Antibiotic Update 1998: Part 2Matching Drugs with Bugs
Author: Gideon Bosker, MD, FACEP, Associate Clinical Professor, Department of Emergency Medicine, Oregon Health Sciences Center, Portland, OR. Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine.
Peer Reviewers: Norman C. Christopher, MD, Director, Emergency and Trauma Services, Children’s Hospital Medical Center of Akron, Akron, OH; Stephen P. Ernst, PharmD, Clinical Pharmacy Coordinator, Columbia Terre Haute Regional Hospital, Terre Haute, IN; Jonathan Edlow, MD Clinical Director, Beth Israel and Deaconess Medical Center, Boston, MA; Instructor in Medicine, Harvard Medical School, Cambridge, MA; Albert Weihl, MD, Emergency Medicine Residency Program Director, Yale-New Haven Medical Center, Section of Emergency Medicine, Department of Surgery, Yale University School of Medicine.
Editor’s NoteThis issue concludes the second of our two-part series: Antibiotic Update 1998. The focus is on helping the practitioner choose the most appropriate antimicrobial agents for common clinical conditionsmatching the drugs with the bugs.
Outcome-Effective Antibiotic Selection
Recommendations for the empiric antibiotic therapy of bacterial infections are listed in Table 1. In addition, selected comments on some of the common indications for antibiotic therapy follow.
Community-Acquired Pneumonia. A variety of antibiotics are available for outpatient management of pneumonia. Although the selection process can be daunting, as mentioned, a sensible approach to antibiotic selection for patients with pneumonia is provided by treatment categories for pneumonia generated by the Medical Section of the American Lung Association, and published under the auspices of the American Thoracic Society.1 This classification scheme will not only help make clinical assessments useful for guiding therapy, but it is also predictive of ultimate prognosis and mortality outcome. (See Table 2.)
The most common pathogens responsible for causing community-acquired pneumonia include the typical bacteria: S. pneumoniae, H. influenzae, and M. catarrhalis, as well as the atypical pathogens: Mycoplasma, Legionella, and Chlamydia pneumoniae.2 H. influenzae and M. catarrhalis are both found more commonly in patients with COPD. Clinically and radiologically, it is difficult to differentiate between the typical and atypical pathogens; therefore, coverage against all these organisms may be necessary. In patients producing sputum-containing polymorphonuclear leukocytes, the sputum Gram’s stain may contain a predominant organism to aid in the choice of empiric therapy. For most patients, therapy must be entirely empiric and is based on the expected pathogens.3,4
It must be understood that outpatient therapy for pneumonia is almost always empiric in nature. Hence, for the vast majority of otherwise healthy patients who have community-acquired pneumonia, but who do not have comorbid conditions and who are deemed well enough to be managed as outpatients, therapy directed at S. pneumoniae, H. influenzae, M. pneumoniae, and M. catarrhalis is appropriate. In these cases, one of the newer macrolides, such as azithromycin or clarithromycin, should be considered the initial agent of choice. The extended spectrum quinolones, levofloxacin and sparfloxacin, provide similar coverage and are also approved as initial therapy in this patient subgroup. Because of their excellent in vitro activity against S. pneumoniae, the use of levofloxacin and sparfloxacin should be strongly considered as initial therapy in urban areas where surveillance studies demonstrate a high incidence of macrolide-resistant S. pneumoniae species.
For the older patient with CAP who is considered stable enough to be managed as an outpatient, but in whom the bacterial pathogen list may also include gram-negative aerobic organisms, the combined use of a second-generation cephalosporin or amoxicillin-clavulanate plus a macrolide, or an advanced quinolone such as levofloxacin or sparfloxacin, is recommended. The advanced quinolones may be used as monotherapy, and, therefore, provide convenience and cost advantages in this high-risk subgroup. In those unusual cases in which a definitive, specific, etiologic diagnosis can be made (e.g., Mycoplasma, C. pneumoniae, Legionella species), agents with known activity against these organisms should be employed.
Some experts emphasize that in non-smoking adults without COPD (i.e., patients at a low risk for having H. influenzae), therapy with erythromycin should be strongly considered.4 This is a matter of clinical judgment, but in any event, the newer macrolides, azithromycin and clarithromycin, are recommended in cases of erythromycin intolerance. In patients with COPD, TMP-SMX or doxycycline usually provides adequate coverage against S. pneumoniae and H. influenzae, but TMP-SMX will not cover atypical pathogens. Except for the newer quinolones such as levofloxacin and sparfloxacin, empiric use of the older quinolones is not recommended for treatment of community-acquired respiratory infections, primarily because of their variable activity against S. pneumoniae and overly broad gram-negative coverage. Although the older quinolones should generally not be used for the empiric treatment of community-acquired pneumonia, they may provide an alternative therapy for treatment of bronchiectasis, particularly when gram-negative organisms such as Pseudomonas are cultured from respiratory secretions.5
The use of levofloxacin as a first-line drugin particular, as a substitute for the advanced generation macrolidesto treat uncomplicated community-acquired pneumonia or acute bacterial exacerbations of COPD in patients less than 60 years of age is more questionable and has become a matter of intense debate. Determining which of these antibioticsmacrolides vs. quinolonesshould be considered "workhorse" drugs in the primary care setting for treating bacterial "bugs and crud" above the belly button requires a thoughtful analysis that includes cost, convenience, spectrum, and potential for inducing resistance as part of the drug selection equation.
