Short-Course Antibiotic Therapy

Authors: Robert D. Powers, MD, MPH, Division of Emergency Medicine, University of Connecticut School of Medicine, Farmington; Department of Emergency Medicine, University of Virginia School of Medicine, Charlottesville; Robin M. Naples, MD, Resident in Emergency Medicine, University of Virginia Health System, Charlottesville; and Hannah M. Bernard, DO, Resident in Emergency Medicine, University of Connecticut School of Medicine, Farmington.

Peer Reviewers: Larry Mellick, MD, FAAP, FACEP, Medical Consultant, FBI Academy, Quantico, VA; Professor, Department of Emergency Medicine, Medical College of Georgia, Augusta; and Steven M. Winograd, MD, FACEP, Attending Physician, Emergency Department, Adena Regional Medical Center, Chillicothe, OH.

Introduction

The duration of antimicrobial therapy for common infections has been a subject of debate and investigation for decades. During this time, there has been a general trend toward shorter duration treatments, particularly in the area of urinary and genital tract infections. The recent development of well-absorbed, wide spectrum agents has broadened this approach to include other ailments, most notably upper and lower respiratory tract infections. Short-course therapy has many potential clinical benefits, including favorable pharmacokinetic, efficacy, and convenience factors. Many also believe that shorter courses will result in less total antibiotic use, thereby limiting exposure and slowing the development of resistance.

Widespread resistance among common pathogens is thought to be brought, at least in part, by indiscriminate use of antibiotics. Of particular concern is the development of a monoclonal resistance of Streptococcus pneumoniae to advanced generation of fluoroquinolones. While the majority of the isolates of quinolone-resistant streptococci have been seen in Europe and the Far East, rates as high as 4.2% have been found in the northeastern United States.1-4 This development has led to practice guidelines by both the CDC and the Infectious Disease Society of America (IDSA) recommending discretionary use of respiratory fluoroquinolones.5

Resistance to macrolides also has been seen in isolates of S. pneumoniae in the United States. The resistance is mediated by genes that either encode for an efflux pump (more common in the United States) or for an enzyme that methylates the ribosomal macrolide binding site (European isolates).6-8 One study has shown bactericidal eradication by azithromycin in macrolide-resistant strep that contained the efflux pump gene.9 It may be that the efflux-mediated resistance can be overcome by the higher concentrations achieved by single-dose therapy, although no studies have confirmed this mechanism.

Upper Respiratory Infections

Otitis Media. Acute otitis media (AOM) is a common pediatric illness, affecting 71% of children by age 3.10-12 Although it often is viral in origin, it is the most common childhood infection for which antibiotics are prescribed.13-16 Traditional therapy for AOM is a 10-day course of oral antibiotics, often requiring multiple doses throughout the day. Compliance often decreases after the child's symptoms improve.17-19 Short-course or single-dose therapy is an attractive alternative to improve compliance.

Bacterial causes of AOM are the typical upper respiratory pathogens, including Streptococcus pneumoniae, Hemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes.13,20,21 Antimicrobial therapy directed against these agents must take into account the increasing frequency of penicillin-resistant S. pneumoniae. During the 1990s, streptococcal resistance to penicillin rose as much as fourfold in the United States, with the greatest prevalence in the Southeast region.22-24 This increase in resistance is especially true of isolates from middle ear effusions.21,25

The broad spectrum parenteral cephalosporin ceftriaxone has a long serum half-life. A single intramuscular injection has been shown to produce serum levels for seventy five hours that exceed the minimum inhibitory concentrations (MICs) for typical AOM pathogens.26 Levels in middle ear fluid are approximately 10% of serum concentration, resulting in desirable MICs for 56 hours after a single dose.27 Intramuscular ceftriaxone (50 mg per kg—maximum dose 1 g) has been compared in several trials to traditional 10-day courses of both amoxicillin and amoxicillin-clavulanate, and has been found to have similar clinical efficacy, otoscopic findings, recurrence rates, and adverse event rates. Additionally, a significantly higher patient/parent preference rate was seen with the ceftriaxone treatment group over those receiving 10-day oral therapy.28-30 One study of ceftriaxone addresses the issue of penicillin-resistant S. pneumoniae. When single-dose ceftriaxone was compared with 10 days of amoxicillin-clavulanate, patients had similar success rates. This occurred despite a penicillin-resistant S. pneumoniae rate of 52%. However, the amoxicillin-clavulanate group had a rise in penicilllin-resistant nasopharyngeal isolate rates to 83% as compared to 63% in the ceftriaxone group.31

