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APPROPRIATE USE OF FLUOROQUINOLONE ANTIBIOTICS
IN UTI AND URI
Edited by
L. Kendall Shaw, Pharm.D.
Editor/Publisher, RxFactStat.com
Introduction
The fluoroquinolones have emerged as a valuable resource in our arsenal against bacterial infection. In order to utilize them responsibly, maximize efficacy, and minimize development of resistance, this discussion focuses on their appropriate application in both urinary and respiratory tract infections. Understanding the current views of pathophysiology, epidemiology, complications, and resistance involved in both of these broad disease states is essential for rational and responsible antibiotic choices.
Urinary Tract Infections
An estimated 7 to 8 million urinary tract infections (UTIs) occur annually in the United States, based on surveys of office practices. For adult women at age 40 to 50, 40 to 50% report a history of UTI. The average young, sexually-active woman suffers one infection every two years, according to one study published in The New England Journal of Medicine. Another study showed 27% of college students presenting with their first UTIs had recurrent infections within six months after the first. Around 3% have a second recurrence within six months, so recurrence is common. There are also women who have UTIs every month or so for years, but incidence remains undocumented for this rare occurrence.
Two decades of study on the epidemiology and risk factors for urinary tract infections has provided a fairly reliable basis for devising rational strategies for treatment and prevention. Adult patients can generally be divided into convenient categories that help with both research issues and management strategies:Young women with acute, uncomplicated cystitisYoung women with recurrent UTIWomen with frequent recurrent UTIsYoung women with acute, uncomplicated pyelonephritisAdults of both sexes with complicated urinary tract infectionAdults of both sexes with asymptomatic bacteruria (ASB)
The important question arises as to how these patients differ. While women with recurrent infection may be genetically more susceptible than those with only occasional or no UTIs, recurrent infection may be more a function of colonization with more virulent uropathogens. Studies haven’t been done to determine which factor is more significant, and either may be more significant in individual women.
While preschool boys and girls have a small incidence infection, the rate for boys drops to almost zero until they become older and start having prostate trouble. Incidence increases for girls when they become sexually active, and it is conjectured to continue increasing during postmenopausal years, though there have been no reliable studies of postmenopausal healthy women to verify that. There are some data demonstrating the deleterious effect of estrogen deficiency in postmenopausal women and that estrogen may reduce the risk of recurrent UTI, so estrogen deficiency is a risk factor. This may be balanced out for a lot of women because of decreasing sexual activity during postmenopausal years.
Uncomplicated UTI
Uncomplicated UTI typically occurs in a young, nonpregnant woman with symptoms enduring for less than seven days and no evidence of urologic abnormality. Complicated UTI is everything else. Simple cystitis is associated with significant morbidity. (Slide # 11) One study showed that the average woman with cystitis complained of symptoms for six or more days, had restricted activity for two and a half days, was unable to work for little over one day, and was bedfast and unable to do things around the house for half a day.
Many clinicians consider any UTI in a man complicated, but uncomplicated UTIs occur in 5 to 8 per 10,000 men between the ages of 21 and 50. Risk factors include: Anal sex, where a healthy man with no bladder or kidney problems may pick up a virulent uropathogen from the anal or rectal flora; sex with a woman infected or colonized with a virulent vaginal organism; and lack of circumcision. Strains of uropathogens in men tend to be highly urovirulent, since an infecting organism must be able to ascend the male’s longer urethra to reach the bladder and evade a man's other resistance factors, which have yet to be adequately defined. With UTI in men, the possibility of prostatitis must be considered, as they may present with UTI-like symptomatology. Drugs like nitrofurantoin should probably be avoided. The pathogen profile and susceptibility are usually similar to those for young women, but nitrofurantoin does not, of course, provide therapeutic concentrations in the prostate.
There has been little written about male UTI because it doesn't occur very often; but it may be more common than previously thought. An otherwise healthy man of 25 or 35 with no urinary difficulties and normal sexual activity generally does not need a full urological workup. Being uncircumcised is a risk factor, but it isn’t appropriate to remedy that based on a single UTI. If he has a second UTI, a workup is in order. Urethritis is more common in men than cystitis, and treating for it with a fluoroquinolone or azithromycin, for instance, will generally cure either ailment; so cystitis in men may go undetected and underreported.