With its once-daily, minimum duration seven-day course, levofloxacin has dosing and duration advantages as compared to the macrolide clarithromycin, which requires 20 doses over 10 days. Moreover, the seven-day course of levofloxacin is comparatively priced with clarithromycin. Based on this analysis, but excluding the potential pitfalls associated with "broad" or, so-called, "over-extended" (i.e., not absolutely necessary gram-negative) spectrum of coverage, levofloxacin appears to provide a very reasonable alternativeand, perhaps, even a slight advantageto clarithromycin in managing patients with CAP.
In the case of azithromycin, however, its five-day duration of therapy, $39-$42 cost per course of treatment, and targeted coverage of S. pneumoniae, H. influenzae, M. catarrhalis, and M. pneumoniae, must be weighed against levofloxacin’s 7-14 day duration of therapy, its $68-$82 cost per treatment course, and the fact that its spectrum of coverage includes not only the appropriately targeted, aforementioned organisms commonly implicated in CAP, but extensive activity against gram-negative organisms, to which resistance may develop with indiscriminate use.
It appears, then, that when gram-negative coverage of Klebsiella and other species is not required, the advanced generation macrolide azithromycin may still represent a more prudent, less costly choice as initial therapy, especially in individuals less than 60 years of age. However, in the older patient, in whom gram-negative infection is more of a concernas well, as in areas in which there is a high prevalence of S. pneumoniae resistancethe newer quinolones are an important alternative to two-drug combinations, especially in the elderly patient where spectrum of coverage may be especially important.
Finally, there is an increasing problem in the United States concerning the emergence of S. pneumoniae that is relatively resistance to penicillin and, less commonly, to extended-spectrum cephalosporins (see below). These isolates are often also resistant to macrolides, sulfonamides, and tetracyclines.6-8 Except for vancomycin, the most favorable in vitro response rates to S. pneumoniae have been observed with the advanced macrolides and, more recently, with extended spectrum quinolones, especially sparfloxacin. Thus far, the majority of lower respiratory tract infections respond to standard therapy, though there have been profound implications for the empiric treatment of meningitis. Therapy for upper respiratory tract infections, such as sinusitis and otitis media, as well as for lower respiratory tract infections may be dramatically affected in the future if these mechanisms of resistance become more common.
Bacterial Exacerbations of Chronic Obstructive Pulmonary Disease (COPD). Chronic obstructive pulmonary disease (COPD) affects approximately 20% of all adults and is the fourth leading cause of death in the United States.9 Exacerbations of COPD are usually manifested by an increase in cough, change in quantity or color of sputum, or worsening dyspnea and may lead to hospitalization. There are numerous possible causes of exacerbations of COPD, but infection is one of the most common identifiable etiologies. As a result, antibiotics have become a mainstay in the of treatment of patients with this disorder. Despite the widespread use of antibiotics in this setting, their efficacy remains somewhat uncertain.
In a recent report, academic investigators performed a widespread literature search in order to conduct a meta-analysis to answer the question, "Are antibiotics beneficial in patients with COPD exacerbations?"9 English language studies published in the last 40 years were included in the analysis if they were randomized trials comparing antibiotic to placebo in patients thought to be having an exacerbation of COPD and had follow-up for at least five days. Nine studies were included (230 studies were excluded for a variety of reasons), but there were no uniform outcome measures for all the trials.
These trials were conducted in both the outpatient and inpatient settings. The earliest trial included was from 1957, and the most recent was from 1992. Seven of the nine trials showed a benefit of antibiotics over placebo with the overall effect size indicating a small benefit in the antibiotic treated group. In six trials in which peak expiratory flow rates (PEFR) were one of the outcome measures, the summary effect size was also small, with a summary change in PEFR of 10.75 L/min in favor of the antibiotic treated group, which is small, but can be clinically significant, particularly in COPD patients with low baseline PEFR.
