Systemic Antibacterial Agents

Questions

Q9.1 What are some dermatologic indications of antibiotic use in chronic inflammatory skin disorders, based on their anti-inflammatory properties? (Pgs. 70, 86x3)
Q9.2 Which antibiotic classes have significant alterations in bioavailability because of foods and divalent cations? (Pgs. 73, 75, 78, 81, 82, 84x2, 91, 92)
Q9.3 What are some of the drugs with the potential for a cross-reaction in patients allergic to penicillins, and what is the true risk (frequency and magnitude) of such cross-reactions? (Pgs. 73, 77)
Q9.4 What two drugs discussed in this chapter can induce a serum sickness-like reaction? (Pgs. 77, 88)
Q9.5 What are three to four of the mechanisms by which bacteria develop resistance to antibacterial agents? (Pgs. 78, 84, 91, 95, 96)
Q9.6 What are two relatively unique cutaneous ‘hypersensitivity’ reactions to vancomycin? (Pg. 78)
Q9.7 Which drugs/drug groups mechanism is to interfere with bacterial ribosome subunits (1) 30S, (2) 50S, and (3) 23S portion of the 50S subunit? (Pgs. 78, 83, 95, 96)
Q9.8 What are several antibiotic classes with significant anti-inflammatory activity, and what are several of the mechanisms for this anti-inflammatory activity? (Pgs. 78, 83x2)
Q9.9 Concerning macrolides and azalides, what are some important differences in (1) infections most effectively treated, and (2) cytochrome P-450–drug interactions? (Pgs. 78x3, 79)
Q9.10 Which antibiotics are inappropriate for use in pediatric populations and why? (Pgs. 79, 82, 89)
Q9.11 What are several of the bacterial enzymes inhibited by antibacterial agents discussed in this chapter? (Pgs. 81, 89, 93)
Q9.12 Which drugs discussed in this chapter are most likely to induce photosensitivity reactions? (Pgs. 82, 83, 88)
Q9.13 What are some practice guidelines for use of systemic antibiotics in chronic inflammatory dermatoses to reduce antimicrobial resistance? (Pg. 84)
Q9.14 What are several relatively unique hypersensitivity and autoimmune reactions caused by minocycline? (Pgs. 88x2, 89)
Q9.15 Which two drug groups discussed in this chapter are listed as pregnancy category D? (Pgs. 89, 94)
Q9.16 Concerning community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections, what are (1) several of the best oral antibiotic choices, and (2) several antibiotics with a trend toward increasing resistance? (Pgs. 91x2, 94, 96, 97x4)
Q9.17 What is the scientific basis for various antibacterial groups possibly reducing the effectiveness of hormonal contraceptives? (Pg. 92x2)
Q9.18 What are antibacterial agents with a risk of antibiotic-associated colitis caused by Clostridium difficile ? (Pgs. 95, 97x2)

Abbreviations used in this Chapter

AAP

American Academy of Pediatrics

ACE

Angiotensin-converting enzyme

Amox/Clav

Amoxicillin/clavulanate

Amp/Sulb

Ampicillin/sulbactam

ANA

Antinuclear antibody

Anti-dsDNA

Antidouble-stranded DNA

ARA

American Rheumatologic Association

AVSE

Acute vestibular side effect(s)

AZT

Azidothymidine (zidovudine)

BIH

Benign intracranial hypertension

CA-MRSA

Community-acquired MRSA

CAP

Community-acquired pneumonia

CBC

Complete blood count

CMT

Chemically modified tetracycline

CRP

Confluent and reticulated papillomatosis

CSSTI

Complicated skin and soft tissue infection(s)

CYP

Cytochrome P-450 (enzyme)

ddI

Didanosine

DHS

Drug hypersensitivity syndrome

DRESS

Drug reaction eosinophils systemic symptoms

EE

Ethinyl estradiol

ER

Extended release

FQ

Fluoroquinolone(s)

G6PD

Glucose-6-phosphate dehydrogenase

GI

Gastrointestinal

GABA

γ-amino butyric acid

HA-MRSA

Hospital-acquired MRSA

hVISA

Heteroresistant VISA

IM

Intramuscular

INR

International normalized ratio

IR

Immediate release

LABD

Linear IgA bullous dermatosis

LE

Lupus erythematosus

LFT

Liver function test(s)

LLS

Lupus-like syndrome

MAC

Mycobacterium avium complex

MIC

Minimum inhibitory concentration

MMP

Matrix metalloproteinase

MR

Modified release

mRNA

Messenger RNA

MRSA

Methicillin-resistant Staphylococcus aureus

MSSA

Methicillin-sensitive S. aureus

NMMT

N -methyl thiotetrazole

OC

Oral contraceptive

PAN

Polyarteritis nodosa

pANCA

Perinuclear anticytoplasmic antibody

Pip/Tazo

Piperacillin/tazobactam

PK

Pharmacokinetic

RA

Rheumatoid arthritis

ROS

Reactive oxygen species

SCC-MEC IV

Staphylococcal cassette type IV chromosome mec element

SIADH

Syndrome of inappropriate antidiuretic hormone

SJS

Stevens–Johnson syndrome

SMX

Sulfamethoxazole

SSLR

Serum sickness-like reaction

TB

Tuberculosis

TCN

Tetracycline (drug)

TCNs

Tetracyclines (drug family)

TEN

Toxic epidermal necrolysis

Ticar/Clav

Ticarcillin/clavulanate

TJD

Tendon or joint disorder(s)

TMP

Trimethoprim

USSTI

Uncomplicated skin and soft tissue infection(s)

VISA

Vancomycin-intermediate S. aureus

VRE

Vancomycin-resistant enterococcus

VRSA

Vancomycin-resistant S. aureus

WHO

World Health Organization

Introduction

Systemic antibiotics play a vital role in dermatology, with oral antibiotic prescriptions estimated to represent approximately 20% of all outpatient prescriptions, written by dermatologists annually. From 2003 to 2013, dermatologists in the United States prescribed approximately 8 to 9 million oral antibiotic prescriptions per year. Of all medical specialties, dermatologists have the highest antibiotic prescription rate per physician. Many of these antibiotics are used for the treatment of chronic noninfectious inflammatory disorders, such as rosacea and acne. For this reason, the prescribed duration of antibiotic therapy for noninfectious dermatologic disease is markedly longer than antibiotic therapy for infections. The frequent and prolonged use of this drug category highlights the impact dermatologists have on bacterial resistance patterns and microbiome alterations.

Q9.1 Of the millions of antibiotics prescribed by dermatologists, up to three-fourths of these are for tetracycline family (TCNs) agents, especially minocycline and doxycycline. This antibiotic class possesses significant antibacterial and anti-inflammatory activity, leading to their use for the treatment of both infectious and noninfectious skin disease, including acne vulgaris and rosacea.

Rational antibiotic selection for dermatologic disorders warrants consideration of several factors to optimize therapeutic outcome and safety:

1.
Host-related properties (age, comorbidities, allergy status, pregnancy status, breastfeeding status);
2.
Nature of the disease state to be treated (infectious vs. inflammatory disease, severity, affected sites);
3.
Microbiologic factors if applicable (suspected or confirmed pathogen, virulence, antibiotic sensitivity and resistance profiles);
4.
Applicable antibiotic options (efficacy, adverse reactions, drug interactions);
5.
Antibiotic-specific pharmacokinetic (PK) properties (route of administrations, oral formulation differences, sites of infection); and
6.
Specific adverse reactions to some antibiotics may be more common and more severe in immunocompromised patients.