Single dose of oral azithromycin has been investigated as an alternative to traditional 10-day therapy for AOM. A dose of 30 mg per kg has been compared to both amoxicillin and amoxicillin-clavulanate. Similar to the ceftriaxone trials, azithromycin has comparable clinical efficacy with significantly improved compliance.32-35 Three- and five-day courses of azithromycin have similar results when compared with 10-day courses of traditional agents.36-38

Rhinosinusitis. The infection usually called "sinusitis" infection typically is viral, and symptoms generally resolve without antibiotic therapy within 10-14 days.39 A small minority of patients will develop acute bacterial rhinosinusitis (ABRS), a secondary infection caused by obstruction of the sinus ostia and impairment of the mucus clearance mechanisms following viral upper respiratory tract infection. Epidemiologic studies estimate that fewer than 2% of viral upper respiratory infections will result in ABRS.40-42

While clinical signs and symptoms of viral and bacterial sinusitis are very similar, there are general guidelines for diagnosing ABRS.43,44,53-58 These guidelines include: symptoms for 7-10 days; worsening after initial resolution; purulent nasal discharge; unilateral maxillary sinus tenderness; and facial or maxillary tooth pain. Clinicians should become familiar with them to avoid unnecessary prescribing. Overuse of antibiotics is common with this disorder, as sinusitis is the fifth most common diagnosis for which antibiotics are utilized.45 S. pneumoniae and H. influenzae are the most common organisms isolated from sinus aspiration in patients with ABRS. M. catarrhalis, S. pyogenes, and anaerobic bacteria cause a small percentage of infections.46-47 Patients requiring antibiotic therapy for ABRS should receive agents effective against these pathogens. Traditional recommendations include therapy for 10-14 days with agents such as amoxicillin-clavulanate or cefuroxime axetil.

Short-course antibiotic therapy with azithromycin has been studied in most upper respiratory tract infections, including ABRS. Trials of a 3-day course of azithromycin (500 mg q day) have shown similar clinical efficacy and improved compliance when compared to 10-day regimens of amoxicillin or amoxicillin-clavulanate.48-50 Telithromycin, a new ketolide, also has been investigated as a 5-day, 800-mg daily course for ABRS. This regimen was found to have similar clinical efficacy, bacterial eradication, and adverse event rates as a 10-day course of cefuroxime.51 The newer respiratory quinolones also have been studied for their efficacy in short-course ABRS treatment. Gatifloxacin 400 mg once a day for 5 days has been compared to itself for 10 days, as well as to10 days of amoxicillin-clavulanate. In both cases, short-course outcomes were similar to the longer treatments.52 Resistance of pathogens to fluoroquinolones already is a concern59-61 and eventually may limit their utility in the therapy of upper respiratory infections, including sinusitis.

Pharyngitis. Sore throat is a common complaint of patients seen in ambulatory and emergency practices. Most cases are of viral etiology; Group A beta hemolytic streptococci (GABHS) is the most common bacterial cause of tonsillopharyngitis (TP). Depending on the time of year and age group evaluated, GABHS causes TP in 5-36% of cases. It is most common in the winter months, and in children between the ages of 4 and 13.62 It is important to recognize bacterial TP because treatment of GABHS has been shown to prevent rheumatic fever and decrease suppurative complications as well as to reduce duration of symptoms and transmissibility.63,64

Differentiation between viral and streptococcal TP is quite challenging, but the advent of rapid antigen testing and clinical scoring rules has allowed physicians to achieve a measure of bedside certainty that was not previously available. Predictive rules now dictate an evidence-based strategy that is clinically sound and cost-effective. Table 1 shows the clinical criteria that have been validated prospectively, allowing physicians to risk stratify patients and delineate those who should be treated empirically from those who require antigen testing or throat culture.65-68 In the proper epidemiologic setting, it is prudent to treat patients with three or four criteria present, and either screen or culture patients with fewer signs and symptoms.