Exacerbations of COPD are commonly seen in the outpatient setting and, not infrequently, lead to hospitalizations. Infection is believed to be a common cause of exacerbations, although they are often difficult to document definitively. Based on the evidence in this meta-analysis study, antibiotics should be used in this setting, although the benefit appears to be relatively small. Nevertheless, agents that cover common respiratory pathogens such as Streptococcus pneumoniae, Hemophilus influenzae, Moraxella catarrhalis, and, perhaps, atypical organisms (chlamydiae, legionella) are reasonable for this problem. (See Table 3.)
The shortest and most convenient regimens include azithromycin or levofloxacin, whereas the least expensive regimens include TMP-SMX or doxycycline. In addition to antibiotics, avoidance of airway irritants (tobacco, allergens), use of bronchodilators and systemic or inhaled corticosteroids are mainstays in the treatment of patients with exacerbations of COPD.
Upper Respiratory Tract Infection. Although penicillin remains the drug of choice in the treatment of pharyngitis caused by S. pyogenes, it appears that the newer cephalosporins and macrolides may yield a superior bacteriologic eradication rate and, possibly, a decreased relapse rate.10,11 Since the prevention of rheumatic fever requires eradication of the infecting Streptococcus, the newer cephalosporins and the macrolides are assumed to be at least as effective as penicillin in achieving this goal. The more convenient dosing schedule of these newer agents may enhance compliance.
The most common etiologies of acute sinusitis include: S. pneumoniae, H. influenzae, M. catarrhalis, and a variety of less common organisms. Many antibiotic regimens have been shown to yield the expected bacteriologic cure rate of greater than 90%.12 Interestingly, a recent trial using TMP-SMX in the treatment of acute sinusitis indicates that a shorter treatment duration of three days may be as effective as a traditional 10-day course for selected patients with mild infections.13 (See Figure 1.)
Otitis Media in Children. The most commonly isolated bacterial pathogens in both acute and recurrent otitis media are S. pneumoniae, H. influenzae (nontypable), and M. catarrhalis.14,15 Although there are studies that show high spontaneous cure rates in mild to moderate cases of acute otitis media, treatment with antibiotics is still the standard of care in the United States. Unfortunately, drug resistance among bacteria involved in otitis media is rapidly emerging.15,16 In this regard, beta-lactamase production is common among isolates of H. influenzae and M. catarrhalis, rendering about 30-50% of H. influenzae and up to 80% of M. catarrhalis isolates resistant to ampicillin.17
Although variable from patient to patient and region to region, these emerging resistance patterns may explain the failure rates associated with such traditional therapeutic measures as amoxicillin.15,16 Accordingly, the evolution of antibiotic-resistant bacterial strains implicated in otitis media has fueled interest in alternatives to amoxicillin, which, primarily because of its cost, has been the traditional first-line agent for this infection, despite showing increasing resistance. This problem can be circumvented by adding a beta-lactamase inhibitor such as clavulanic acid to amoxicillin (i.e., amoxicillin/clavulanate) or by choosing alternative antibiotics, among them, azithromycin, loracarbef, and second-generation cephalosporins.
Without question, as previously emphasized in the case of CAP for adults, a most disturbing trend is the emergence of penicillin-resistant S. pneumoniae. Although the incidence of resistant strains demonstrates regional variations, the continued prevalence of S. pneumoniae as the principal etiologic agent in otitis media has important therapeutic implications, especially in light of the trend toward emergence of penicillin- and cephalosporin-resistant strains of this organism. From a clinical perspective, it should be emphasized that the development of penicillin-resistant strains has been associated with increased resistance to other beta-lactam antibiotics, including amoxicillin, cefaclor, cefuroxime, and cefixime, as well as the non-beta-lactam antibiotics TMP-SMX and erythromycin.18,19
Based on currently available studies, about 25% of S. pneumoniae isolates obtained by tympanocentesis from patients with otitis media in various regions of the United States demonstrated intermediate or complete resistance to penicillin. Currently, intermediate or complete resistance to the advanced macrolides, azithromycin and clarithromycin, has been identified in about 5-8% of S. pneumoniae isolates, as compared to 10-25% of isolates shown to be resistant to such antibiotics as penicillin, amoxicillin, cefixime, TMP-SMX, and other cephalosporins.14-16
These findings suggest that in vitro resistance patterns to S. pneumoniae are one factor that should be considered in the selection process of an antibiotic for treatment of otitis media. (See Table 4.) The only antibiotic to which drug resistance has not been found is vancomycin.
Urinary Tract Infection. Cystitis, urethritis and pyelonephritis, and prostatitis are common infections managed in the primary care setting. An estimated 10-20% of women are afflicted at some point with a urinary tract infection (UTI), and the incidence in older men approaches that of women.20 The development of new antibiotic agents, streamlining of the standard of care for young females with suspected UTI, and the recognition that a wide array of clinical and microbiologic entities can present with dysuria have led to a change in the approach to patients with UTI.