Complicated UTI
Complicated UTI occurs primarily in older men and women, but classification is rarely that simple. A 70- or 80-year-old woman with cystitis may be healthy, ambulatory, sexually-active or not, have no genitourinary abnormalities, and no history of antibiotics. She may not necessarily have a complicated infection; but a 70-year old person is more likely to have factors that complicate the management of UTIs. Broad presentation spectrum, from mild cystitis to urosepsis, a wide variety of bacterial pathogens (Slides #21 & 22), and frequent resistance problems make individualized therapeutic choices essential. The complicated UTI is typically characterized by resistant uropathogens or poor response of a susceptible pathogen because of complicating factors like obstructions, stones, or urogenic bladder. Complications can also be a result of poor response to therapy.
For complicated UTI, fluoroquinolones have become the most reasonable first-line oral agents, largely because of their broad spectrum. Depending on how ill the patient may be, treatment should generally continue for 7 days as opposed to the recommended three-day regimen for uncomplicated UTI.
Evaluation of the urinary tract is considered unnecessary for young, healthy women, even those with multiple UTIs, though obstruction, structural or functional abnormality, foreign bodies, or other complications may be found retrospectively in a young and seemingly healthy person with a UTI who fails to respond to therapy. Diabetes and pregnancy can also complicate therapy. Once a patient has had 20 or 30 UTIs, evaluation may be worthwhile, but the yield is very low until that point.
Pathophysiology)
Generally, it can be said that causative bacteria colonize the gut, probably from what the patient eats. They then colonize the female introitus and ascend to the urethra, where they may again colonize without pathology. As they ascend to the bladder they may cause cystitis or again only asymptomatic bacteruria. Some women present with acute onset of back pain, fever, and malaise of pyelonephritis, often without earlier symptoms of cystitis. Asymptomatic bacteruria explains why these patients hadn’t sought treatment before progression to pyelonephritis, because progression from symptomatic cystitis to pyelonephritis is unusual.
The infection is treated; the organism is eradicated from the urinary tract; and yet some women develop recurrent cystitis. One theory suggests that with recurrent infection, failure to eliminate the causative organism from the gut or from the diet simply facilitates reinfection with the same organism from the original source, so it goes through the same sequence of events to cause symptomatic UTI again.
Certainly, genetic and behavioral factors can increase the risk of recurrent infection. Sexual intercourse greatly facilitates this whole process, because the bacterial count of uropathogens is demonstrably much increased in bladder urine after intercourse. Bacterial virulence determinants are also important risk factors, as it is well documented that certain genetically-selected characteristics of organisms are associated with pyelonephritis, others with cystitis, and others with E. coli colonizing the rectum. For bacteria to cause disease, they must attach to epithelial cells and invade the tissue; and the alacrity with which a given strain is able to attach, invade, and even evade host defenses determines its virulence.
Tissue invasion normally sets up a cytokine cascade that attracts leucocytes into the tissue to eradicate the bacteria. Cell replication in the bladder epithelium is prolific (slide #13), so cells perpetually die and rupture, and are shed in the urine through exfoliation as one of the main defense mechanisms of the human host. In the animal model, some bacteria are able to invade the lower levels of the bladder tissue and persist there, so for some women with recurrent infections, the bacteria may actually arise from latent organisms in these deep epithelial layers instead of reinfection by rectal flora. When this is the case, more aggressive or longer treatment may be the key to prevention of recurrent infections.
Risk Factors
Women with history of UTI are at much greater risk for getting a subsequent UTI, whether due to genetic or behavioral factors.Recent antimicrobial use is a risk factor. Studies of vaginal washes in monkeys before and after application of amoxicillin show that colonization with E. coli is very difficult before, but very easy after. In humans the tendency to develop UTI is much higher after antibiotic use than before, so antibiotics alter vaginal flora enough to create a niche for uropathogens like E. coli and allow urinary tract infection to occur.Sexual intercourse is a relative risk factor of UTI, with a step-wise increase as the number of times a woman has engaged in sexual intercourse in the previous seven days increases.