Table 1. Clinical Criteria for Diagnosing GABHS13-16

Penicillin has long been the mainstay of treatment for GABHS. Unfortunately, oral dosing of penicillin requires completion of a 10-day course to achieve maximal pharyngeal eradication rates.64,69 This poses a compliance challenge for most patients, and limits the efficacy of therapy. A single IM injection of 1.2 million units (or 25 units per kg) of benzathine penicillin G has proven effective for eradication of GABHS. The principal side effect of this therapy is tenderness and pain at the injection site. A commercial mixture of benzathine penicillin and procaine penicillin will decrease this adverse effect, but contains only 900,000 units of benzathine penicillin. This limits its usefulness in adults or large children.62,63

Several antibiotics have been studied in comparison with traditional 10-day oral penicillin. Unfortunately, most of these trials are not able to show the ability of alternatives to prevent rheumatic fever. Two studies followed patients for one year after treatment with either five days of cefuroxime or 10 days of oral penicillin. Both study groups had similar GABHS eradication and clinical efficacy, and there were no cases of rheumatic fever in either group.70 Studies of other short-course oral cephalosporins have shown equivalent or superior GABHS eradication rates and clinical responses. The ability of these agents to prevent rheumatic fever is unknown.71-76

Five days of treatment with amoxicillin-clavulanate has been compared with traditional 10-day penicillin therapy. In one randomized prospective trial, amoxicillin-clavulanate had similar clinical and bacteriologic efficacy. While this study could not demonstrate any ability to prevent rheumatic fever, the regimen may offer some protection since it uses the proven agent amoxicillin.77 The ketolide telithromycin also has been investigated as a possible short-course alternative to penicillin. Studies have found similar clinical response and equivalent bacteriologic eradication between a five-day course of telithromycin and a 10-day course of penicillin.78,79 Similar studies looking at five days of clarithromycin vs. 10 days of penicillin have shown conflicting results. One study showed equivalent clinical efficacy in bacteriologic eradication while another group showed decreased bacteriologic eradication rates compared to penicillin due to proven in vitro resistance of GABHS to clarithromycin.80

Lower Respiratory Infections

Bronchitis. Bronchitis—or more properly tracheobronchitis— is an inflammation of the lower respiratory tree, typically involving the airways more than the alveoli. Although the characteristic cough, dyspnea, and occasional wheezing often prompt the use of antibiotics, there is little evidence to support their routine use in otherwise healthy non-smokers. The vast majority of cases of bronchitis are viral and will resolve without antimicrobials within a week or 10 days. Patients do benefit from symptomatic relief, and should be prescribed anti-tussives, NSAIDs, and bronchodilators as needed.

Acute bacterial exacerbation of chronic bronchitis (ABECB) will be the focus of this section. It is a complication of chronic lung disease, and bacterial infection is a component of the syndrome. This disorder is defined by published criteria, and many investigators and clinicians believe that antibiotics should be part of the therapy of moderate to severe cases.

In the United States, about 16 million adults have chronic obstructive pulmonary disease (COPD). Those who suffer from ABECB are almost always tobacco smokers with underlying COPD/chronic bronchitis. Acute exacerbations include some combination of worsening dyspnea, increased sputum purulence, and increased sputum volume. Anthonisen and his colleagues81 developed a scale to assess the severity of episodes of ABECB. Although it never has been validated, it remains widely used. Type 1 (severe) includes all three clinical findings listed above, type 2 (moderate) exhibits two, and type 3 (mild) has one of the above findings and at least one of the following: an upper respiratory tract infection within the past 5 days, fever without any apparent cause, increased wheezing, increased cough, or a 20% increase in heart/respiratory rate above the baseline.

Clinical studies have shown that individuals with more severe ABECB are most likely to benefit from antibiotics, so recommendations for therapy of type 2 or 3 episodes usually do not involve antibiotics along with other modalities.82

Some of the most persuasive evidence supporting antibiotic therapy is a study of 173 patients with 362 exacerbations (identified as dyspnea, increased sputum volume, and sputum purulence). Sixty-eight percent of those receiving antibiotics improved, as compared to 50% improvement with placebo. For exacerbations that met only one criterion for ABECB, antibiotics conferred no clinical advantage; for those with two features, improvement was only marginal. When all three criteria were met, antibiotic recipients experienced greater success (63% vs 43%) and less deterioration (14% vs 30%).83 The microbiology of ABECB is variable and difficult to characterize. Pathogens isolated include viruses, C. pneumoniae, and M. pneumoniae. The roles of S. pneumoniae, H. influenzae, and M. catarrhalis remain controversial.84