Acute cystitis and subclinical pyelonephritis are common in young females and are often impossible to distinguish clinically. Up to 25% of women presenting with the classic symptoms of lower UTIs actually suffer from "subclinical" pyelonephritis. Enterobacteriaceae (predominantly E. coli) account for 80% and Staphylococcus saprophyticus account for 10-15% of UTIs in young women when sexually transmitted pathogens are excluded. The precise etiology of UTIs in an individual patient may be difficult to determine. In one study, only 66% of young women presenting to a family practice setting with urinary tract symptoms could be assigned a specific microbiologic diagnosis despite an extensive work-up.20
In young women, acute cystitis and urethritis occur in the absence of classical criteria for bacteriuria (105 bacteria per mL of urine) in as many as 50% of cases.20-22 The constellation of dysuria, frequency, and pyuria in the absence of "significant" bacteriuria has been termed the acute urethral syndrome. In many cases, this syndrome is caused by low level infections with E. coli (102-104 organisms per mL) or with a sexually transmitted pathogen such as Chlamydia trachomatis. The modern standard for a positive urine culture in a patient with dysuria is now widely accepted to be 102 rather than 105 organisms per mL.
Sexually transmitted pathogens can cause urethritis, vaginitis, and prostatitis, conditions that can clinically mimic the infections of classic uropathogens such as E. coli. Microorganisms including Trichomonas vaginalis, Neisseria gonorrhoeae, C. trachomatis, and Ureaplasma urealyticum are common offenders. Urethritis and epididymitis caused by sexually transmitted pathogens are increasingly common among promiscuous males, and UTI may be associated with HIV or herpes virus infection. With advancing age, the rate of UTI in males approaches that seen in females and is often associated with prostate disease. Some unusual pathogens of iatrogenic origin are also found in the elderly. Pseudomonas and Staphylococcus species are associated with urinary tract manipulation, and enterococcus is found in patients who had previously received cephalosporin antibiotics.
Asymptomatic bacteriuria is diagnosed when more than 105 colonies of a single bacterial species are recovered on two consecutive urine cultures in patients without symptoms. In most of these patients, antibiotic therapy does not yield any lasting benefit. During pregnancy, however, asymptomatic bacteriuria occurs in as many as 30% of women and commonly leads to full-blown pyelonephritis if left untreated. Often, these infections are caused by Streptococcus agalactiae, a common flora of the female genitourinary tract that has been associated with premature delivery, neonatal sepsis, and postpartum endometritis. Asymptomatic bacteriuria can also be found in as many as 33% of residents of skilled nursing facilities, and may be a nidus for sepsis in some. Antibiotic treatment in these patients is usually followed by relapse of bacteriuria, and it is therefore not routinely recommended.
The majority of uncomplicated urinary tract infections, the diagnosis of which will usually not require cultures, are caused by E. coli. However, insomuch as up to one-third of E. coli are resistant to amoxicillin, this antibiotic can no longer be recommended for treatment. In contrast, TMP-SMX is reliably active and is considered the treatment of choice. A recent trial concluded that a three-day regimen of TMP-SMX was more effective and less expensive than three days of nitrofurantoin, amoxicillin, or cefadroxil in the treatment of uncomplicated cystitis in women.23 A new oral antibiotic, fosfomycin, is approved for single dose therapy, costs about $22, and has a success rate of about 70%.
In general, broader-spectrum agents offer no distinct advantage and are considerably more expensive than such agents as TMP-SMX. Nevertheless, it should be stressed that the quinolones play a major role in the treatment of urinary tract infection, especially when allergy or intolerance, bacterial resistance, or complicated infection is present. The optimum duration of therapy for uncomplicated cystitis appears to be three days; however, a seven-day course is indicated in patients with diabetes, in individuals with more than seven days of symptoms, a history of recent urinary tract infection, diaphragm use, age greater than 65 years, and in pregnant women.
As emphasized, for pyelonephritis, 14 days of therapy with TMP/SMZ, a fluoroquinolone, or a third-generation cephalosporin is indicated.20,22 Treatment of asymptomatic bacteriuria is unnecessary except during pregnancy. Pregnant women should have a urinalysis and culture at their first prenatal visit and urine dipsticks during the course of pregnancy. Asymptomatic bacteriuria should be treated with 10 days of antibiotics and followed closely to assure that relapse does not occur. Antibiotics that are considered non-teratogenic include any of the beta-lactams, nitrofurantoin, and sulfasoxazole. Trimethoprim and quinolone antibiotics should not be used in pregnant patients.