This chapter emphasizes the oral antibacterial agents used primarily for skin and soft tissue infections and inflammatory dermatoses.

Penicillins

Penicillins represent an important, widely used drug class and belong to the β-lactam group, which also includes cephalosporins, monobactams, and carbapenems. Penicillins remain the drug of choice for many infectious diseases, including those relevant to dermatology practice. Penicillin G (benzylpenicillin) is produced naturally by the fungus Penicillium chrysogenum . Subsequent to the discovery in 1928 of penicillin G, many semisynthetic penicillins have been developed. The safety and efficacy of the penicillins have been established overall in the pediatric population. All penicillins and their derivatives, including penicillins combined with β-lactamase inhibitors, have been assigned a pregnancy category B rating. In addition, sensitization of infants has been associated with ampicillin use in nursing mothers, as low concentrations of penicillins in breast milk have been reported.

Pharmacology

Mechanism of Action

Please see Table 9.1 . All β-lactam antibiotics share similar mechanisms of action which include:

1.
Attachment to specific penicillin-binding proteins (which vary in their affinities for different β-lactam antibiotics);
2.
Inhibition of bacterial cell wall peptidoglycan synthesis; and
3.
Disinhibition of cell wall autolysis.

Table 9.1

Summary of Systemic Antibacterial Agents of Dermatologic Significance

Drug	Mechanism of Action	Coverage	Mechanism of Resistance	Metabolism	Pregnancy Category
Penicillins	β-lactam ring binds to bacterial enzyme DD-transpeptidase to inhibit formation of peptidoglycan cross-links in bacterial cell wall	Generations: First = dicloxacillin, oxacillin → GP cocci (ex. MSSA) Second = aminopenicillins (ampicillin and amoxicillin) → GN bacilli and GP cocci Third and Fourth = carboxypenicillins (carbenicillin) and ureidopenicillins (piperacillin) → antipseudomonal activity (piperacillin >carbenicillin)	Hydrolysis by β-lactamases (produced by Staphylococcus aureus and Enterobacteriaceae species) Modification of penicillin-binding sites Reduction in outer membrane permeability preventing drug from reaching target site (ex. GN bacteria)	Renal, except nafcillin, oxacillin and piperacillin (biliary)	B
Cephalosporins	Same as penicillins, but have a 6-membered dihydrothiazine ring	Generations: First = cefadroxil and cephalexin → GP cocci (except MRSA and penicillin-resistant pneumonia) and oral anaerobes (except Bacterioides fragilis ) Second = cefaclor and cefuroxime → more GN activity and less GP activity; good for Haemophilia influenza, Moraxella catarrhalis, Neisseria meningitides, Neisseria gonorrhoeae and some Enterobacteriaceae Cephamycins (cefoxitin and cefotetan) → B. fragilis Third = cefixime, cefdinir, cefotaxime, ceftazidime, cefpodoxime and ceftriaxone → increased GN activity (because of greater β-lactamase stability), but less GP activity Cefditoren → assorted GP and GN coverage, but not Pseudomonas aeruginosa Ceftazidime → P. aeruginosa , but not S. aureus Cefdinir → S. aureus and Streptococcus pyogenes (good for USSTI) Fourth = cefepime (IV) → broad coverage (MSSA, nonenterococcal streptococci and GN, including P. aeruginosa ); no B. fragilis coverage Fifth = ceftaroline (IV) → MRSA, VISA, hVISA, VRSA, MSSA and CNS	Two-ring combination renders inherent resistance to β-lactamases	Varies Renal—first, second and fifth generation Hepatic—most third generation (i.e., ceftriaxone)	B
Glycopeptides (Vancomycin and Teicoplanin)	Inhibit bacterial cell wall synthesis by forming noncovalent complexes with bacterial peptidoglycan precursors	Only GP organisms (important use in MRSA)	Reduction in drug permeability Reduction in binding bacterial cell wall receptor Bacterial expression of encoding proteins that reprogram cell wall biosynthesis	Renal	C
Macrolides	Bind to 50s subunit of bacterial ribosome, inhibiting RNA-dependent protein synthesis Anti-inflammatory properties	Mostly GP (clarithromycin > azithromycin > erythromycin), except MRSA and enterococcus Clarithromycin and azithromycin → GN and atypical mycobacterial coverage (see text)	Modification of drug target via methylation of rRNA nucleotides or mutation of ribosomal components Decreasing intrabacterial accumulation via drug efflux pump	Renal: erythromycin and clarithromycin Hepatic: azithromycin	B
Fluoroquinolones	Interfere with bacterial DNA replication via inhibition of DNA gyrase (bacterial topopisomerase II) +/- topoisomerase IV	GP (target is topoisomerase IV) and GN (target is DNA gyrase) First- and second-generation quinolones (ciprofloxacin, ofloxacin and nalidixic acid) only target DNA gyrase → only effective against GN organisms Third and fourth generation quinolones (levofloxacin, moxifloxacin, sparfloxacin and gatifloxacin) target both topoisomerase forms (IV>II) → increased GP coverage, but decreased GN coverage Ciprofloxacin, ofloxacin and levofloxacin have some activity against atypical mycobacteria	Alteration of drug target mechanism Decreasing intrabacterial accumulation via drug efflux pump	Renal, except moxifloxacin	C
Tetracyclines	Bind to 30s subunit of bacterial ribosome, inhibiting RNA-dependent protein synthesis Anti-inflammatory properties (see text)	Various GP and GN skin infections, including MRSA and those caused by Chlamydia spp., Rickettsia spp., Mycoplasma spp., atypical mycobacteria, spirochetes and Lyme disease	Decreasing intrabacterial accumulation via decreasing influx or increasing efflux Alteration of drug target (see text)	Renal, except doxycycline (mainly via GI tract)	D
Rifamycins	Bind to β-subunit of bacterial DNA-dependent RNA polymerase, inhibiting RNA and protein synthesis	Various mycobacteria ( M. tuberculosis, M. leprae, M. marinum) and some other GP (staphylococcus) and GN organisms	Alteration of drug target (see text)	Hepatic	C
Trimethoprim-Sulfamethoxazole	Dihydrofolate reductase inhibitor (trimethoprim) and dihydropteroate synthetase inhibitor (sulfamethoxazole) → decreased tetrahydrofolic acid → decreased bacterial nucleic acid and protein synthesis	Various GP cocci (MRSA, Enterococcus faecalis and S. pyogenes ), H. influenzae , Pneumocystis jirovecii , Nocardia spp., Chlamydia , and various GN	Alteration of drug target via acquired mutations and/or plasmid acquisition Decreasing intrabacterial accumulation via active drug efflux Auxotrophic bacteria (naturally resistant)	Hepatic, Renal	D
Clindamycin	Binds to 50S subunit of bacterial ribosomal RNA → decreased ribosomal translocation and protein synthesis	GP cocci ( Staphylococcus spp. and Streptococcus spp.) and anaerobes ( Bacteroides spp. and Clostridium perfringens ), but not usually GN (except Capnocytophaga canimorsus )	Alteration of drug target via acquired mutations and/or plasmid acquisition (see text) Auxotrophic bacteria (naturally resistant)	Hepatic	B

For those with renal excretion, dose adjustment needed in context of renal failure.