Treatment involves inhaled anticholinergic bronchodilators, oral corticosteroids tapered over two weeks, oxygen or non-invasive positive pressure ventilation, and smoking cessation.85,87 Regarding the use of antibiotics, some clinicians remain critical about measured endpoints, a validated severity rating system, and sufficient participants in many studies. Investigators continue to seek better metrics and evidence-based antibiotic regimens. Short courses of three to five days' duration now are recommended by some authors. Croom and Goa provide support for the use of levofloxacin for 7 days with improved symptom resolution.86 Shorter regimens with the 750-mg strength may hold promise. Milstone et al demonstrated improved outcomes when treating with a 3-day course of azithromycin 500 mg po qd as opposed to standard therapy with a 5-14 day course of other agents.83 Researchers compared a 5-day course of cefuroxime 250 mg po bid to a 7-day course of clarithromycin 250 mg po bid and were able to demonstrate their approximate equivalence.88

Pneumonia. Pneumonia is caused by bacterial or viral infestation of the alveolar spaces through aspiration of oropharyngeal secretions, inhalation of infectious aerosols, or hematogeneous dissemination. Characteristic symptoms include fever and productive cough; headache, nausea, vomiting, diarrhea, myalgia, arthralgia, and/or fatigue also may occur. Physical findings may include tachypnea, rales, and signs of pulmonary consolidation. The bacterial pneumonias are responsive to many antibiotics; short-course therapy is advised only for community-acquired pneumonias (CAP)—those infections acquired outside of health care facilities.

CAP affects 2-3 million adults each year in the United States, and about 80% are treated in the outpatient setting.89 Causative organisms typically include S. pneumoniae, H. influenzae, Staphylococcus aureus, M. pneumoniae, and less commonly, Chlamydophila pneumoniae (previously known as Chlamydia pneumoniae), M. catarrhalis, Legionella species, aerobic gram-negative bacteria, influenza viruses, adenoviruses, and respiratory syncytial virus (RSV).90 

For the past decade, the newer macrolides have been advocated as monotherapy for CAP. This practice, and even the use of macrolides in combination with beta-lactams, now is under scrutiny. Approximately 20% of S. pneumoniae strains are resistant to macrolides, and penicillin resistance is a growing concern.91

Recommendations for duration of therapy in pneumonia vary widely, ranging from 3 days after the patient becomes afebrile to prolonged 1-2 week courses in complex clinical scenarios.92 Abbreviated courses are supported by the IDSA, which recommends antibiotic treatment until the patient has been afebrile for 72 hours.93 

Short-course therapy for CAP may be appropriate for patients without significant co-morbidities. In circumstances where macrolides are thought to be appropriate, azithromycin is attractive because of a uniquely prolonged half-life in the tissues that distinguishes it from other antibiotics. A five-day course (500 mg po x 1, followed by 250 mg qd x 4d) is as effective as 10 days of erythromycin.94 

The respiratory fluoroquinolones have emerged as an attractive choice for antibiotic therapy based on two characteristics. Levofloxacin exhibits concentration-dependent bactericidal activity, making it an ideal choice for short-course/high-dose regimens. The fluoroquinolones' therapeutic efficacy also is closely aligned with the ratio of the area under the concentration-time curve to the MIC.95 Capitalizing on these properties, Dunbar et al have shown that oral levofloxacin 750 mg per day for 5 days compares favorably to itself given 500 mg per day po or IV for 10 days.96 These early data are intriguing, but areas of concern in this study include criticism of the study design and the observation that the control group appeared to be clinically more severely ill than the study group.97 Additional investigation is under way, and clinicians soon will have many trials to review as they decide whether this application of the newer quinolones will gain widespread acceptance.

Gastrointestinal Infections

Diarrhea. Visitors to foreign shores face considerable risk of contracting gastrointestinal infections. High-risk destinations include Latin America, Asia, Africa, and the Middle East.98 According to the CDC, each year 20-50% of international travelers, an estimated 10 million individuals, develop traveler's diarrhea (TD). This ailment traditionally is defined as a disease acquired while traveling that manifests as passage of at least three unformed stools in a 24-hour period, nausea, vomiting, abdominal pain or cramps, fecal urgency, tenesmus, and bloody or mucoid stools.99 Individuals usually are affected for 3-5 days, but also may suffer symptoms up to 7-10 days after returning home.