Similarly, spermicide use is a significant risk factor, and the more volume and more frequent applications of spermicide utilized, the more likely a urinary tract infection will occur. Risk is increased even more dramatically for women using diaphragms with a spermicide, and even a spermicide-coated condom can increase the risk of UTI in a woman. A new sex partner in the past year is also similarly important, though whether frequency of intercourse, position, or other variables might be responsible remains unstudied. There are some biological risk factors for UTI. Everyone is either a secretor or a non-secretor of blood group antigens, and women with history of recurrent UTI are more likely to be nonsecretors of blood group antigens. In nonsecretors different receptors on epithelial cells tend to facilitate attachment of E. coli to increase susceptibility.Peritoneal anatomy is also important.
In women with recurrent UTIs, distance from anus to urethra tends to be shorter, a factor that seems most important for women who are not sexually active and who don't use spermicides. Urethral length, though, does not seem to be associated with recurrent UTIs.IL-a is a chemotactic cytokine that attracts white cells necessary for microbial eradication in inflamed tissues. There are data to suggest that children with recurrent pyelonephritis have mutations in the receptor for this cytokine that impairs the ability to recruit white cells, thus impairing the ability to eradicate infections.
A number of risk factors in addition to the decrease in estrogen levels are related to menopause. Urinary incontinence, history of UTI before menopause, being a non-secretor, cystocele, and increased postvoid residual volume are all significantly associated with recurrent UTI.Other factors that one might assume increase risks are surprisingly not associated with increased risk for UTI. Potential genetic or familial factors like history of UTI in the patient’s mother, a first UTI at an early age don’t seem to increase risk. While no clear association has been shown between UTI and fluid intake, voiding soon after intercourse, or wiping habits, studies to verify that lack of association haven’t been done.
Pathogens
E. coli is by far is the most common causative organism, especially in complicated UTI. Some young, healthy women present with Enterococcus or Pseudomonas aeruginosa, but it's very uncommon; and when non-E. coli organisms like Citrobacter, Enterobacter, and Pseudomonas are seen, there may be underlying problems of some kind. That doesn't necessarily mean a urological workup is in order.
Among the Gram-positive organisms, the only relevant coagulation-negative Staph in cystitis is Staph saprophyticus, but it is far more common in uncomplicated UTI than complicated. Enterococcus is the second most common.
Culture
Pretreatment urine culture is generally not indicated for uncomplicated UTI, since treatment is usually well underway by the time results could be obtained, and the resistance profile has been fairly predictable. Results arrive too late to be of much value, and it's not predictive of treatment outcome; so routine culture is not thought to be cost-effective. The patient has either responded or failed to respond and returned with persistent or worsened symptoms. For complicated UTI, pretreatment culture can be very helpful in determining how to treat.
Post-therapy urine culture is obviously unnecessary if the symptoms resolve, because most recurrences are symptomatic. Asymptomatic bacteruria after treatment doesn’t affect treatment, and it's not uncommon to see bacterial counts of 105 after treatment and after symptoms subside. Follow-up cultures show that most of these resolve spontaneously. Post-therapy culture is only really recommended if symptoms persist or recur or in the presence of a known complicating factor.
Resistance
There have been increasing reports of trimethoprim/sulfamethoxazole (TMP/SMX) resistance among urinary E. coli, and it complicates the management of uncomplicated UTI considerably. A retrospective study of UTI patients in a large HMO looked at susceptibility patterns for four different antibiotics from 1992 to 1996. (Slide #26) Twenty-five percent of the strains were resistant to ampicillin in 1992 and 35% by 1996. There was no appreciable change with ciprofloxacin or nitrofurantoin, but resistance to TMP/SMX increased from 9% to 18% over that four-year period.
A review of resistance in urinary tract infection from the early '90s to the late '90s shows that E. coli strains resistant to TMP/SMX have ranged from 15 to 18% in most studies. It varies regionally, but 15 to 20% E. coli strains causing cystitis will be resistant to TMP/SMX in the United States. Worldwide, it can be much greater. In Mexico it is much higher, and they can range from 30 to 50 % in Israel.
Resistance is important for a number of reasons, including: patient morbidity, costs of reassessment and retreatment, and hospitalization with its liabilities of cost and nosocomial infection. As an example, look at the patient treated for cystitis appropriately with TMP/SMX and no pretreatment culture. She may initially improve, then have a recurrence and pyelonephritis 2 or 3 days later. She is admitted to the hospital, and culture from that episode shows TMP/SMX-resistant strains. That is a significant cost of reassessment and treatment, especially if when hospitalization is involved.