CNS , central nervous system; DNA, deoxyribonucleic acid; GI, gastrointestinal; GP , gram-positive; GN , gram-negative; hVISA , heteroresistant vancomycin-intermediate S. aureus ; IV , intravenous; MRSA , methicillin-resistant S. aureus ; MSSA, methicillin-sensitive S. aureus ; RNA , ribonucleic acid; rRNA , ribosomal RNA; USSTI, uncomplicated skin and soft tissue infection; VISA , vancomycin-intermediate S. aureus ; VRSA, vancomycin-resistant S. aureus .

Each of these functions serves to initiate bacterial cell lysis and death.

Antimicrobial Activity

Both penicillin G and penicillin V are categorized as natural first-generation penicillins. The semisynthethic first-generation penicillins ( isoxazolylpenicillins ) are characterized by their penicillinase resistance. First-generation penicillins share a similar antimicrobial spectrum against Gram-positive cocci and rods, Gram-negative cocci, and anaerobes (see Table 9.1 ). Second-generation agents ( aminopenicillins ) exhibit expanded coverage to include inhibition of Gram-negative bacilli. Third generation extended-spectrum penicillins ( carboxypenicillins ) and the fourth-generation penicillins ( ureidopenicillins ) are both parenteral and exhibit antipseudomonal activity, especially when combined with an aminoglycoside antibiotic. Only oral antibacterial agents will be discussed in this chapter.

Pharmacokinetics

Q9.2 Penicillin absorption upon oral administration differs depending on each agents’ acid stability and binding onto food. Gastrointestinal (GI) absorption can be optimized by administration 1 hour before or after a meal. The elimination half-lives for most penicillins are short (<1.5 h). Table 9.1 reviews the metabolism of penicillins.

Clinical Use

Dermatologic Uses

Antibacterial Indications

Staphylococcal and Streptococcal Infections ( Table 9.2 )

Most penicillins show good coverage for Streptococcus pyogenes and Methicillin-sensitive Staphylococcus aureus (MSSA) and may be used for a wide range of uncomplicated skin infections, including erysipelas, cellulitis, impetigo, folliculitis, furunculosis, bacterial paronychia, and ecthyma. In regards to penicillin use for treatment of these entities, recent studies have revealed several important findings:

1.
For extensive impetigo and ecthyma, oral antibiotics are recommended. In addition, a large Cochrane review (including 57 trials) revealed that, among oral antibiotics, most penicillins were inferior to erythromycin and dicloxacillin in treatment of impetigo.
2.
Early stages of erysipelas are often treated with penicillin (oral or intramuscular [IM]) and for prophylaxis, IM penicillin administered weekly has been used successfully, with the risk of recurrence to pretreatment levels, after discontinuation of therapy.
3.
In a recent study of antibiotic sensitivities of S. aureus cultured from patients with staphylococcal scalded skin syndrome (SSSS), 86% of isolates were sensitive to oxacillin (MSSA). Thus empiric therapy of SSSS should include a penicillinase-resistant penicillin in combination with clindamycin, while awaiting culture results. Furthermore, although clindamycin inhibits toxin production by S. aureus , it should not be used as a monotherapy in the treatment of SSSS.

Table 9.2

Antimicrobial Therapy for Staphylococcal and Streptococcal Infections of Dermatologic Significance

Disease Entity	Antibiotic	Adult Dosage	Comments
Impetigo ( Staphylococcus and Streptococcus )	Dicloxacillin Cephalexin Erythromycin Clindamycin Amoxicillin-clavulanate	250 mg QID PO 250 mg QID PO 250 mg QID PO 300–400 mg QID PO 875/125 mg BID PO	Some strains of S. aureus and S. pyogenes may be resistant
MSSA SSTI	Nafcillin or oxacillin Cefazolin Clindamycin Dicloxacillin Cephalexin Doxycycline, minocycline TMP-SMX	1–2 g every 4 h IV 1 g every 8 h IV 600 mg every 8 h IV or 300–450 mg QID PO 500 mg QID PO 500 mg QID PO 100 mg BID PO 1–2 double-strength tablets BID PO	Parental drug of choice; inactive against MRSA Used for penicillin-allergic patients; more convenient than nafcillin, with less bone marrow suppression Bacteriostatic; cross-resistance potential and emergence of resistance in erythromycin-resistant strains; inducible MRSA resistance Oral agent of choice for MSSA in adults Used for penicillin-allergic patients; suspension requires less frequent dosing Bacteriostatic; limited recent clinical experience Bactericidal; efficacy poorly documented
MRSA SSTI	Vancomycin Linezolid Clindamycin Daptomycin Ceftaroline Doxycycline, minocycline TMP-SMX	30 mg/kg/day IV in 2 divided doses 600 mg every 12 h IV or 600 mg BID PO 600 mg every 8 h IV or 300–450 mg QID PO 4 mg/kg every 24 h IV 600 mg BID IV 100 mg BID PO 1–2 double strength tablets BID PO	For penicillin-allergic patients; parenteral drug of choice for MRSA infections Bacteriostatic; limited clinical experience; no cross-resistance with other antibiotic classes; expensive Bacteriostatic; cross-resistance potential and inducible resistance in erythromycin-resistant strains Bactericidal Bactericidal Bacteriostatic; limited recent clinical experience Bactericidal; limited published efficacy data
Streptococcal Skin Infections	Penicillin Clindamycin Nafcillin Cefazolin Penicillin VK Cephalexin	2–4 million units every 4–6 h IV 600–900 mg every 8 h IV 1–2 g every 4–6 h IV 1 g every 8 h IV 250–500 mg every 6 h PO 500 mg every 6 h PO	N/A
Staphylococcal Folliculitis, including Folliculitis Barbae (Sycosis)	Cephalexin Dicloxacillin TMP-SMX Clindamycin Doxycycline	250 to 500 mg QID PO 250 to 500 mg QID PO 1–3 double strength tablets BID PO 300 to 450 mg QID PO 100 mg BID PO	For extensive skin involvement, oral therapy is indicated for a 7–10 day course of treatment. First-line therapy First-line therapy First-line therapy if MRSA is suspected or cultured First-line therapy if MRSA is suspected or cultured First-line therapy if MRSA is suspected or cultured Note: occasionally treatment for >14 days is required for resolution of MRSA folliculitis
Staphylococcal Scalded Skin Syndrome (SSSS)	Nafcillin, oxacillin, dicloxacillin Ceftriaxone Clindamycin Vancomycin Erythromycin	100–200 mg/kg/day IV in divided doses every 6 h 50 mg/kg IV once daily 20–40 mg/kg/day IV divided every 6–8 h 40–60 mg/kg/day IV divided every 6–8 h 15–20 mg/kg/day IV divided every 6 h	Maximum daily dose = 12 g Maximum daily dose = 1 g Maximum single dose = 600 mg; Should never be used as monotherapy (see text) Maximum daily dose: 2–4 g; second-line therapy or if evidence of MRSA Maximum daily dose: 4 g; second-line therapy Note: infant/children doses reported
Scarlet Fever	Penicillin V Amoxicillin Cephalexin Azithromycin Clindamycin	500 mg BID to TID PO 500 mg BID PO 500 mg BID PO 500 mg PO × 1 followed by 250 mg PO on days 2–5 300 mg TID PO	Treatment of choice for GAS pharyngitis; should be administered within first 48 hours of illness and treated for 10 days to reduce risk of acute glomerulonephritis and rheumatic fever Used in penicillin-allergic patients Used in penicillin-allergic patients and if concern for macrolide resistance
Erysipelas	Penicillin Amoxicillin Cephalexin Clindamycin TMP-SMX	500 mg every 6 h PO 875 mg BID PO 500 mg QID PO 300 to 450 mg QID PO 1 to 2 double strength tablets BID PO	Duration of treatment: 5–14 days Note: if systemic symptoms, inability to tolerate PO, or progression on oral therapy, parenteral treatment is warranted Used in penicillin-allergic patients Used in penicillin-allergic patients Used in penicillin-allergic patients