Transmission of pathogens occurs primarily through the fecal-oral route, and prevention is the key to reducing the incidence of illness. The following recommendations have been made to reduce risk: 1) avoid eating raw or undercooked meat or seafood; 2) avoid eating raw fruits or vegetables, unless the traveler is able to peel them; and 3) avoid eating food or consuming beverages purchased from street vendors or other establishments where unhygienic conditions may be present.98,100

Contaminated water is the major source for the infections affecting tourists.100 Bacterial pathogens responsible for TD include enterotoxigenic Escherichia coli (ETEC) and species of campylobacter, shigella, and salmonella. ETEC is isolated most frequently; it causes disease through one or more heat-liabile and heat-stable toxins.101 Less common etiologies of traveler's diarrhea include viral and parasitic infections.

Although fluoroquinolones have long been the drugs of choice for diarrhea, recent concerns have surfaced regarding fluoroquinolone-resistant strains of TD pathogens, particularly Campylobacter jejuni.102 As a result, the primary suggested regimens for traveler's diarrhea are single-dose azithromycin (1 g po) or rifaximin 200 mg po tid x 3 days. Pediatric patients should receive the following modified dose: azithromycin 5-10 mg/kg x 1 dose. Levofloxacin 500 mg po x 1 dose is a secondary alternative.103 Rifaximin is a relative of rifampin; it will shorten the duration of traveler's diarrhea secondary to non-invasive bacterial pathogens and can reduce the occurrence of the disease when used as prophylaxis.104

Special considerations also must be made for pregnant patients, who are at increased risk of traveler's diarrhea because of decreased gastric acidity and increased intestinal transit time.105 Diarrheal illness in a pregnant traveler predisposes the patient to the potential of premature labor and shock. Pregnant patients should carry oral re-hydration packets during travel and use them at the first signs of dehydration secondary to diarrheal illness.106 Antibiotics such as tetracycline and quinolones (categories D&C) are contraindicated in pregnancy as is bismuth subsalicylate (category C). Those patients without penicillin allergy can be treated with ampicillin or amoxicillin, but many common enteric pathogens are resistant to these drugs.107

Antimicrobial prophylaxis regimens to prevent traveler's diarrhea include the following: ciprofloxacin 500 mg qd, norfloxacin 400 mg qd, ofloxacin 300 mg qd, doxycycline 100 mg qd, and TMP-SMX 160/800 qd. However, these regimens are not indicated routinely secondary to concerns about resistance and potential side effects of antibiotic usage.100 A low-cost alternative is bismuth subsalicylate (Pepto-Bismol); patients should be forewarned that common side effects include black tongue and dark stools. Certain individuals should not take bismuth subsalicylate. These include patients with aspirin allergies, pregnant patients, and those taking probenecid, methotrexate, or anticoagulants.99

Infections of Skin and Soft Tissue

Cellulitis. Skin and soft-tissue infections encompass a wide spectrum of pathology. Severity can range from trivial to life-threatening; those amenable to short-course therapy are classed as simple cellulitis in uncompromised hosts. Cellulitis is an infection of the subcutaneous and dermal tissues, most frequently caused by gram-positive organisms including Staphylococcus aureus or Group A beta-hemolytic streptococcus.108 In general, staphylococcal cellulitis tends to be more localized and purulent, while streptococcal cellulitis tends to spread rapidly and cause regional lymphadenitis.109 Cellulitis commonly presents on the lower extremity as tender, warm, erythematous, shiny, swollen skin without sharp demarcations.110

Various underlying circulatory or endocrine conditions predispose patients to cellulitic infections; these include peripheral vascular disease, lymphedema, and diabetes. Traumatic inoculation of skin bacteria from minor trauma, bites, or drug injection also may provide the nidus for infection. Uncomplicated cellulitis can be treated with a variety of oral and parenteral regimens, typically involving the penicillins, cephalosporins, macrolides, or clindamycin.111