The bigger concern, though, is that TMP/SMX resistance opens the door for broader use of fluoroquinolone antibiotics, which creates a vicious circle of broader-spectrum antibiotic use and more resistance associated with fluoroquinolones.
The situation is similar in respiratory infections resistant to penicillins. The data is sparse, but treatment failure is 40 to 50% in cystitis patients with TMP/SMX-resistant strains.
According to guidelines for management of urinary tract infection published by the Infectious Disease Society of America (IDSA), empiric management of acute uncomplicated cystitis and pyelonephritis should be TMP/SMX for three days as the current standard, but a meta-analysis shows that trimethoprim alone for three days produces equivalent results. While TMP/SMX is used most often in the United States, more trimethoprim is used in Europe, with no apparent difference in the susceptibility patterns or treatment outcomes. Clearly, trimethoprim alone should be utilized more often, eliminating the sulfa component, the main cause of allergic reaction.
All available fluoroquinolones also work well and all are of similar clinical effectiveness; but fluoroquinolones are not officially recommended as initial empiric therapy, unless regional resistance to trimethoprim or TMP/SMX is greater than 10 or 20%. The primary reason for relegating fluoroquinolones to second-line status is their expense, but considering overall costs associated with medication, follow-up, phone calls, re-culturing, and adverse events, there is no appreciable difference between treating initially with a fluoroquinolone for three days or TMP/SMX for three days.
Development of resistance with quinolones is the focus of much debate. In Canada, where quinolones are utilized more extensively than here, resistance is increasing, though not yet significantly. Especially with the newer quinolones, some of the pharmacokinetic and pharmacodynamic data suggest that these agents may be significantly less prone to resistance development. Potential resistance development remains a valid concern, so fluoroquinolones should probably be reserved for situation where it is essential.
Beta-lactams are less effective in a three-day regimen, and amoxicillin is generally not a good choice due to resistance. First-generation cephalosporins have also been shown less effective than TMP/SMX or fluoroquinolones, with much higher failure rate in 3-day regimens; so 5- to 7-day regimens are essential when these agents are used.
Nitrofurantoin and fosfomycin may become more useful as resistance increases. With nitrofurantoin, no increase in resistance among E. coli is seen, but some fairly common organisms like Proteus mirabilis are resistant to it. While 90% of causative organisms are susceptible, it's not as effective against some of the other gram-negative rods. Even with a susceptible organism, it's usually not quite as effective as TMP/SMX, and it should be given twice daily for 7 days. Fosfomycin has been used in Europe for a long time, a single-dose three-grain sachet mixed with water and given orally. Results with it have not been impressive.
Cefpodoxime, a third-generation cephalosporin is utilized in situations where fluoroquinolones are inappropriate, like pregnancy for instance; and 3-day regimens are generally inadequate. While amoxicillin alone is usually inappropriate, amoxicillin/clavulanic acid can be, in spite of its expense, and should be given twice daily for 7 days.
Empiric Therapy
The inherent dilemma of empiric therapy is that UTI is a condition associated with significantly lower morbidity than respiratory infections. Symptoms can be miserable, and cystitis occasionally progresses to pyelonephritis; but UTI is rarely fatal. It may be wise in this light to utilize antibiotics that are somewhat less effective, perhaps even agents not indicated for UTI, in an effort to avoid cross-resistance. It is reasonable to use trimethoprim or TMP/SMX as first-line agents, except when resistance is suspected. Fosfomycin and nitrofurantoin may be better choices than TMP/SMX where emerging resistance is a problem, or even the fluoroquinolones where emerging resistance may eventually become a problem.
If TMP/SMX resistance can be predicted, use of fluoroquinolones can simply be limited to those situations. A number of risk factors can be identified.Current use of antibiotics or use within the past three months shows a high odds ratio, and TMP/SMX is specifically implicated when used recently. Someone who has been on an antibiotic in the past few months is more likely to harbor a resistant strain in the rectum.Resistance is suspected in any uncomplicated UTI with treatment failure. This includes not only the recurrent infection soon after therapy, but the infection that fails to respond to therapy, where other complicating factors may be significant issues. Resistance is likely in a woman who develops symptomatic UTI a few weeks after return from regions where TMP/SMX resistance is high. A mother with a UTI whose child has been on antibiotics is at increased risk due to constant transmission of resistant bacteria from child to mother.