BID , twice a day; GAS , group A streptococcus; IV, intravenous; MRSA , methicillin-resistant Staphylococcus aureus ; MSSA, methicillin-sensitive S. aureus ; PO , per os = oral; QID , 4 times a day; SSTI , skin and soft tissue infection; TID, 3 times a day; TMP-SMX , trimethoprim-sulfamethoxazole.

Other Antimicrobial Uses

Some sexually transmitted diseases (STD), such as syphilis and chlamydial infections, are susceptible to penicillins. Furthermore, penicillin G benzathine remains the first-line therapy for syphilis (see dosing, later). Pregnant patients with syphilis and penicillin allergy undergo desensitization followed by penicillin therapy.

Penicillins have also been used for the treatment of erysipeloid, scarlatina, cutaneous anthrax, Lyme disease, actinomycosis, listeriosis, gas gangrene, gingivostomatosis, and leptospirosis (Weil disease). In the clinical setting, individual selection among the penicillins is highly dependent on the diagnosis and causative organism, with substantial variability of activity based on the drug chosen.

Nonspecific Penicillin Benefits

Scant data support the use of penicillins in noninfectious inflammatory dermatoses, such as pityriasis rubra pilaris, Behçet disease, and scleroderma.

Adverse Effects ( Box 9.1 )

Hypersensitivity Reactions

Of all drug classes, β-lactams are the most frequently reported causes of drug-related adverse effects (AE), most commonly observed as hypersensitivity reactions ranging from morbilliform eruptions to anaphylaxis. However, emerging evidence suggests these reactions are not as frequent as previously established. The number of patients with true immunoglobulin (Ig)E-mediated hypersensitivity caused by penicillins comprises only 5% to 10% of reported allergic reactions. Before documentation of penicillin allergy, thorough investigation including identification of the specific agent implicated, reaction experienced, and temporal relationship and concomitant drugs administered are recommended. Management algorithms to guide skin testing and desensitization have been formulated to aid clinicians in management of patients with β-lactam allergy.

Box 9.1

Drug Risks Profile—Penicillins

Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. ( https://www.wolterskluwercdi.com/facts-comparisons-online/ ).

Contraindications
Hypersensitivity to penicillins or other beta-lactam antibiotics	Primarily an issue with anaphylaxis, SJS/TEN
Boxed Warnings
None related to oral formulations
Warnings & Precautions ^a
Hypersensitivity ^a Urticaria/angioedema SJS/TEN rarely (predominantly IV forms) ^a Potential cross-reaction with cephalosporins and other beta-lactam antibiotics (see text)	Gi Cholestatic jaundice with amox/clavulanate Diarrhea more often with amox/clavulanate than amox alone Infections EBV infections in combination with ampicillin exanthem
Pregnancy Prescribing Status
Traditional US Food and Drug Administration rating —category C	Newer rating ^b —compatible

Amox , Amoxicillin; EBV , epstein-Barr virus; GI , gastrointestinal; IV , intravenous; SJS/TEN , Stevens–Johnson syndrome/toxic epidermal necrolysis.

a Under “Warnings & Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid.

b See Chapter 65 , Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings.

A skin eruption that is not truly allergic in origin may arise when ampicillin is given to patients, with infectious mononucleosis or lymphocytic leukemia, and is also seen when ampicillin is coadministered with allopurinol. The eruption is generalized, maculopapular, pruritic, and typically manifests within 7 to 10 days after the initiation of the antibiotic, with persistence for up to 1 week after ampicillin is discontinued. This eruption does not preclude future treatment with other penicillins/β-lactams.

Cross-Reaction Potential

Q9.3 In patients with a history of severe and life-threatening allergic reaction to a penicillin or cephalosporin, avoidance of other β-lactams, including carbapenems and monobactams, was previously considered or advised. However, the risk of cross-reactions between specific β-lactam classes is lower than previously thought, with recent studies suggesting less than 5% cross-reactivity between penicillins and cephalosporins. Cross-reactions are not universal and pertain to specific agents with similar side chains or metabolites of the β-lactam core. Thus patients with IgE-mediated reactions to one agent in this superfamily of antibiotics are able to receive alternate classes of β-lactam antibiotics.

Other Important Adverse Effects

Drug Interactions.

Few clinically significant drug interactions are noted with the penicillins. Probenecid prolongs the renal excretion of penicillins. β-lactams may alter the anticoagulant effects of warfarin, warranting closer monitoring of international normalized ratio (INR) values. The impact on efficacy of oral contraceptives is reviewed under the Drug Interactions sections for both TCNs and rifamycins ( Box 9.1 ).

Dosage

Table 9.2 contains common dermatologic indications and dosage guidelines for penicillins. A single IM injection of 2.4 × 10 ⁶ U of penicillin G is used to treat primary or secondary syphilis, although latent syphilis requires 3 weekly injections. For penicillin-susceptible Neisseria gonorrhoeae , one of the aminopenicillins may be given as single-dose treatment (ampicillin 3.5 g or amoxicillin 3 g), along with probenecid. For other Gram-negative infections such as Haemophilus influenzae , ampicillin 2 to 4 g daily, divided into three or four doses, is given with probenecid if higher blood levels are needed.

Cephalosporins

Cephalexin and Many Others

Most cephalosporins are antibiotics produced and derived as byproducts of the mold Cephalosporium acremonium . Cephalosporins have a basic structural core consisting of a 4-membered β-lactam ring attached to a 6-membered dihydrothiazine ring, and therefore are β-lactams. The two-ring combination gives the cephalosporin structure inherent resistance to β-lactamase enzymes, as compared with penicillins, which are composed of a 5-membered thiazolidine ring. Most cephalosporins are considered safe in children. Cephalosporins are generally pregnancy category B, with a low likelihood of congenital malformations when used during the second and third trimesters. Caution is suggested in women who are breastfeeding, as the small quantities of cephalosporins in breast milk have been associated with reports of diarrhea, candidal infections, and skin eruptions in nursing infants.

Pharmacology

Mechanism of Action (See Penicillins)

Antimicrobial Activity.