In sexually active patients, dysuria and pyuria may represent urethritis secondary to N. gonorrhoeae or chlamydia. A history of similar symptoms in a sexual partner or the presence of vaginal discharge may provide additional clues and prompt the appropriate genitourinary cultures. Some cases of acute urethral syndrome in females and most cases of epididymitis in young males are caused by chlamydia, which can be effectively treated with a seven-day course of doxycycline (100 mg bid). Trimethoprim and the fluoroquinolones have excellent penetration into inflamed prostatic tissue, making them excellent choices in elderly males where recurrent UTI is often associated with prostatitis. Nevertheless, relapses are common even after a month of antibiotic therapy.
Recurrent episodes of UTI may require a urologic evaluation for underlying problems such as urinary tract obstruction or stone disease. If no precipitating factors are discovered, prophylactic therapy should be considered. A nightly dose of 50 mg nitrofurantoin or 1 DS TMP/SMZ every other night will prevent recurrence in 90% of such patients. In a randomized, double-blind, placebo-controlled trial over eight months involving 93 postmenopausal women, investigators demonstrated that topical, intravaginal estrogen cream (0.5 mg estriol cream once each night for 2 weeks followed by 2 times per week for 8 months) led to a profound reduction in the rate of recurrent UTI and overall antibiotic use.20,22,24 The mechanism appeared to be related to favorable alterations in vaginal pH and vaginal bacterial flora with increased presence of lactobacilli and reduced presence of Enterobacteriaceae.
Sexually Transmitted Diseases. Uncomplicated gonorrhea is treated with single-dose therapy. There are a variety of effective regimens based on quinolones, cephalosporins, and the macrolide azithromycin that vary considerably in cost. (See Table 5.) Chlamydia must always be empirically treated along with gonorrhea. The importance of effective communication in enhancing compliance with medication regimens cannot be overemphasized.21 Current standards of care for the sexually transmitted diseases have been recommended by the CDC.25 Because significant noncompliance has been reported with doxycycline, one-dose therapeutic modalitiesazithromycin 1 gm po once for uncomplicated chlamydial infection and a choice of several agents for uncomplicated GCare preferred. (See Table 6.)
The chlamydia problem deserves special attention. From an emergency therapeutics perspective, what is instructive about the chlamydial epidemic is the fact that, to a significant extent, it has grown significantly, in large part because of poor compliance with the traditional, seven-day bid doxcycline regimen, which has been the weak link between the prescription pad and optimal clinical outcome.26 In one "real world" study, only 65% of all patients prescribed a seven-day course of doxycycline therapy reported sufficient intake of the antimicrobial to achieve clinical cure of their chlamydial infection.26-28 When this occurs, a significant percentage of patients will return for retreatment because of noncompliance-mediated therapeutic failures. In addition, these patients are at risk for infecting other partners who must also access the healthcare system for treatment. The end result is "turnstyle STDs," a phenomenon in which pharmacologic reservicing for STDs and PID is required because of therapeutic failures associated with inadequate adherence to medication regimens. These observations strongly support the use of single dose therapy given under supervision, on site, for treatment of uncomplicated chlamydial infections.
Pelvic Inflammatory Disease. Pelvic inflammatory disease (PID) is a term that is most commonly used to describe infection of the uterus, fallopian tubes, and adjacent pelvic structures that is not associated with surgery or pregnancy. An estimated 1 million women per year are diagnosed with PID, a condition that is particularly common and problematic among lower socioeconomic groups in urban areas.28-31
In addition to the acute manifestations of the infection, long-term sequelae such as ectopic pregnancy and infertility occur in 25% of cases.26-28 In 1994, the direct and indirect costs of the disease and its complications were estimated to be greater than $4 billion. In view of the impact of this infection, a systematic approach to diagnosis and therapy is mandatory for all primary care practitioners who encounter patients with this condition and its related complications.
In virtually all cases, PID results from ascending spread of organisms from the cervix and vagina to the upper genital tract. Sexual transmission of Neisseria gonorrhea and/or Chlamydia trachomatis account for more than half of all cases of PID, but H. hominis and other organisms have also been implicated.28-30 N. gonorrhea is the major cause of PID in urban areas, where gonococcal infection is prevalent, whereas C. trachomatis is responsible for a greater proportion of cases among college students, in whom gonococcal infection is less common. Organisms such as E. coli and other enteric pathogens, as well as pathogens from the vaginal flora, also may cause PID, particularly when the normal vaginal flora (lactobacilli) are supplanted with other organisms. However, infection in the upper genital tract does not always result in clinically recognizable disease; indeed, many women with adverse sequelae associated with PID, such as infertility, have no known history of the disease.28-30
In one prospective study, infertility due to tubal occlusion occurred in 8% of women after one episode of PID, in 19.5% after two episodes, and in 40% after three or more episodes.24 Furthermore, as previously mentioned, many cases of PID are clinically silent, but as many as 70% of women who are infertile due to tubal obstruction have serum antibodies against chlamydia vs. only about 25% of women who are infertile for other reasons.27,29,31
A high index of suspicion and a low threshold for initiating treatment are important for facilitating detection and appropriate management. This approach should be applied to all women of child-bearing age with pelvic pain. Although laparoscopic visualization of inflamed fallopian tubes and pelvic structures is possible and, according to some experts, serves as a "gold standard" for the diagnosis, it is seldom practical. As a rule, the physician must initiate antibiotic therapy on clinical grounds, despite its limitations. In addition to the clinical symptoms, lower abdominal tenderness, adnexal tenderness, and pain on manipulation of the cervix are present in physical examination in up to 90% of women.28,30,31 Other manifestations, such as elevated erythrocyte sedimentation rate or C-reactive protein and abnormal vaginal discharge vary widely in frequency. At present, there are no effective ways to detect clinically silent disease.