Ongoing surveillance by the CDC and NIH may eventually help assess current prevalence of resistance in a given community for both urinary tract infections and respiratory infections, but adequate monitoring of trends to develop optimally effective empiric regimens is lacking. Current national surveillance systems are biased toward complicated infections, because only UTIs and URIs where resistant strains are suspected are routinely cultured. Thus, they tend to overestimate resistance.
Pyelonephritis
The Infectious Disease Society of America (IDSA) recommended 14-day therapy for uncomplicated pyelonephritis. A six-week regimen in not necessary, and 7-day therapy may be sufficient for the vast majority of patients. Mild cases can be managed with oral medication in the outpatient setting, though they may initially require IV fluids and even a dose of parenteral quinolone or ceftriaxone to ensure the medication can be tolerated.
Fluoroquinolones are recommended as first-line agents for pyelonephritis, and TMP/SMX should only be used when susceptibility is confirmed, often with the added advantage of an initial parenteral dose. Even amoxicillin can be appropriate if susceptibility is confirmed. If Gram-positive organisms are present, the likelihood of Enterococcus as the causative agent may necessitate addition of amoxicillin or amoxicillin/clavulanic acid to whatever other agent used.
A multi-center, randomized, double-blind trial compared ciprofloxacin (400mg twice a day for seven days, with or without an IV dose of ciprofloxacin) with TMP/SMX (for 14 days with or without an IV dose of ceftriaxone). Of 255 patients evaluated, one-third in each group received an initial IV dose. Bacteriologic eradication, both soon after therapy and three-to-four weeks after therapy, showed significant advantage of ciprofloxacin over TMP/SMX at both endpoints. There was almost 100% cure rate among patients who had a TMP/SMX-susceptible strain, who were treated with TMP/SMX, but a 50% failure rate in patients who had a TMP/SMX-resistant strain. Only 35% of the women who had TMP/SMX-resistant strain treated with TMP/SMX were clinically cured.
Short-course therapy of seven days is appropriate for mild or moderate acute, uncomplicated pyelonephritis, though some have advocated a 3- to 5-day course. A very sick patient, though, obviously requires longer therapy, urine culture, and adjustments in therapy as necessary. The patient should respond to therapy within 24 hours, and temperatures should be near normal within 72 hours. When back pain and low-grade fever persist, therapy should be extended to 10 to14 days, and urologic workup should be considered.
Recurrent Infections
Most recurrent urinary tract infections are re-infections that can be re-treated with the same regimen. At that point, it is reasonable to do a culture to make sure there is no developing resistant flora, though urologic evaluation is generally not indicated. Quinolones are good choices for such infections; and behavior modification may help, as eliminating things like spermicides by changing contraceptive measures can be important. Though no hard data confirms their value, measures like urination soon after intercourse, increased fluid intake, and drinking cranberry juice may be viable protective factors. Topical estrogen can be useful in the postmenopausal woman, dramatically reducing urinary tract infections by normalizing the vaginal flora.
Studies are underway evaluating a vaccine to the tip of the type-1 pilus on E. coli that prevents attachment to epithelial cells of the urinary tract. In women with recurrent UTIs, this may facilitate mounting a more effective immune response and perhaps prevent subsequent UTIs. Studies are also evaluating probiotics, instilling Lactobacillus suppositories into the vagina to normalize vaginal flora and reduce the colonization risk of E. coli. Those studies are focusing on bacterial vaginosis, but they obviously will impact recurrent UTIs.
In summary, UTIs are products of complex host biologic and behavioral characteristics and pathogen virulence characteristics. Understanding these factors better should lead to better treatment and prevention strategies. Antibiotics are concentrated to a high degree in the urine, so laboratory demonstration of resistance may not be an accurate predictor of treatment failure with TMP-SMX. In this light, though fluoroquinolones are unquestionably efficacious in the treatment of UTI in most cases, their utilization in certain simple UTIs may not be appropriate. Ready utilization of fluoroquinolones for empiric therapy in such cases may increase the chance for development of coliforms not susceptible these invaluable antibiotics.
Respiratory InfectionAcute Pharyngitis
Diagnosis of pharyngitis is not difficult, but determining whether it warrants antibiotic therapy is. Most patients present with sore or scratchy throats, coryza, and cough; and the pharynx is inflamed and edematous. Most cases are viral and due to rhinovirus, coronavirus, or parainfluenza virus; but bacterial disease may be suspected when an exudate is seen, most commonly due to Strep pyogenes, which accounts for 15% of bacterial pharyngitis.