The cephalosporins have been grouped into ‘generations’ based on their general spectrum of antimicrobial activity. There are five generations of cephalosporins. Table 9.1 reviews the common agents in each generation and their antimicrobial spectrums.

Future Directions

A second fifth-generation cephalosporin, ceftobiprole is under consideration for US Food and Drug Administration (FDA) approval for treatment of complicated skin and soft tissue infection (CSSTI). Ceftobiprole has shown activity against methicillin-resistant S. aureus (MRSA), in addition to Streptococcus pneumoniae, Pseudomonas spp., and enterococci.

A new antipseudomonal cephalosporin, ceftolazone, has demonstrated activity against carbapenem-resistant and multidrug-resistant Pseudomonas aeruginosa clinical strains. In addition, newer studies have demonstrated promising results with ceftolazone combined with tazobactam.

Pharmacokinetics

The absorption properties of the currently available cephalosporins vary greatly, with peak serum concentrations dependent on administration in relation to food intake. Q9.2 Cefaclor, cefadroxil, and cephalexin are best absorbed from an empty stomach, whereas the bioavailability of cefuroxime is increased when taken with food. The half-life of most parenterally administered cephalosporins varies between 0.5 and 2 hours, although the 6 to 8 hour half-life of ceftriaxone permits once-daily dosing. Table 9.1 reviews the metabolism of cephalosporins.

Clinical Use

Dermatologic Indications

Oral cephalosporins are used primarily in ambulatory dermatologic practice to treat uncomplicated skin and soft tissue infection (USSTI), such as impetigo, folliculitis, furuncles, carbuncles, acute bacterial paronychia, cellulitis, ecthyma, erysipelas, and postoperative wound infections. Severe infections, such as complicated cellulitis and necrotizing fasciitis require intravenous (IV) antibacterial agents. Additional special uses of individual cephalosporins include selected STD (i.e., gonorrhea), P. aeruginosa infections, including ecthyma gangrenosum, diabetic foot infections and Lyme disease.

See Table 9.3 for list of cephalosporins classified by generation, and Table 9.2 for common dermatologic indications and dosage guidelines for cephalosporins.

Table 9.3

Currently Available Us Food and Drug Administration-Approved Cephalosporins

Generic Name ^a	Trade Name(s)	Route	Pregnancy Category	Lactation Category	Adult Dose
First-Generation Cephalosporins
Cefadroxil	Duricef	PO	B	S	500 mg BID to 1–2 g/day (QD or BID)
Cefazolin	Ancef	IM, IV	B	S	0.5–1.5 g every 6–8 hours
Cephalexin	Keflex, Panixine Disperdose ^b	PO	B	U	250–500 mg 4 times daily
Second-Generation Cephalosporins
Cefaclor	Ceclor	PO	B	U	250–500 mg 3 times daily
Cefprozil	Cefzil	PO	B	PS	250–500 mg a day (QD or BID)
Cefuroxime axetil	Ceftin	PO	B	PS	250–500 mg twice daily
Cefuroxime	Zinacef	IV/IM	B	PS	0.75–1.5 g every 6–8 hours
Cephamycins (second generation)
Cefotetan	Cefotan	IM, IV	B	U	1–3 g every 12 hours
Cefoxitin	Mefoxin	IM, IV	B	S	1–2 g every 4–6 hours
Third-Generation Cephalosporins
Cefixime	Suprax	PO	B	U	200 mg twice daily or 400 mg QID
Cefdinir	Omnicef	PO	B	PS	300 mg twice daily
Cefotaxime	Claforan	IM, IV	B	PS	1–2 g every 4–8 hours
Cefpodoxime	Vantin	PO	B	PS	100–400 mg twice daily
Ceftazidime	Fortaz, Tazicef	IM, IV	B	PS	0.5–2 g every 8–12 hours
Ceftibuten	Cedax	PO	B	U	400 mg once daily
Cefditoren ^c	Spectracef	PO	B	U	200–400 mg twice daily
Ceftriaxone	Rocephin	IM, IV	B	PS	0.5–2 g every 12–24 hours
Fourth-Generation Cephalosporins
Cefepime	Maxipime	IM, IV	B	U	1–2 g every 12 hours
Fifth-Generation Cephalosporins
Ceftaroline	Teflaro	IV	B	U	600 mg every 12 hours

For Lactation category: S , Safe; PS , probably safe; PU , possibly unsafe; U , unknown.

BID, Twice a day; IM, intramuscular; IV, intravenous ; PO, per os = oral; QD , every day.

a Cephalothin (Keflin), cephapirin (Cefadyl), cefmetazole (Zefazone), cephaloridine (Ceporin), cephradine (Velosef), loracarbef (Lorabid), cefoperazone (Cefobid) and ceftizoxime (Cefizox) are no longer available in the United States.

b Dispersible tablet formulation.

c For uncomplicated skin infections, cefditoren 200 mg BID has been used.

Adverse Effects

Hypersensitivity Reactions and Cross-Reaction Potential

Hypersensitivity reactions, reported in only 1% to 3% of treated individuals, include cutaneous findings, such as urticaria, maculopapular eruptions, and pruritus ( Box 9.2 ).

Box 9.2

Drug Risks Profile—Cephalosporins

Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. ( https://www.wolterskluwercdi.com/facts-comparisons-online/ ).

Contraindications
Hypersensitivity to cephalosporins and related antibiotics
Boxed Warnings
None listed
Warnings & Precautions ^a
Hypersensitivity Reactions Cross-allergenicity to penicillins (see text) ^a Serum sickness like reactions (esp. cefaclor) with fever, arthralgias, arthritis, esp. with second course	Infections ^a CDAD (has been reported to occur 2 months after d/c rx) Coagulation ^a May ↑ INR in warfarin patients—nutritionally deficient patients, chronic therapy, liver and kidney disease
Pregnancy Prescribing Status
Traditional US Food and Drug Administration rating— category B	Newer rating ^b —compatible

a Under “Warnings & Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid.

b See Chapter 65 , Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings.

CDAD , Clostridium difficile -associated disease; INR , international normalized ratio.

The incidence of anaphylaxis secondary to cephalosporin administration is even more infrequent, estimated between 0.0001% to 0.1%. For discussion on potential cross-reactivity of cephalosporins with penicillins, see penicillin section. Q9.3 The cross-reactivity between penicillins and cephalosporins is related to the structural similarities of their individual side chain determinants. However, even when side chains are similar, cross-reactions are not guaranteed. Thus, careful skin testing with multiple β-lactam determinants should be performed in patients with history of β-lactam allergy who require penicillin or cephalosporin therapy.

Other Adverse Effects

Q9.4 Box 9.2 summarizes the most important AE associated with cephalosporin administration. GI toxicities are relatively frequent with cephalosporin use, including nausea, vomiting, or diarrhea. Other potential AE include vaginal candidiasis, hematopoietic changes, mental and sleep disturbance, and transaminitis.