Because new and highly effective treatment regimens have been introduced for PID, physicians now have a number of therapeutic options available for managing these problematicand, frequently, poorly compliant patients with STDs and PID.32-34 In this regard, the CDC recommend a number of possible regimens, most of which mandate the use of a broad-spectrum cephalosporin administered parenterally (initially) along with an oral agent effective against chlamydia such as doxycycline. Commonly used regimens for inpatient treatment of PID include the combination of cefoxitin, ceftriaxone, or cefotetan plus doxycycline; plus intravenous metronidazole followed by oral therapy with metronidazole plus doxycycline; gentamicin plus clindamycin; and intravenous ampicillin-sulbactam plus doxycycline.
As previously described, the oral formulation of azithromycin has been indicated for uncomplicated urethral and endocervical chlamydial infections and offers the unique advantage of efficacy with a single dose of 1 g po. Recently, however, efficacy and safetyas well as FDA approvalhave been established for intravenous azithromycin therapy followed by oral azithromycin for the treatment of PID.
One study evaluated results in a total of 221 women with PID treated with the following regimens: 1) azithromycin monotherapy (administered as 500 mg IV as the initial dose on day 1, followed by 250 mg daily for 6 additional days); 2) azithromycin in combination with metronidazole; and 3) metronidazole (either intravenous metronidazole 500 mg bid on day 1 followed by oral administration of 500 mg bid for 11 days or oral administration of 500 mg bid for 12 days), plus doxycycline (100 mg po bid ´ 14 days), plus cefoxitin (2 g IV or IM) with probenecid 1 g on the first day of treatment.35,36
In an intent-to-treat analysis conducted 15 days after therapy with these regimens, 93% of the patients receiving azithromycin alone, 94% of patients receiving azithromycin plus metronidazole, and 93% of those receiving the triad of cefoxitin, doxycycline, and metronidazole were either cured or improved.36 The bacteriologic eradication rates for all all three regimens were in the 93-95% range. Azithromycin was well-tolerated in patients with PID. The most common side effects were diarrhea (8.5%) and nausea (6.6%). The addition of metronidazole to azithromycin increased slightly the incidence of gastrointestinal side effects, with 10.3% reporting nausea, 3.7% abdominal pain, and 2.8% vomiting.36
Based on these data, azithromycin IV (500 mg qd for 1 or 2 days) followed by oral azithromycin 250 mg po qd to complete a total of seven days of therapy should be considered a primary treatment modality for managing patients who require initial intravenous therapy for PID caused by C. trachomatis, N. gonorrhoeae, or M. hominis. The timing of the switch from intravenous to oral therapy should be made by the physician, who should make this decision based on clinical parameters. Moreover, it should be stressed that when anaerobic infection is strongly suspected to play an etiologic role in any individual patient with PID, the physician should combine an antimicrobial agent such as metronidazole that provides anaerobic coverage along with azithromycin.
Although many patients with PIDespecially those who appear to be systemically toxic, have abdominal rebound tenderness, have WBC counts greater than 15,000, have a unilateral mass suggestive of tubo-ovarian abscess, have a history or profile indicating risk for poor medication compliance, are in the adolescent age group, and those in whom preservation of fertility is a high prioritywill require hospitalization, a significant percentage can be treated with initial IV or IM therapy, followed by oral therapy out of the hospital to complete the antimicrobial course.
Current options for out-of-hospital management of mild PID include the well-established regimen of ceftriaxone 500 mg IM, followed by doxycycline 100 mg po bid ´ 14 days with or without metronidazole 500 mg po tid for 10-14 days. With approval of the azithromycin IV/oral sequenced combination regimen outlined above, it is now possible to streamline therapy for PID into a seven-day course and substantially reduce the number of oral doses required to complete the treatment course. The practical implications are as follows: If, on the basis of the clinical findings, the physician deems that a patient with mild PID can be managed out of the hospital, and that a single intravenous dose of azithromycin is sufficient prior to oral therapy, then azithromycin should be administered as an infusion at a rate of 2 mg/mL over one hour, or 1 mg/mL over three hours. Azithromycin IV should always be infused over a period of not less than one hour and should never be administered by bolus or intramuscular injection. If patients with PID have signs and symptoms that suggest the need for more than one intravenous dose, hospitalization will usually be necessary.