Adenovirus and infectious mononucleosis due to Epstein-Barr virus can also cause an exudate, so these may be suspected in a patient with a very inflamed throat after 10 days of illness but that doesn’t look that sick. Similarly, vesicular enanthem on the soft palate between uvula and tonsils may not be herpes, but Coxsackie herpangina; and acute retroviral syndrome presents with a deeper non-exudative pharyngitis.
Acute Otitis Media (AOM)
In acute otitis media, edema initially causes blockage of the eustachian tube, which connects the middle ear to the nasopharynx. This allows collection of fluid in the middle ear and mastoid cavities, providing a warm, damp environment conducive to bacterial growth. Ear infections frequently follow viral illness and are most common in fall, winter, and spring. Typical symptoms include ear pain, fever, and decreased hearing acuity. The tympanic membrane is usually red, opaque, bulging, or retracted, though transillumination is difficult to do correctly and may appear completely normal, indicating that bacterial cause is unlikely. It may move poorly upon insufflation.
Acute Maxillary Sinusitis
In acute sinusitis, again Strep pneumoniae is the most common bacteria. The common theme here is Strep pneumoniae as the most common bacterial pathogen, and its resistance to penicillins is also predictive of its resistance to other antibiotics like macrolides.
The maxillary and ethmoid sinuses develop first and are present at birth. The frontal sinuses develop after age 2, followed by the sphenoid around age 7. As with acute otitis media, the passageways between the various sinuses (the ostia or openings) become edematous to cause blockage, create a closed fertile bacterial environment, and bring about sinus infection. Thus viral infections set the stage for acute sinusitis, but other processes like allergies, nasogastric or nasotracheal intubation, and dental infections can also cause edema, as can barotrauma from airplane travel and deep-sea diving.
Symptoms typically include purulent postnasal drainage, nasal congestion, sinus pain that worsens when the patient bends over or is supine, fever in about half the patients. Location of the sinus pain depends on which sinus is most involved. An infected maxillary sinus may cause upper tooth pain or cheek pain; retro-orbital or cheek pain is probably the ethmoid sinus; pain above the eyebrows is in the frontal sinuses; and sphenoid sinus pain may be in the upper half of the face or retro-orbital with radiation to the occiput.
COPD
Chronic obstructive pulmonary disease (COPD) is not a disease of infections but of inhalation injury, usually due to smoking, its major risk factor. It affects 10 to 20% of the population, and it is the fourth leading cause of death in the United States. Chronic bronchitis is defined as a cough with excessive mucous production and a productive cough occurring most days for 3 months during 2 consecutive years.
In acute exacerbation of chronic bronchitis (AECB), the patient with a constant smoker's cough suddenly becomes worse, with an increase in volume and purulence of the sputum, along with dyspnea and wheezing. In this case, bacterial infection is likely, and Haemophilus influenzae is the most common organism involved. COPD differs in that respect from sinusitis. The patient with FEV-1 less than 50% of predicted has a five-year survival, so it’s lethal. (Slide #63)
Community-Acquired Pneumonia (CAP)
With community-acquired pneumonias, it may be difficult to know what the infection is. In the office no one takes sputum samples or nasotracheal samples. A chest x-ray can help narrow it down more than just the clinical exam and clinical history. A focal infiltrate is more likely to be bacterial. Rapid progression from small infiltrate to multi-focal infiltrates is probably Legionella, Pneumococcus, and Staph. Cavitary, interstitial tends to be Mycoplasma, psittacosis, or viruses.
Stre.p pneumoniae is usually seen in winter and spring, with most infections caused by one of 23 serotypes present in the vaccine, so the vaccine is very useful. The vaccine doesn’t confer lifetime immunity, and revaccination is recommended at five years. With Strep the patient is rapidly ill, with abrupt onset, toxic appearance, chest pain, rusty-colored sputum, the classic one shaking chill, and lobar pattern on the x-ray.
Legionella typically affects the middle-aged to elderly patients with very toxic appearance, and gastrointestinal symptoms. This organism is associated with water, so if the patient is a middle-aged air conditioning worker, suspect Legionalla. Klebsiella is seen in immunosuppressed populations like alcoholics and diabetics and is associated with 50% mortality.