Drug Interactions

Some of the most important drug interactions for cephalosporins include the following:

1.
Cephalosporins (such as cefotetan), which contain a N -methyl thiotetrazole (NMMT) ring, may induce disulfiram-like reactions with alcohol ingestion.
2.
The NMMT ring inhibits production of vitamin-K clotting factors, resulting in prolongation of INR in patients on warfarin.
3.
Probenecid competes with renal tubular secretion of some cephalosporins, increasing and prolonging their plasma levels.
4.
Some cephalosporins may increase the risk of nephrotoxicity, when coadministered with aminoglycosides or potent diuretics.
5.
The potential impact of oral antibiotics on the efficacy of oral contraceptives is reviewed under the ‘Drug Interactions’ sections for both TCNs and rifamycins.
6.
Ceftaroline appears to exhibit minimal interaction with the cytochrome P-450 (CYP) system, although no studies on drug interaction have been performed with this newer cephalosporin.

Dosage

Table 9.2 contains common dermatologic indications and dosage guidelines for cephalosporins. A single IM injection of ceftriaxone 1 g is an effective treatment for uncomplicated gonorrhea, (as are single oral doses of cefpodoxime and cefixime). For ecthyma gangrenosum, treatment with IV ceftazidime 2 g every 8 hours is recommended; in the setting of immunosuppression or sepsis, multiagent antipseudomonal therapy is warranted.

β-Lactam and β-Lactamase Inhibitor Combinations

Amoxicillin/Clavulanate and Others

β-lactamase enzymes render β-lactam antibiotics inactive by irreversibly hydrolyzing the amide bond of the β-lactam ring. The production of a β-lactamase is controlled by either chromosomal or plasmid genes, and these genetic capabilities may be transferred among bacteria. β-lactamase inhibitors, such as clavulanate, sulbactam, and tazobactam, when combined with a β-lactam antibiotic, inhibit β-lactamase produced by Enterobacteriaceae, S. aureus , and Gram-negative anaerobes, thereby restoring the spectrum activity of the β-lactams.

Antibacterial Activity

Significant activity against β-lactamase produced by MSSA, Haemophilus spp, Klebsiella spp., Escherichia coli , Proteus spp., and Bacterioides fragilis has been noted. However, β-lactamase inhibitors do not inhibit β-lactamases produced by P. aeruginosa , Enterobacter, and Citrobacter spp.

Pharmacokinetics

When clavulanate is given orally with amoxicillin (Amox/Clav), it is rapidly absorbed, with peak concentrations reached 40 to 60 minutes after ingestion, and bioavailability not significantly affected by food. Ampicillin–sulbactam (Amp/Sulb), ticarcillin–clavulanate (Ticar/Clav) and piperacillin–tazobactam (Pip/Tazo) are administered intravenously. These agents are subject to renal metabolism and warrant dose adjustment in renal insufficiency.

Clinical Use

Dermatologic Indications

The broad-spectrum antimicrobial coverage provided by Amox/Clav, Amp/Sulb, Ticar/Clav, and Pip/Tazo makes these agents useful for the treatment of polymicrobial infections. The recommended treatment for animal or human bites infected by combined aerobic and anaerobic pathogens is Amox/Clav. Ticar/Clav and Pip/Tazo exhibit an even broader antibacterial spectrum and are effective in treating CSSTI, such as diabetic foot ulcers, infected decubiti, and burn wounds.

Adverse Effects

GI AE are most often associated with Amox/Clav and Pip/Tazo, most commonly diarrhea. Diarrhea is less frequent when Amox/Clav is administered with food.

Drug Interactions

When administered concomitantly with β-lactam/β-lactamase inhibitor combinations, oral probenecid slows the rate of renal tubular secretion of the β-lactam agent, resulting in an increase in serum concentration and delayed renal excretion. The potential impact on the efficacy of oral contraceptives is reviewed later under the ‘Drug Interactions’ sections for both TCNs and rifamycins.

Dosage

Amox/clav is dosed at 875/125 mg twice daily.

Other Systemic Antibacterials that Inhibit Cell Wall Synthesis

Glycopeptides

Vancomycin and teicoplanin inhibit bacterial cell wall synthesis by forming noncovalent complexes with precursors of bacterial peptidoglycan, a contrasting mechanism to that of the β-lactam agents.

Pharmacology

Antibacterial Activity

Vancomycin and teicoplanin inhibit a broad range of Gram-positive bacteria, including staphylococci, streptococci and most enterococci.

Q9.5 Resistance to vancomycin is mediated by several mechanisms (see Table 9.1 ) and has resulted in the increased prevalence of vancomycin-resistant S. aureus (VRSA), vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant enterococci (VRE). Derived from vancomycin, the lipoglycopeptides, dalbavancin, oritavancin, and telovancin treat VRSA, VISA, and VRE. The recently described increasing minimal inhibitory concentration (termed MIC creep ) of vancomycin is not uniform when analyzed across multiple centers.

Pharmacokinetics

Vancomycin and teicoplanin are administered parenterally given their minimal intestinal absorption. As compared with vancomycin, teicoplanin has a longer half-life and is less nephrotoxic. Glycopeptides are pregnancy category C, excreted in breast milk, and approved for use in children.

Clinical Use

Dermatologic Indications

Vancomycin is primarily used for the treatment of skin and soft tissue infection (SSTI) caused by MRSA.

Adverse Effects

Cutaneous Reactions and Hypersensitivity

Q9.6 Red man syndrome and shock secondary to histamine release may follow rapid infusion of vancomycin. In addition, vancomycin is one of the most common causes of drug-induced linear IgA bullous dermatosis (LABD). LABD occurs within 2 to 21 days of vancomycin administration and presents as vesicobullae, erythematous papules, erosions, urticarial plaques, or eczematous patches. Multiple studies have demonstrated immunoreactivity to a variety of target antigens in drug-induced LABD, including BP180, LAD285 and the α-3 subunit of laminin-332. Although toxic epidermal necrolysis (TEN) has been reported rarely, direct immunofluorescence is helpful in differentiation from vancomycin-associated LABD simulating TEN.

Other Adverse Effects

Dose-related hearing loss has been reported in patients with renal failure with IV vancomycin. Concurrent administration of vancomycin with aminoglycosides increases the risk of nephrotoxicity. Other AE include fever, neutropenia, thrombocytopenia, and phlebitis. Of note, cutaneous and extracutaneous AE are significantly less common with teicoplanin.

Drug Interactions

Vancomycin may enhance the activity of nondepolarizing muscle relaxants.

Dosage

See Table 9.2 .

Macrolides

Erythromycin, Azithromycin, and Clarithromycin

The major oral macrolide antibiotics used in dermatology are erythromycin and clarithromycin, with azithromycin being the major azalide agent. Q9.7 Unlike β-lactams, macrolides are bacteriostatic antibiotics, which bind reversibly the (50S) subunit of the bacterial ribosome, inhibiting ribonucleic acid (RNA)-dependent protein synthesis. Q9.8 Macrolides also demonstrate specific anti-inflammatory properties, underlying their therapeutic benefit in inflammatory facial dermatoses, such as acne and rosacea. Erythromycin was previously useful for SSTI secondary to staphylococcal organisms and in the treatment of acne; however, the emergence of erythromycin-resistant organisms, including S. aureus and Propionibacterium acnes , has limited the current clinical utility of this drug.