The one-hour minimum infusion time required for this antibiotic is not as convenient as the IM route of administration required for the ceftriaxone (plus oral doxycycline) regimen. However, the post-parenteral therapy phase of the azithromycin treatment regimen (which requires only an additional 6 days of oral therapy following the IV dose) is considerably more convenient and compliance-enhancingboth with respect to daily dose frequency and duration of therapythan the ceftriaxone regimen, which requires consolidation with 28 oral doses of doxycycline over a 14-day period. In a patient population at high risk for noncompliance, the azithromycin regimen offers a potential window of opportunity that should be considered in this difficult patient population.
All women seen with suspected or confirmed PID require a pregnancy test to determine appropriate management. If present, intrauterine devices should be removed once antibiotic therapy is initiated. Close follow-up of outpatients within 24-48 hours after treatment is started is important. Failure to improve indicates the need for reassessment of the diagnosis (using laparoscopy, ultrasonography, or hospitalization) rather than a change in antibiotic therapy.
Male sexual partners of patients with PID need to be evaluated; this should include examination for sexually transmitted infections other than chlamydial and gonococcal disease, although, as a minimum, they must be treated for these two infections. Women who have had PID should be advised against the use of intrauterine devices and to protect themselves as much as possible against subsequent sexually transmitted infection to reduce their likelihood of infertility and other long-term sequelae. In women with concomitant HIV infection, hospitalization and intravenous therapy are indicated.
Skin and Skin Structure Infections. The majority of uncomplicated skin and skin structure infections are caused by staphylococci and streptococci. Conventional treatment with cephalexin or dicloxacillin is highly effective; the newer agents should be reserved for resistant organisms. Diabetic foot infections are more frequently polymicrobial, and common offending agents include anaerobes, gram-positive organisms, and gram-negative bacteria. Consequently, treatment is often empiric. In the outpatient setting, an oral quinolone (plus clindamycin when anaerobic and enhanced gram-positive activity is required) is an appropriate first-line agent.
The newer oral cephalosporins, quinolones, and macrolides often have an extended in vitro spectrum of activity, more desirable side-effect profiles, and improved pharmacokinetic patterns compared to older, conventional antibiotics. Frequently, there is a price to pay for such advances and advantages, including higher acquisition cost and increasing selective pressure for the emergence of resistant organisms. Although many common bacterial infections can usually be treated successfully with standard agents at a reduced cost, there are many circumstances when total outcome costs will be reduced by employing antibiotics with a shorter duration of therapy, less frequent daily dosing, and a more targeted spectrum of coverage that encompasses the most likely etiologic agents in specific patient subgroups. In particular, patient compliance with medications must always be considered when prescribing antibiotics.
References
1. American Thoracic Society, Medical Section of the American Lung Association. Am Rev Respir Dis 1993;148:1418-1426.
2. Fang G-D, Fine M, Orloff J, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy. Medicine 1990;69:307-316.
3. LaForce FM. Antibacterial therapy for lower respiratory tract infections in adults: A review. Clin Infect Dis 1992;14:S233-S237.
4. American Thoracic Society. Guidelines for the initial management of adults with community-acquired pneumonia: Diagnosis, assessment of severity, and initial antimicrobial therapy. Am Rev Respir Dis 1993;148:1418-1426.
5. Thys JP, Jacobs F, Byl B. Role of quinolones in the treatment of bronchopulmonary infections, particularly pneumococcal and community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 1991; 10:304-315.
6. Jacoby GA. Prevalence and resistance mechanisms of common bacterial respiratory pathogens. Clin Infect Dis 1994;951-957.
7. Friedland IR. Therapy of penicillin and cephalosporin-resistant pneumococcal infections. Ann Intern Med 1993;25:451-455.
8. Steele RW. Drug-resistant pneumococci: What to expect, what to do. J Resp Dis 1995;16:624-633.
9. Saint S, et al. Antibiotics in chronic obstructive pulmonary disease exacerbations. JAMA 1995;273:957-960.
10. Pichichero ME. Group A streptococcal tonsillopharyngitis: Cost-effective diagnosis and treatment. Ann Emerg Med 1995;25:390-403.
11. Vukmir RB. Adult and pediatric pharyngitis: A review. J Emerg Med 1992;10:607-616.
12. Gwaltney JM Jr, Scheld WM, Sande MA et al. The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: a 15-year experience at the University of Virginia and review of other selected studies. J Allergy Clin Immunol 1992;90:457-462.
