Microbiology, Infections, and Antibiotic Therapy
Thuy-Anh N. Melvin
Murugappan Ramanathan Jr.
INTRODUCTION
Infections of the ears, nose, throat, and head and neck constitute a tremendous number of physician office visits and subsequently antibiotic treatment. Therefore, it is crucial that the otolaryngologist be familiar with common infections of the head and neck and management of these disease processes. In this chapter, we provide a brief overview of commonly prescribed antibiotics and discuss their utility in treating otolaryngologic infections based on current evidence. Due to emerging trends of antibiotic resistance and the introduction of new antibiotics, the reader is urged to supplement this material with The Sanford Guide to Antimicrobial Therapy, the online Johns Hopkins Antibiotic Guide, as well as current infectious diseases literature.
Commonly Utilized Antimicrobial Agents in Otolaryngology
Listed below are brief overviews of commonly prescribed antibiotics, which include their mechanism of action and common side effects. The antimicrobial coverage is discussed in more detail in the management section.
Penicillins
Penicillins target actively dividing cells affecting the third stage of cell wall synthesis in bacteria. This group of drugs is active against gram-positive cocci (Streptococcus, Group A and B) and bacilli (Corynebacterium), gram-negative cocci (Neisseria) and bacilli (Streptobacillus), some anaerobes (Fusobacterium, Clostridium, Bacteroides), and other bacteria such as Treponema, Leptospira, Enterobacter, and Acinetobacter. Adverse reactions include 1% to 5% risk of rash, which does not preclude future use of penicillin since recurrence of rash only occurs in 50% of patients. More serious allergic reactions can involve anaphylaxis, hives, angioedema, and bronchospasm, which require lifelong contraindication to penicillin use. However, allergy testing for major and minor determinants of penicillin is available and currently identifies 90-97% of those with allergy to penicillin. There have also been reported cases of nephropathy. Resistance has emerged through alterations in penicillin-binding proteins, inability to penetrate bacterial cell walls via porin channel blockage, beta-lactamase production, and enzymatic hydrolysis of penicillin (1). The spectrum of coverage for the various types of penicillins is depicted in Table 10.1.
Cephalosporins
Similarly, cephalosporins act by inhibiting the third stage of cell wall development. They also affect the binding of specific proteins on cell membranes, cause cell permeability changes, and inhibit protein synthesis and autolysin release. There are four generations of cephalosporins with the first having the most gram-positive efficacy and with the third and fourth generations being more active against gram-negative anaerobes (see Table 10.2). A newer fifth-generation cephalosporin class is emerging with activity toward methicillin- resistant Staphylococcus aureus (MRSA) (2, 3). Side effects include hypersensitivity, neutropenia, thrombopenia, gastrointestinal disturbances, and renal impairment. Resistance has evolved through beta-lactamase and decreased cell wall permeability. Since penicillins and cephalosporins are structurally related, patients with a penicillin allergy are often not given cephalosporins for concern for cross-reactivity. Studies have examined the tolerability of cephalosporins in penicillin-allergic patients and found that there is a low risk of allergic reactions or anaphylaxis. Generally, first-generation cephalosporins such as cephalexin and cefazolin show higher rates of allergic reactions in patients with penicillin allergy. On the other hand, second- and third-generation cephalosporins such as cefuroxime, cefprozil, and cefdinir seem to have lower rate of allergic reactions in people with penicillin allergy. Overall, the clinician must err on the side
of caution when giving a penicillin-allergic patient cephalosporins and an oral challenge under medical supervision is recommended prior to use (4, 5).
of caution when giving a penicillin-allergic patient cephalosporins and an oral challenge under medical supervision is recommended prior to use (4, 5).
TABLE 10.1 PENICILLIN ANTIBIOTIC COVERAGE AND RESISTANCE | ||||||||||||||||||||||||
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Macrolides
Macrolides, for example, erythromycin, exhibit bacteriocidal activity by binding to the 50S subunit of the 70S rRNA complex, thereby inhibiting protein synthesis. Effective against similar pathogens such as penicillins, they are also effective against atypical bacteria such as Mycobacterium, Legionella, and Actinomyces species. Adverse reactions are hypersensitivity, gastrointestinal upset, and cholestatic hepatitis. Resistance in macrolides has emerged through alterations of the 50S subunit and plasmids, which primarily affects Haemophilus influenza, Staphylococcus aureus, and Streptococcus pneumoniae.
TABLE 10.2 CEPHALOSPORIN ANTIBIOTIC COVERAGE AND RESISTANCE | ||||||||||||||||||||||||
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Clindamycin
Clindamycin inhibits protein synthesis by binding to the 50S ribosomal subunit. It is useful against anaerobic gramnegative (e.g., Prevotella, Fusobacterium, and Bacteroides), grampositive cocci (e.g., S. aureus, community-acquired MRSA and S. pneumoniae), and aerobic gram-negative (e.g., Pseudomonas, Legionella, H. influenzae, and Moraxella) bacteria. Untoward reactions include the development of pseudomembranous colitis, nausea/diarrhea, hypersensitivity, and leukopenia.