Culture of organisms from cellulitis is notoriously difficult. Various studies examining fine needle aspirates of cellulitic tissue reveal a disease characterized by a strong inflammatory response with low bacterial yields.112,113 These findings support the concept that most subcutaneous bacteria may be eradicated within the first few days of antibiotic therapy, making an abbreviated course as effective as a standard 7-10 day course. One study has shown that a 5-day course of 500 mg qd of levofloxacin is as effective as a 10-day course.114 Macrolides, particularly azithromycin with its prolonged functional tissue half-life, also can be efficacious over a short course. Azithromycin in courses fewer than 7 days compares favorably to dicloxacillin,115 erythromycin, cloxicillin,116 and cephalexin.117 Short-course treatment with newer once-a-day agents may be less expensive than longer-duration therapy with traditional agents, even when the per-pill charges are higher. Clinicians should become familiar with regional drug prices and total prescription costs before settling on a regimen that confers the best combination of efficacy, compliance, and cost.

Urogenital Infections

Urinary Tract Infections. Urinary tract infections (UTIs) account for more than 7 million outpatient visits each year and affect 40-50% of American women at least once.118 These infections can be classified as uncomplicated or complicated, depending on host factors and the extent of organ involvement. Uncomplicated infection—also called acute cystitis—is found in non-pregnant women with normal urologic anatomy who have no features of upper tract or systemic involvement. Signs and symptoms of complicated infection include costo-vertebral angle tenderness, fever, or systemic illness. Infections occurring in men, pregnant women, patients with abnormal urologic anatomy, indwelling catheters, or frequent instrumentation also are defined as being complicated. Short-course antibiotic therapy is effective for uncomplicated UTI, but not recommended for any complicated infections.

The gram-negative rod E. coli is the most frequent urinary tract pathogen and is responsible for 80-90% of uncomplicated cases. Other pathogens also contribute, with Staphylococcus saprophyticus accounting for 5-10% of cases, and Proteus species, Enterococcus, and other gram-negative rods making up the remainder.119,120 Three-day oral antimicrobial therapy is a well-established treatment regimen for uncomplicated cystitis. While single-dose therapy once was considered appropriate, it has fallen out of favor because of a higher frequency of bacteriologic recurrence.121,122

Oral trimethoprim-sulfamethoxazole (TMP-SMX) is a standard therapy for uncomplicated UTI. When given in a twice-daily dosing regimen for three days, it has demonstrated cure rates of up to 95%. Single-dose therapy with TMP-SMX will cure up to 87% of patients, and is associated with lower rates of adverse events.123,124 Resistant strains of bacteria have been implicated in many common infections, and UTIs are no exception. There are increasing numbers of E. coli isolates resistant to TMP-SMX. Current recommendations by the IDSA call for the use of TMP-SMX in regions where E. coli resistance is less than 20%.124 When isolates are resistant in vitro, treatment with TMP-SMX still may result in bacterial cure rates up to 50%.123,126

The fluoroquinolones also have been extensively studied as short-course UTI therapy. Treatment with ofloxacin has efficacy similar to TMP-SMX. Ofloxacin is given as a single, daily 200-mg oral dose for three days.123,127-129 Ciprofloxacin also has been compared to short-course and 7-day treatment regimens of TMP-SMX and other quinolones. Doses as low as 100 mg BID are efficacious, but 250 mg twice daily for three days is the current recommendation.121,124,130 Most of the newer quinolones are assumed to have efficacy similar to that of ofloxacin and ciprofloxacin for treatment of UTIs. One known exception to this assumption is moxifloxacin, which has poor urinary excretion and is not recommended.

The phosphonic acid derivative fosfomycin is a single-dose option for treatment of uncomplicated cystitis. This urinary anti-infective is packaged as a water-soluble powder in a sachet and given as a single 3-g oral dose. It is less effective than TMP-SMX or the quinolones, but may be useful when other medications cannot be tolerated or patient compliance is in question.124,131 (See Table 2.)