Pharmacology (see Table 9.1 )

Antimicrobial Activity

Macrolide antibiotics (from here on “macrolides” also include azithromycin) are effective against Gram-positive organisms, with the notable exceptions of MRSA and enterococcus. Q9.9 As compared with erythromycin, azithromycin and clarithromycin have increased activity against Gram-positive organisms, owing to their PK properties. Unlike erythromycin, clarithromycin and azithromycin possess increased activity against several Gram-negative pathogens. Azithromycin is active against E. coli , N. gonorrhoeae , Haemophilus ducreyi , Ureaplasma urealyticum , and Chlamydia trachomatis . Azithromycin also has activity against organisms isolated in animal bites, such as Pasturella multocida and in human bites, such as Eikenella corrodens . Both clarithromycin and azithromycin are effective against the atypical mycobacteria Mycobacterium avium-intracellulare , Mycobacterium leprae , and Mycobacterium chelonei . Clarithromycin is the most active macrolide against M. leprae . Both clarithromycin and azithromycin are active against Toxoplasma gondii , Treponema pallidum, and Borrelia burgdorferi .

Pharmacokinetics

Q9.2 Unless administered in an enteric-coated form, erythromycin base is vulnerable to gastric acid inactivation and must be taken on an empty stomach. Azithromycin and clarithromycin are more stable in gastric acid than erythromycin, increasing their absorption. Clarithromycin is well absorbed with or without food, but azithromycin absorption is decreased with food and should be taken 1 to 2 hours before a meal. Azithromycin and clarithromycin demonstrate superior cellular penetration and blood concentrations to a comparable dose of erythromycin.

Dosages of clarithromycin and erythromycin must be adjusted in renal disease. As azithromycin is subject to hepatic metabolism, no dosage adjustment is required in renal disease.

Clinical Use

Dermatologic Indications

Indications for Cutaneous Infections

Q9.9 The macrolides are effective in the treatment of SSTI and demonstrate a highly favorable safety profile. Particularly in oral formulations, macrolides are useful in the treatment of USSTI, including pyodermas, abscesses, infected wounds, infected ulcers, and erysipelas (see Table 9.2 ). However, erythromycin use is not a treatment of choice for any USSTI, owing to the high prevalence of resistant staphylococcal and streptococcal strains.

Other indications for erythromycin include erythrasma, anthrax, erysipeloid, chancroid, and lymphogranuloma venereum. Erythromycin is the treatment of choice for early Lyme disease (erythema migrans) in children under 8 years of age. Available data supports the efficacy of azithromycin and clarithromycin for these indications as well.

Q9.9 Azithromycin is effective for donovanosis, cat-scratch disease, toxoplasmosis, and Mediterranean spotted fever. A single dose of azithromycin is effective for treatment of uncomplicated urethritis or cervicitis caused by N. gonorrhoea or C. trachomatis . Azithromycin is an excellent choice for infections associated with animal and human bites caused by Pasteurella and Eikenella spp, respectively. Clarithromycin is effective in leprosy, as well as the atypical mycobacterial skin infections caused by Mycobacterium cheloneae , M. simiae , M. avium complex (MAC), M. kansasii , and M. intracellulare .

Indications for Inflammatory Dermatoses

As an alternative therapy, azithromycin has been used with some success in acne and rosacea. Because of its prolonged persistence in tissue, intermittent regimens with oral azithromycin have been suggested (250 mg 3 times weekly, after an initial ‘tissue load,’ with daily dosing for 5 days). In one study, azithromycin was as effective as TCN for rosacea and may be considered in the context of intolerance to TCN. The use of erythromycin to treat inflammatory dermatoses has declined, given the global prevalence of erythromycin-resistant P. acnes .

Multiple reports have described the efficacy of azithromycin in treatment of confluent and reticulated papillomatosis (CARP). Given its favorable AE profile, azithromycin may be preferred over minocycline in select cases of CARP. The efficacy of macrolides for the treatment of pityriasis rosea is uncertain, given conflicting data and a lack of supportive evidence for this indication from randomized control trials.

Adverse Effects

Common Adverse Effects

The most common AE of erythromycin are nausea, abdominal pain, and diarrhea, occurring in 15% to 20% of patients, depending on the oral formulation used ( Box 9.3 ). Erythromycin binds to motilin receptors throughout the GI tract, thereby releasing motilin, which stimulates migrating digestive contractions, leading to GI disturbance. Cardiac conduction abnormalities, including QTc prolongation and torsades de pointes, have been associated with erythromycin: risk factors include advanced age, higher dosages, rapid administration, and history of cardiac disease.

Box 9.3

Drug Risks Profile—Macrolides

Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. ( https://www.wolterskluwercdi.com/facts-comparisons-online/ ).

Contraindications
Erythromycin —dihydroergotamine, ergotamine, pimozide ^a Azithromycin —(a) hypersensitivity telithromycin, (b) cholestatic jaundice or hepatic dysfunction with prior azithromycin	Clarithromycin —(a) cholestatic jaundice with prior clarithromycin, (b) hx QTc prolongation, torsades, (c) dihydroergotamine, ergotamine, pimozide
Boxed Warnings
None listed
Warnings & Precautions ^a
Cardiovascular ^a Altered cardiac conduction, QTc prolongation, Hx torsades de pointes (uncorrected hypomagnesemia, hypokalemia) Clarithromycin possibly a risk in patients with CAD Hypersensitivity Reactions Urticaria, angioedema, SJS/TEN, DRESS, vasculitis (HSP)	GI ^a Elevated LFT/hepatitis (esp. clarithromycin), usually reversible upon discontinuation ^a Caution azithromycin patients significant liver impairment ^a CDAD (has been reported to occur 2 months after d/c rx) Neurologic May aggravate weakness in patients with myasthenia gravis
Pregnancy Prescribing Status
Traditional US Food and Drug Administration rating— category B (clarithromycin C)	Newer rating ^b —compatible

a Under “Warnings & Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid.

b See Chapter 65 , Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings.

CAD, coronary artery disease; CDAD , clostridium difficile -associated disease; DRESS , drug reaction eosinophils systemic symptoms; GI , gastrointestinal; HSP , Henoch-Schonlein purpura; LFT , liver function tests; SJS/TEN , Stevens–Johnson syndrome/toxic epidermal necrolysis.

The most common AE associated with clarithromycin is a metallic or bitter taste. Rarely, fixed drug eruption, leukocytoclastic vasculitis and hypersensitivity reactions have been reported.

Also rare, azithromycin has been associated with irreversible deafness, angioedema, photosensitivity, and hypersensitivity. Macrolides are well described in the pathogenesis of acute generalized exanthematous pustulosis (AGEP). Macrolide antibiotics also rarely cause cholestatic hepatitis and exacerbate myasthenia gravis.

Use in Infants

Q9.10 Macrolides are excreted into breast milk, and infant exposure during lactation is a risk factor for hypertrophic pyloric stenosis. Multiple studies have demonstrated a significant association between treatment with macrolide antibiotics and development of pyloric stenosis in infants. This association is stronger when exposure occurs within the first 2 weeks of life. Therefore, the use of macrolides in infants and lactating mothers should be strictly limited to select cases in which the benefits clearly outweigh the risks.