With Chlamydia and Mycoplasma, the extrapulmonary manifestations can be helpful in making a diagnosis: red, knotty rash, erythema nodosum, chest wall pain, myopericarditis, and patchy infiltrate on the chest x-ray. Tetracycline and macrolides are the classic choices for these infections.
Mycoplasma pneumoniae may affect the young adult who presents with a persistent cold and fatigue. The patient may not look too bad, but rales are heard on the exam. Extrapulmonary manifestations can be delayed by up to three weeks and include meningitis, transverse myelitis, cranial nerve palsies, myopericarditis, arthritis, rash, and hemolytic anemia, which is the most common.
Fluoroquinolones in Respiratory Infection
The minimum inhibitory concentration (MIC) is that which inhibits 90% of growth, the basis on which decisions are made of whether or not an organism has in vitro resistance to an antibiotic. Lower MIC indicates that less drug is necessary to attain adequate therapeutic levels. Consider anaerobes in an elderly patient with neurologic disease that causes swallowing difficulty and aspiration pneumonia, for instance. Moxifloxacin covers anaerobes well, comparable to clindamycin and better than metronidazole. Gatifloxacin is not as good, and levofloxacin is not a good choice for anaerobes.
Note that with Strep pneumoniae, (Slide # 80) the most common bacterial pathogen overall, MIC for moxifloxacin and gatifloxacin are lower than that for levofloxacin. For H. influenzae, Moraxella, and atypical bacteria like Chlamydia, Legionella, and Mycoplasma, all 3 agents are good choices.
The quinolones as a class have a variety of similarities, starting with side effects of nausea, vertigo, diarrhea and tendonopathy. Moxifloxacin causes QTC prolongation, an increase in the difference between polarization and repolarization of the ventricle by 6 milliseconds, plus or minus 26 milliseconds. Under normal circumstances, an individual’s variation in QTC interval is up to 70 milliseconds, so the effect of moxifloxacin clinically insignificant for the most part. Worldwide one death has been attributed to it, a very sick gentleman who developed an arrhythmia. Nonetheless, moxifloxacin is not for the patient with long QTC in his chart.
Levofloxacin and gatifloxacin are mostly excreted renally, so dosage may need to be adjusted with renal impairment. Moxifloxacin is excreted by triple routes -- hepatic, renal, and fecal, so excretion is a lesser concern with it.
There are significant differences in the pharmacokinetics and pharmacodynamics. Against Strep pneumoniae, quinolones are bactericidal, with rapid kill. (Slide #81) Both levofloxacin and gatifloxacin kill quickly, within 10 hours; but moxifloxacin kills 99.9% of bacteria within two hours, which is very important from the standpoint of resistance development.
Beta-lactams, macrolides, tetracycline, TPM-SMX all have in vitro problems with in vitro resistance where upper respiratory pathogens are concerned, and all seem to have a problem with Staph. MIC is based on serum concentrations, but penetration of other more relevant compartments like the alveoli, macrophages, and epithelial lining fluid is actually more important. The quinolones are adept at penetrating these compartments.
Area under the concentration curve (AUC) is relevant to efficacy of antibiotics and demonstrated with time on the X-axis and concentration on the Y-axis, as it peaks and drops in a bell-shaped curve. With bacteriocidal antibiotics, the higher the concentration, the greater the kill rate. With bacteriostatic agents, once an effective concentration is attained, time is the main factor, and greater concentration not necessarily better.
Meaningful comparison of the quinolones regarding potency and development of resistance is difficult based on serum concentration and AUC. The ratio AUC to MIC (AUIC) compares the time the antibiotic spends above a certain concentration to kill, allowing expression of relative potency.
Resistance
Early fluoroquinolones targeted DNA gyrase, a bacterial enzyme required in replication, transcription, and repair of bacterial DNA. They showed activity primarily against gram-negative organisms, including Pseudomonas aeruginosa; but activity against gram-positives was modest. Resistance developed soon after employment of these agents, usually via chromosomal mutation and efflux. The newer fluoroquinolones, trovafloxacin, gatifloxacin, and moxifloxacin not only target DNA gyrase but topoisomerase IV as well, which significantly improves bacteriocidal activity against gram-positive organisms. Structural changes have also helped to decrease bacterial mutational activity and potential for efflux, reducing.