Table 2. Recommended Short-Course Antibiotic Regimens for Uncomplicated UTIs

Vaginitis. Trichomonas vaginalis is a protozoan that is responsible for the urogenital infection trichomoniasis. While men with trichomonas urethritis often are asymptomatic, women may experience vaginal irritation and copious amounts of frothy yellow-green discharge with a distinct pungent smell. T. vaginalis may be seen on traditional microscopic examination of vaginal secretions or on microscopic urinalysis. Current recommendations for treatment include a single 2-g dose of metronidazole. With this dose, trichomonocidal levels remain in secretions for 24–48 hours, and cure rates exceed 95%.132-134

Bacterial Vaginosis. Overgrowth of normal vaginal flora, specifically Gardnerella vaginalis, causes bacterial vaginosis (BV). Diagnosis of BV is made by clinical presentation. (See Table 3.) While the CDC does not recommend single-dose or short-course antimicrobial therapy as a first-line treatment, a single 2-g dose of metronidazole is an alternative therapy that has been shown in some cases to be equivalent to a 7-day regimen. Single-dose therapy should be considered when compliance is an issue or when underlying ethanol use may interfere with the proper drug ingestion. Metronidazole has a disulfiram-like interaction with ethanol, and compliance with a week of therapy is particularly difficult for regular consumers of alcohol.135,136

Table 3. Clinical Parameters for Diagnosis of BV

Candida Vaginitis. Vulvovaginal candidiasis (VVC) is another common cause of vaginal irritation and infection. Approximately 75% of women in the United States will experience at least one episode of VVC. The CDC divides treatment options based on whether the infection is uncomplicated or complicated. Uncomplicated VVC, typically caused by Candida albicans, is characterized by sporadic or infrequent episodes that are mild to moderate in severity in immunocompetent women. Fluconazole 150 mg as a single oral dose has been shown to be effective in this setting. Like other single-dose therapies, the ease of dosing must be balanced against the increased cost of oral agents when compared to topical suppositories. There are many inexpensive short-course and single-dose intravaginal regimens.137-139 (See Table 4.) The CDC defines complicated VVC as severe local or recurrent VVC in an abnormal host such as a diabetic, or infection with a less sensitive fungus such as Candida glabrata. These cases require 10-14 day treatment with either oral or topical medications.

Table 4. Short-Course and Single-Dose Intravaginal Options for VVC

Sexually Transmitted Diseases

Gonorrhea. Neisseria gonorrhea continues to be an important pathogen, causing at least 330,000 infections in the United States in 2004.139 These infections are urogenital, ano-rectal, pharyngeal, and conjunctival. Occasionally, they are complicated by bacteremia and the syndrome of disseminated gonococcal infection. Localized infections are amenable to outpatient therapy, while bacteremia and musculoskeletal involvement typically requires inpatient or multiple-treatment outpatient regimens.

The emergence in 1975 of penicillinase-producing N. gonorrhea changed treatment strategies for gonorrheal infection.140 Cephalosporins and quinolones became the mainstays of therapy through the 1980s and 1990s. Developing resistance to quinolones in N. gonorrhea (QRNG) has once again dictated a change in approach. The rate of QRNG isolation has been increasing steadily worldwide since 1991, especially in the Far East, Middle East, and Pacific Islands. CDC guidelines now advise against fluoroquinolone use in cases thought to be contracted in these parts of the world.139 Additionally, CDC has established a gonococcal isolate surveillance project to track the number of QRNG cases in the United States. In 2004, the project revealed significant numbers of QRNG in Hawaii (22.8% in Honolulu), California (25% in Long Beach), and Washington (16.2% in Seattle). Isolates collected from the remaining states revealed a QRNG prevalence of only 3%. Current recommendations reflect these findings, and suggest alternative therapy in the high-prevalence states. CDC recommendations take into account a 23.8% prevalence of QRNG isolates from men who have sex with men, regardless of geography. Fluoroquinolones are not recommended for treatment of these patients.139-146

Ceftriaxone is an efficacious and well-established treatment for gonorrheal infections. A single 125-mg intramuscular injection has been shown to be 98-100% effective in uncomplicated urogenital and ano-rectal gonorrhea. Pharyngeal gonorrhea is more difficult to eradicate, but 125 mg of ceftriaxone is effective in at least 86% of cases in small studies. For gonorrheal conjunctivitis, the CDC recommends 1 g of ceftriaxone based on a small study noting high cure rates with this therapy.143-151

The cephalosporin cefixime provides an oral alternative to ceftriaxone. While studies have shown that this antibiotic does not maintain a higher sustained bactericidal level, it still has a cure rate of 96.4% with a single 400-mg oral dose in uncomplicated urogenital or ano-rectal infections. When available, cefixime may be a more attractive treatment option due to the ease of oral dosing and decreased overall cost compared to ceftriaxone.143 Unfortunately, it no longer is distributed widely in the United States.