Use in Pregnancy

Data regarding the safety of macrolides in pregnancy are widely variable. In general, oral erythromycin is considered to be safe in pregnancy because only low concentrations cross the placenta. However, the safety of chronic use in pregnancy for acne vulgaris, rosacea, or perioral dermatitis has not been clearly described. Administration of erythromycin estolate for longer than 3 weeks in the second trimester of pregnancy is associated with 10% risk of maternal hepatotoxicity, which is reversible upon discontinuation. Use of erythromycin during pregnancy is also limited by its rare association with cardiotoxicity. In a review of maternal erythromycin use over 15 years, erythromycin was persistently associated with cardiovascular defects (risk estimate 1.70; 95% confidence interval [CI], 1.26–2.39). Thus, prolonged use of erythromycin during the first and second trimester of pregnancy should be discouraged. In contrast, short-term use of macrolides in the third trimester of pregnancy is subject to a different risk–benefit analysis. In the third trimester, short-term erythromycin safely reduces maternal and infant colonization with group B β-hemolytic streptococcus and reduces the risk of pregnancy loss and low-birthweight infants, in women with genital mycoplasma infections.

Azithromycin has generally been considered safe for use in pregnancy (Pregnancy Category B). However, data from animal studies of clarithromycin (Pregnancy Category C) have been conflicting. Like erythromycin, clarithromycin should also be used with caution during pregnancy.

Drug Interactions

Q9.9 Erythromycin, and to a lesser extent clarithromycin, inhibits the hepatic and intestinal (‘first-pass’) CYP system, primarily CYP3A4, leading to decreased metabolic clearance of several drugs, often rapidly after initiation of erythromycin/clarithromycin therapy. Erythromycin is a more potent inhibitor of CYP3A4 than clarithromycin. Both drugs raise plasma levels, prolong the clearance of many drugs, subject to metabolism by CYP3A4, including ( Table 9.4 ):

1.
Carbamazepine and phenytoin;
2.
Theophylline;
3.
Certain benzodiazepines (i.e., triazolam, midazolam);
4.
Warfarin, with potential for severe bleeding complications;
5.
Cyclosporine, with potential for renal toxicity and hypertension;
6.
Drugs with potential for QTc prolongation and torsades de pointes (terfenadine, astemizole, cisapride, and pimozide; all but pimozide have been withdrawn from the market);
7.
Some HMG-CoA reductase inhibitors or ‘statins’ (i.e., atorvastatin, simvastatin, lovastatin), enhancing their risk for rhabdomyolysis.
8.
Coadministration with ergot alkaloids (dihydroergotamine, ergotamine, etc.) can lead to ergotism and is contraindicated.
9.
Clarithromycin may reduce the absorption of zidovudine (AZT) by 20% and may also reduce the serum levels of didanosine (ddI).
10.
In contrast, clarithromycin may significantly increase linezolid serum concentrations when coadministered.
11.
Macrolide-induced digoxin toxicity has been described, because of alterations in gut flora or P-glycoprotein.

Table 9.4

Drug Interactions—Macrolides and Azalides

Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. ( https://www.wolterskluwercdi.com/facts-comparisons-online/ ); Hansten PD, Horn JR. The Top 100 Drug Interactions: a Guide to Patient Management , 2019 Edition. Freeland, WA: H&H Publications, 2019. ( http://www.hanstenandhorn.com/ ).

Drug Category	Drug Examples	Comments
Relatively High-Risk Drug Interactions ^a
Calcineurin inhibitors	*Cyclosporine* (and oral *tacrolimus* )	CYP3A4 substrate ↑ drug levels and risk of severe toxicity (HBP, renal failure, hyperlipidemia, others)
Statins	*Simvastatin, atorvastatin, lovastatin*	same (risk myopathy, rhabdomyolysis)
Benzodiazepines	*Alprazolam, triazolam, midazolam*	same (risk excessive sedation)
*Calcium-channel blockers*	All are CYP3A4 substrates	same (hypotension, bradycardia)
Sulfones	*Dapsone*	same (risk hemolysis, agranulocytosis)
Anticoagulants	*Warfarin*	R-enantiomer of warfarin (CYP3A4 2nd most important substrate pathway after CYP1A2) risk bleeding
Antigout meds	*Colchicine*	Possible ↑ myelotoxicity
*Antidysrhythmic agents*	Amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine	Risk QTc prolongation → *torsades de pointes* (risk with erythromycin, clarithromycin, azithromycin)
Antibacterials—macrolides	*Clarithromycin, erythromycin*	same
*Antidepressants*	Amitriptyline, clomipramine, desipramine, likely others	same
*Antipsychotic agents*	Haloperidol, olanzapine, phenothiazines, *pimozide* , ziprasidone	same
β-blockers	*Sotalol*	same (see Ch. 66 on Drug Interactions for more extensive list of drugs ↑ QTc interval)
SSRI antidepressants	Fluoxetine, fluvoxamine	CYP3A4 substrates, generally modest risk
Hormonal	Estrogens, combined oral contraceptives	In general, modest risk (conceptually venous thromboembolism risk; likely a stronger genetic risk)
Retinoids	Isotretinoin (possibly acitretin)	In general, modest risk (most of very few interactions other mechanisms)
Lower-Risk Drug Interactions
PDE-5 inhibitors	Sildenafil, tadalafil, vardenafil	CYP3A4 substrates (sustained erection, priapism)
H ₁ antihistamines	Fexofenadine, loratadine	Primary antihistamines (1 ^st or 2 ^nd generation) which are CYP3A4 substrates; historically, terfenadine, astemizole (both off the market) induced *torsades de pointes* in combination CYP3A4 inhibitors)
Anticonvulsants (aromatic)	Phenytoin, carbamazepine, phenobarbital	CYP3A4 inducers; loss of efficacy azalides, macrolides, interaction takes 1–2 weeks to begin
Rifamycins	Rifampin, rifapentine, rifabutin	same
Antifungals	Griseofulvin	same

CYP , Cytochrome P-450; PDE , phosphodiesterase; SSRI , selective serotonin reuptake inhibitor.

a Overall highest-risk drug interactions indicated in bold italics.

Azithromycin minimally inhibits CYP3A4 isoenzymes, and so may be safely coadministered with other drugs. Nonetheless, toxicity has been reported following coadministration of azithromycin with lovastatin, warfarin, cyclosporine, disopyramide, or theophylline. The potential impact of oral antibiotics on the efficacy of oral contraceptives is reviewed later under the Drug Interactions sections for both TCNs and rifamycins.

Dosage

Dosage guidelines for macrolide antibiotics are summarized in Table 9.2 . The usual adult dosing schedule for erythromycin base is 250 to 500 mg every 6 to 12 hours, and for erythromycin ethyl succinate, 400 to 800 mg every 6 to 12 hours. The adult dosage of clarithromycin is 250 to 500 mg every 12 hours; a newly available XL formulation (500 mg) permits once-daily dosing. For azithromycin, the adult dosage is 500 mg, given as a single dose on the first day of therapy, followed by 250 mg once daily for 4 additional days (also known as a Z-pak ; a 3-day version is also available). For the treatment of uncomplicated chlamydial infections, azithromycin is administered as a single 1-g dose. Localized gonococcal infections may be treated with a single 2-g oral dose. Azithromycin is available in 250, 500, 600 mg tablets, a 2-g extended-release (ER) oral suspension, a 250 mg/5 mL pediatric liquid preparation, and an IV formulation.

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