Similar to macrolides, resistance has developed through alteration in the protein component of the 50S subunit.
Similar to macrolides, resistance has developed through alteration in the protein component of the 50S subunit.
Fluoroquinolones
Fluoroquinolones are bactericidal agents that work by interfering with DNA replication via inhibiting DNA gyrase and topoisomerase II enzymes. They work well against a broad range of bacteria including Pseudomonas, Streptococcus pyogenes, and S. pneumoniae, S. aureus, Moraxella catarrhalis, and H. influenzae. However, resistance has evolved rapidly through mutations in DNA gyrase and topoisomerase enzymes as well as plasmid-mediated resistance.
Fluoroquinolone antibiotics are associated with risk of neurotoxicity and multiple musculoskeletal complications, most commonly, tendon rupture (6). Although once the most commonly prescribed antibiotic to adults, a black box warning was issued by the Federal Food and Drug Administration in 2008 citing increased risk of tendon rupture and tendonitis (7). More recently, another black box warning for levofloxacin was issued from its manufacturer in 2011 for an increased risk of tendon rupture specifically in adults over 60 when given in combination with oral corticosteroids as is commonly prescribed to chronic rhinosinusitis (CRS) patients. Given this well-known side effect, judicious use of this antibiotic is recommended, and when prescribed, patients should be appropriately informed of this possible side effect.
Trimethoprim-Sulfamethoxazole
Trimethoprim and sulfamethoxazole act together synergistically by inhibiting sequential steps in the folic acid synthesis pathway. It is effective against Escherichia coli, S. aureus, community-acquired MRSA, and Listeria. Side effects include mild to severe hypersensitivity (especially in sulfa allergic patients), Stevens-Johnson syndrome, myelosuppression, mydriasis, agranulocytosis, and severe liver damage. Mechanisms of resistance include binding alterations due to folic acid enzyme mutations.
Aminoglycosides
Aminoglycosides, for example, gentamicin, tobramycin, and streptomycin, inhibit protein synthesis by binding to the 30S ribosomal subunit. This class of drugs is useful against aerobic, gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter, Enterobacter, and some Mycobacteria.
Adverse reactions to consider include nephrotoxicity and ototoxicity, which is mediated by injury to the outer hair cells of the cochlea, specifically in patients that harbor a mutation in the 12S rRNA gene (8, 9). Since this mutation is maternally transmitted, eliciting a detailed history can often prevent unnecessary administration of aminoglycosides to susceptible patients preventing deafness.
Vancomycin
Like penicillins, vancomycin targets and interferes with proper cell wall formation in gram-positive bacteria. Vancomycin resistance can emerge from alterations in the tail amino acids to which the drug binds. Nephrotoxicity and ototoxicity have been reported but are rare adverse reactions. Red man syndrome is an infusion reaction that occurs a few minutes after infusion characterized by erythematous rash. It is related to nonspecific mast cell degranulation and is not an IgE-mediated phenomenon. Occasionally, angioedema and hypotension can happen. To prevent red man syndrome, slow infusion is recommended over at least 60 minutes at a maximum rate of 10 mg/min for doses greater than 500 mg. Antihistamines can be used for premedication.
Topical Application of Antibiotics
In light of recent studies that suggest that chronic otolaryngological infections such as sinusitis and otitis media may be caused by bacterial biofilms (10, 11, 12, 13), concurrent topical application of antibiotics in addition to systemic antibiotics may be beneficial in disrupting biofilms (14). Although numerous antibiotics are utilized topically, their efficacy compared to oral antibiotics remains unclear. The best documented topical antibiotics are bacitracin/neomycin/polymyxin-B and mupirocin.
Combinations of bacitracin and neomycin/polymyxin-B, in the form of skin ointments and ototopical preparations (along with hydrocortisone), are utilized for localized skin infections, prevention of skin infections, and otitis externa/media (in the setting of myringotomy tubes). The combination of these agents has efficacy against most gram-negative and gram-positive aerobic organisms and P. aeruginosa (primarily polymyxin-B). In addition, fluoroquinolone-based ototopicals are also effective against P. aeruginosa. The primary adverse reaction of bacitracin/neomycin/polymyxin-B is hypersensitivity. Mupirocin is another topical antibiotic primarily used in the sinonasal cavities to eradicate colonization and infection by MRSA and works by binding to bacterial isoleucine tRNA ligase thereby interfering with protein translation of bacterial ribosomal RNA.
Antifungals
Although numerous antifungal compounds exist, the primary classes of drugs are azole antifungals and polyene antifungals. Azole antifungals (e.g., voriconazole, fluconazole, and ketoconazole) inhibit the enzyme lanosterol 14 α-demethylase, which allows conversion of lanosterol to ergosterol. Therefore, azole antifungals inhibit fungal growth by depleting ergosterol in the fungal membrane thereby disrupting its structure. In general, voriconazole is active against systemic fungal infections with Aspergillus and Candida but lacks efficacy against Mucor. In addition, fluconazole is effective against Candida and Cryptococcus and has excellent CSF penetration. A major disadvantage of azole antifungals is that they have numerous drug-drug interactions with common agents such as statins, oral anticoagulants, and phenytoin.