The fluoroquinolones are the only oral alternative to cefixime for single-dose therapy of gonorrhea. As previously noted, they are no longer recommended in certain circumstances and geographic areas. The CDC still does recommend them, however, for uncomplicated infections in patients at low risk for QRNG. Doses are ciprofloxacin 500 mg, ofloxacin 400 mg, or levofloxacin 250 mg. Efficacy has been reported between 96% and 98% for these medications in the appropriate clinical and epidemiologic settings.152-156

The final alternative for uncomplicated gonorrheal infections is a single 2-g IM dose of spectinomycin. Due to the higher cost and the lower bactericidal concentrations achieved, it should be used only in patients who cannot tolerate other agents.157

Chlamydia. Chlamydia trachomatis is a common cause of non-gonococcal urethritis and cervicitis in women and non-gonococcal urethritis in men. The incidence of chlamydial infections has been increasing in recent years, with nearly 900,000 cases reported in the United States in 2003. This represents a 5% increase over 2002.158 The only currently recommended single-dose therapy is 1 g of azithromycin orally. Single-dose azithromycin has been found in several studies to be equally efficacious to the traditional 7-day course of doxycycline. Azithromycin is a more costly alternative and can cause gastrointestinal distress and loose stools. However, observed single-dose therapy assures appropriate treatment. When weighed against the consequences of insufficient therapy, single-dose azithromycin may be the wisest alternative for a population in whom compliance is questionable.159-161

Chancroid. Chancroid is a sexually transmitted disease caused by Hemophilus ducreyi. It characteristically manifests as necrotizing genital ulceration with buboes. While not often seen in the United States, it is endemic to the Caribbean, Southeast Asia, and Africa. Genital ulcerations have been shown to be a major contributor to HIV transmission, which is epidemic in the parts of the world where chancroid commonly occurs.162-164 Recommendations for the treatment of chancroid are the same from the World Health Organization and the CDC. Both advocate single-dose IM therapy with 250 mg of ceftriaxone. A single 1-g oral dose of azithromycin or 500 mg of ciprofloxacin twice a day for three days also is effective. Patients with chancroid also benefit symptomatically from aspiration of fluctuant buboes.157,164-170

Syphilis. Syphilis is a sexually transmitted disease caused by the spirochete Treponema pallidum. It is clinically manifest in three stages. Primary syphilis presents as a chancre that develops at the original inoculation site. An asymptomatic period often ensues after chancre resolution, followed by the secondary stage characterized by generalized rash, mucocutaneous ulcers, and lymphadenopathy. The term "early syphilis" refers to primary and secondary syphilis and includes the time period up to one year following the resolution of secondary lesions. Late or tertiary syphilis is defined as the stage greater than one year from the secondary outbreak, including those patients with cardiac, neurological, or ophthalmic involvement or gummas. Single-dose treatment is indicated only for early syphilis.

Penicillin is the treatment of choice for T. pallidum infection. The current recommendation for early syphilis is a single IM dose of 2.4 million units of benzathine penicillin G.157 Although most of the data supporting penicillin therapy derives from case series and clinical experience in the early days of antibiotic use, recent work continues to verify its efficacy. An additional advantage of penicillin therapy is that a single dose of 2.4 million units of benzathine penicillin also will prevent a syphilis infection from developing in patients who have been exposed but are not yet symptomatic. Despite some evidence suggesting efficacy, there is no recommended role for treatment with combined formulations of procaine and benzathine penicillin.171-173

Azithromycin in a single 2-g dose has been investigated as therapy for early syphilis. A randomized trial published in 2005 showed cure rates equivalent to benzathine penicillin for primary and early latent syphilis.174 Azithromycin thus may provide an alternative option for patients with penicillin allergy. However, resistance of T. pallidum to azithromycin is emerging in parts of the United States, so close follow-up with repeat serology is advised for any patient receiving this therapy. Widespread use of the drug may contribute to increased development of resistance, so ongoing surveillance will be necessary. Azithromycin has no role in the treatment of syphilis in pregnant or HIV-infected patients.174-179

Advances in pharmacology and improved understanding of pathophysiology are leading to changes in dosage and duration of therapy for common infections. Short-course regimens are safe, convenient, and effective in a variety of clinical circumstances.

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