13. Williams JW, Holleman DR, Samsa GP, et al. Randomized controlled trial of 3 vs. 10 days of trimethoprim/sulfamethoxazole for acute maxillary sinusitis. JAMA 1995;273:1015-1021.
14. Data on file. New York. Pfizer, Inc.
15. Barry AL, et al. In vitro activity of 12 orally administered antibiotics against four species of respiratory pathogens from US medical centers in 1992 and 1993. Antimicrob Agents Chemother 1994;38:2419-2425.
16. Neu HC. Otitis media: Antibiotic resistance of causative pathogens and treatment alternatives. Pediatr Infect Dis J 1995;14:S51-56.
17. Jacoby GA. Prevalence and resistance mechanisms of common bacterial respiratory pathogens. Clin Infect Dis 1994;18:951-957.
18. Caputo GM, Singer M, White S, et al. Infections due to antibiotic-resistant gram-positive cocci. J Gen Intern Med 1993;8:626-634s.
19. Friedland IR, McCracken GH. Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N Engl J Med
20. Faro S. New considerations in treatment of urinary tract infections in adults. Urology 1992;39:1-11.
21. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993; 329:753-756
22. Arav–Boger R, et al. Urinary tract infections with low and high colony counts in young women. Spontaneous remission and single–dose vs. multiple–day treatment. Arch Intern Med 1994; 154:300–304.
23. Hooton TM, Winter C, Tiu F, et al. Randomized comparative trial and cost analysis of three-day antimicrobial regimens for treatment of acute cystitis in women. JAMA 1995;273:41-45.
24. Hooton TM, et al.Randomized comparative trial and cost analysis of 3-day antimicrobial regimens for treatment of acute cystitis in women. JAMA 1995;273:41-5.
25. Centers for Disease Control and Prevention: 1993 Sexually Transmitted Diseases Treatment Guidelines. MMWR Morb Mortal Wkly Rep 1993;42(RR-14):1-102.
26. Katz BP, Zwickl BW, Compliance with antibiotic therapy for Chlamydia trachomatis and Neisseria gonorrheae. Sex Trans Dis 1992;6:351-4.
27. McCormack WM: Pelvic inflammatory disease. N Engl J Med 1994;330:115-119.
28. Therapy for Sexually Transmitted Diseases. Med Lett 1994;913:1-4.
29. Ambulatory PID Research Group. Multicenter randomized trial of ofloxacin versus cefoxitin and doxycycline in outpatient treatment of pelvic inflammatory disease. South Med J 1993;6:604-610.
30. Soper DE, Brockwell NJ, Dalton HP. Microbial etiology of urban emergency department acute salpingitis: Treatment with ofloxacin, Am J Obstet Gynecol 1992;3:653-660.
31. Sweet RL. Pelvic inflammatory disease. Hosp Pract 1993;28 (suppl 2):25-30.
32. Rolle C. (Tuscon Medical Center, personal communication)
33. Evaluation of new anti-infective agents for the treatment of acute pelvic inflammatory disease. Clin Infect Dis 1992;15 (suppl):S33-42.
34. Witkin SS, Ledger WJ. New directions in diagnosis and treatment of pelvic inflammatory disease. J Antimicrob Chemother 1994;2:197-199.
35. Pfizer product mongraph. Azithromycin for IV injection.
36. Data on file. Pfizer, Inc. New York, NY.
Physician CME Questions
1. The most common isolated bacterial pathogens in children with acute otitis media are:
a. Streptococcus pneumoniae.
b. H. influenzae.
c. M. catarrhalis.
2. The shortest approved antibiotic treatment course for acute otitis media is five days of therapy with the following suspension:
a. clarithromycin.
b. loracarbef.
c. trimethoprim/sulfamethoxazole.
d. azithromycin.
e. Fosfomycin.
3. Which of the following is not approved for single-dose therapy for uncomplicated gonorrhea?
a. Cefixime
b. Azithromycin
c. Clarithromycin
d. Ciprofloxacin
e. Norfoloxacin
4. Which of the following regimens offers the shortest (i.e., 7 day) total treatment course for pelvic inflammatory disease?
a. Ceftiraxone plus doxycycline
b. Ceftriaxone plus tetracycline
c. Azithromycin IV/oral sequenced combination regimen
d. Cefotetan plus metronidazole
e. None of the above
5. Atypical pathogens that may be responsible for causing community-acquired pneumonia include Legionella, Mycoplasma, and Chlamydia pneumoniae. Which of the following antibiotics is not indicated for treating all three aforementioned organisms?
a. Levofloxacin
b. Azithromycin
c. Ceftriaxone
d. All of the above
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content