Polyene antifungals, such as amphotericin B, bind to ergosterol in the fungal cell membrane causing a change
in the transition temperature of the cell membrane. Ultimately, this results in a disrupted cell membrane and cellular electrolyte imbalance leading to fungal death. Intravenous amphotericin B is also active against serious systemic fungal infections such as Aspergillus and Mucor but carries potentially serious adverse reactions such as nephrotoxicity, hepatotoxicity, hypotension, high fever, and shaking chills. A newer liposomal formulation of amphotericin B is highly effective against Aspergillosis and Candidiasis refractory to traditional amphotericin with fewer side effects. Liposomal amphotericin B is also the drug of choice for empiric therapy of presumed fungal infections in patients with febrile neutropenia.
in the transition temperature of the cell membrane. Ultimately, this results in a disrupted cell membrane and cellular electrolyte imbalance leading to fungal death. Intravenous amphotericin B is also active against serious systemic fungal infections such as Aspergillus and Mucor but carries potentially serious adverse reactions such as nephrotoxicity, hepatotoxicity, hypotension, high fever, and shaking chills. A newer liposomal formulation of amphotericin B is highly effective against Aspergillosis and Candidiasis refractory to traditional amphotericin with fewer side effects. Liposomal amphotericin B is also the drug of choice for empiric therapy of presumed fungal infections in patients with febrile neutropenia.
Newer more potent antifungals with fewer side effects have emerged in recent years such as caspofungin. Caspofungin exerts antifungal action through inhibition of β-(1, 3)-D-glucan in the fungal cell wall, and is highly effective against invasive Aspergillosis in patients who are refractory to other antifungal therapy.
Antiviral Agents
Antiviral agents are rarely used in otolaryngologic infections since viral infections are usually self-limiting. Common antiviral agents such as acyclovir, valacyclovir, and famciclovir are used to treat Herpes simplex and zoster in the setting of Ramsay-Hunt syndrome and Bells palsy. Acyclovir, valacyclovir, and famciclovir are prodrugs that are converted into a phosphorylated form ultimately exerting antiviral activity by inhibiting viral DNA polymerase.
Emerging Pathogens in Head-and-Neck Infections
While numerous pathogens have been implicated in infections of the head and neck, much attention has focused on anaerobic infections, MRSA, P. aeruginosa, and Aspergillus infections.
Anaerobes
Anaerobes are very common in the mucosal membranes of the head and neck as well as normal skin flora (15). Anaerobic infections comprise a large portion of endogenous infections. Challenges in the management of these infections include their slow growth, increasing resistance, and polymicrobial nature. There are five categories of antimicrobial agents active against anaerobes: carbapenems, metronidazole, chloramphenicol, tigecycline, and combinations of penicillin and a beta-lactamase inhibitor.
Pseudomonas Aeruginosa
Infections of the head and neck due to P. aeruginosa are common under certain circumstances. Paranasal sinus culture samples from patients with cystic fibrosis most commonly grow out P. aeruginosa followed by S. aureus and Streptococcus viridans (16). In addition, CRS patients with relapsing mucopurulent infections frequently harbor Pseudomonas (17, 18). The antibiotic categories to consider when choosing an effective therapy against Pseudomonas include: fluoroquinolones or augmented fluoroquinolones (pipericillin/sulbactam), aztreonam, cefepime, colistin, gentamicin (or tobramycin). Cultures with sensitivities are crucial as there is increasing resistance with certain fluoroquinolones, such as ciprofloxacin and levofloxacin, as well as anti-Pseudomonas penicillins such as ticarcillin (19). The primary mechanism of resistance is through multidrug efflux pumps with chromosomally encoded antibiotic resistance genes (mexAB-oprM, mexXY, etc.) (20, 21). Recent studies have also shown that phenotypic resistance patterns may be due to biofilm formation with poor antibiotic penetration (22).
Methicillin-Resistant Staphylococcus aureus
The evolution of methicillin resistance in S. aureus was recently linked in part to the acquisition of the mecA gene, which encodes for a penicillin binding protein with low affinity for beta-lactam antibiotics (23). The mecA gene has therefore emerged into a molecular target for identifying MRSA and recent studies have identified new divergent homologues of mecA in S. aureus that were previously thought to be methicillin sensitive (24).
Community-acquired methicillin-resistant S. aureus (CA-MRSA) infections are a growing problem (25). Treatment can frequently be managed as an outpatient; however, when infections are severe, inpatient management is necessary. Chemotherapy options vary and reported resistance rates can range significantly as seen in Table 10.3 (26). MRSA outbreaks in hospitals pose a great challenge. One study looking at widespread use of topical mupirocin showed no advantage, whereas, increasing hand hygiene audits and staff training did correlate with better control of MRSA outbreaks in the ICU setting (27).
Aspergillus
Aspergillus is histologically distinct from other fungi through its septate hyphae with 45-degree branching, in contrast to nonseptate hyphae branching at 90 degrees, which is frequently seen with Rhizopus and Mucor. Aspergillus is a chronic colonizing pathogen of the paranasal sinuses and ear. In the sinuses, Aspergillus
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