of the patient history, the haptens in the test solution, and the time elapsed between the allergic reaction and the skin test.^68,70 It is possible that penicillin skin tests may be reliable only for 72 hours after the test is performed.^79,81

Penicillin skin testing can be considerably valuable in determining who might have a severe anaphylactic reaction. Approximately 95% of penicillin-allergic individuals form the penicilloyl-protein conjugate (the major antigenic determinant), and approximately 5% form the 6-aminopenicillanic acid and benzyl-penamaldic acid minor antigenic determinants (Figure 39-3).^79,81 Penicillin skin tests with the major and minor antigenic determinants eliciting a negative skin test virtually eliminate the risk for a serious IgE-mediated reaction. A positive skin reaction to the minor determinant mixture indicates a high risk for anaphylaxis.

FIGURE 39-3 Antigenic determinants of penicillin allergy.

Penicillins are primarily associated with IgE-mediated (Gell and Coombs type I) allergic reactions, but may also induce cytotoxic (type II) or immune complex (type III) reactions. Type I signs and symptoms include skin erythema, itch, angioedema, urticaria, wheezing, hypotension, and bronchospasm resulting from mast cell/basophil release of histamine along with other tissue allergic mediators. Type II reactions are caused by circulating IgM or IgG antibodies that attach to blood cells and induce blood dyscrasias, including hemolytic anemia, leukopenia, thrombocytopenia, and aplastic anemia. Type III reactions result from the deposition of soluble immune complexes on blood vessels and basement membranes resulting in serum sickness, vasculitis, and glomerulonephritis.

Allergic reactions to penicillins can also be classified according to their time of onset. Immediate IgE reactions begin within seconds to 1 hour after drug exposure and are the most life-threatening (it is an allergy truism that the more rapid the onset of the allergic reaction, the more serious the consequences). Accelerated reactions begin 1 to 72 hours after antigen exposure and usually manifest as urticaria or angioedema. Late reactions occur after 72 hours and are characterized by type II and type IV (eczema-like) Gell and Coombs reactions. Of all fatal anaphylactic reactions, 96% occur within the first 60 minutes after penicillin exposure.^79,81

Other adverse reactions to penicillins are likely to be autoimmune in origin and have an obscure etiology, including maculopapular rashes, eosinophilia, Stevens-Johnson syndrome, and exfoliative dermatitis. A maculopapular rash is seen in 2% to 3% of patients late in penicillin therapy.

MULTIPLE ANTIBIOTIC ALLERGY SYNDROME

Most practitioners have encountered at least one patient with a history of allergy to multiple antibiotics (and probably other drugs as well). Whether such an antibiotic allergy syndrome exists is still undetermined, but may constitute 1% to 4% of all patients who have taken multiple antibiotics.⁶⁶ Serious adverse drug reactions such as anaphylaxis with antibiotics are rare except for the β-lactams.⁸⁸

Some difficulties with the health history are that (1) patients may confuse any adverse drug reaction with “allergy,” (2) rarely are any of these “allergies” confirmed by skin testing, and (3) often the patient’s history is nebulous.⁶⁶ The management of such patients requires a detailed medical history, including (1) when during the treatment the reaction occurred, (2) what infectious disease was being treated, (3) what doses of antibiotics were taken and for how long, and, most important, (4) what were the signs and symptoms. The primary concern is to determine the signs and symptoms of an acute IgE-mediated allergic reaction—rash, angioedema, bronchospasm, and syncope—along with the time between drug ingestion or administration and onset of symptoms. If the onset of signs and symptoms occurred within 1 hour of ingestion or administration, it was likely an immediate allergic reaction. After taking a thorough history, a possible skin test (reliable only for β-lactams) is indicated and a specific management plan. Comorbid conditions that may increase the incidence of allergy in general are atopic disease (asthma, eczema), chronic urticaria, nonsteroidal anti-inflammatory drug (NSAID) intolerance, immunosuppression, human immunodeficiency virus (HIV) positivity, and a history of multiple antibiotic use.⁶⁶

NONALLERGIC ADVERSE EFFECTS

Ticarcillin, mezlocillin, and piperacillin may cause abnormal coagulation times; abnormal liver function tests may occur with β-lactamase–resistant penicillins, and Na⁺ overload may be seen with antipseudomonal penicillins. Large intravenous doses of penicillins may induce hyperexcitability, seizures, and hallucinations. Amoxicillin is the most common cause of antibiotic-induced diarrhea/colitis because of its spectrum and widespread use. Penicillins are U.S. Food and Drug Administration (FDA) pregnancy category B drugs.

Approximately 5% to 10% of individuals receiving ampicillin or amoxicillin may have a mild pruritic rash, usually beginning on the trunk and extending to the face, extremities, and extensor portions of the knees and elbows. This nonallergic “ampicillin/amoxicillin rash” is not associated with antibody formation and is of unknown cause. It does not seem to increase the risk of true penicillin allergy. The rash may begin 24 hours to 28 days after the drug is begun and may last 90 minutes to 7 days. The incidence of ampicillin/amoxicillin rash is 95% to 100% in individuals with cytomegalovirus infection/mononucleosis and 22% in individuals given ampicillin and allopurinol.

Rare and reversible disorders reportedly associated with penicillins include acute pancreatitis, neutropenia, aseptic meningitis, hepatotoxicity, and increased prothrombin time/international normalized ratio (INR) in patients taking oral anticoagulants either through impaired platelet function or altered gastrointestinal microbial flora. Untoward bleeding may also occur in patients not taking coumarin anticoagulants and is dose-dependent, with a maximum effect 3 to 7 days after penicillin is begun, with a return to a normal bleeding time in 72 to 96 hours; this bleeding has been reported after a dental extraction.⁸ The mechanism is likely due to an altered adenosine 5′-diphosphate–mediated platelet aggregation response and is seen most commonly in patients with underlying chronic illnesses associated with hypoalbuminemia and uremia.