In order to examine potential for development of resistance for a variety of organisms, they were exposed to several fluoroquinolones diluted to a series of ineffective levels and quantified surviving organisms. (Slides 88, 89, and 90) The results indicate that resistance is indeed possible, and that the potential may be significantly greater with some agents than with others, as moxifloxacin seemed to generate less resistance overall. To extrapolate the data to the real world, as with any antibiotic, longer exposure and repeat exposure increase the likelihood that a patient may harbor strains resistant to the antibiotic. Responsible use of any antibiotic entails not only the accurate assessment of causative organism and optimum choice of effective antibiotic, but the initial decision as to whether or not an antibiotic should be used at all.
Conclusion
Responsible utilization of the newer fluoroquinolones entails efficacious application of the right agent for the right susceptible organism, which requires differential diagnostic skills and understanding of the pathophysiologies and epidemiologies of the infections treated. The clinician must balance the clinical need for knowing exactly which pathogens are causative in individual cases with costs of care and optimum outcome. It also requires recognition of resistance development potential as well as its potential impact on preserving therapeutic potential for other infections. Once the general choice is made of whether or not to utilize a fluoroquinolone, antibiotic choice is generally fairly simple, taking bacteriological and patient-specific parameters into consideration.
The newer fluoroquinolones offer many advantages over older-generation agents as well as other antibiotic options. While resistance to these newer agents is expected to be minimal compared to other options, responsible utilization entails strategies to preserve the efficacy of these valuable medications for cases where they are needed most.
Exam
The average young, sexually-active woman suffers one urinary tract infection every:3 months6 monthsyear2 years
Which of the following would be the most likely risk factor associated with increased incidence of uncomplicated UTI in postmenopausal women?Lowered estrogen levelsUrogenic bladderUrethritisReduced frequency of sexual intercourse
Which of the following is true considering a single episode of cystitis in a young healthy male?It may be more common than previously thought – 5 to 8 cases per 1,000 men.It may be misdiagnosed as urethritis.Causative organisms are more likely resistant to TMP-SMX than those in women.Causative organisms are usually less susceptible to nitrofurantoin.
For complicated UTI, fluoroquinolones have become the most reasonable first-line oral agents because of which of the following?Favorable side effect profileArea under the concentration curve (AUC)Routes of eliminationBroad spectrum
Which of the following is true regarding complicated UTI?UTI in any man is considered complicated.More than 2 UTIs in any patient within a year is considered complicated.UTI in anyone over 60 years of age is considered complicated.Complications can be the result of poor response to therapy.
Which of the following is NOT a typical source of uropathogens for women?Colonization from anal sexNormal vaginal intercourseContamination from food sourcesIntroital colonization
Asymptomatic bacteriuria:Requires full urological workup.Is characterized by back pain, fever, and malaiseMay require no treatmentIs the primary reason post-treatment culture should be routine
Risk factors of UTI include which of the following?History of UTI, recent antimicrobial use, and sexual intercourse without spermicideRecent antimicrobial use, sexual intercourse with diaphragm and spermicide use, and short urethral lengthMenopause, urinary incontinence, and estrogen replacement therapyMenopause, topical vaginal estrogen use, and cystocele
Which is the most common pathogen in UTI?E. coliPseudomonas aeruginosaStrep. pneumoniaeStrep. pyogenes
What is the recommended first-line agent for uncomplicated cystitis in regions where resistance to TMP-SMX is less than 10%?GatifloxacinClarithromycinAzithromycinTMP-SMX
A 19-year-old female college student with no history of UTI presents with acute cystitis, but has a documented history of rashes after taking erythromycin, azithromycin, and TMP-SMX. Rate of TMP-SMX resistance in your area is 18%. Which would be the most appropriate regimen, based on this information?TMP 100mg twice daily for 3 daysClarithromycin 500mg twice daily for 3 daysAmoxicillin/clavulanic acid 500mg twice daily for 3 daysGatifloxacin 400mg twice daily for 7 days
The same patient returns 3 weeks later with the same symptoms. The first regimen worked, but the infection is back. Which would be the most appropriate regimen, based on this information?TMP 100mg twice daily for 3 daysClarithromycin 500mg twice daily for 3 daysAmoxicillin/clavulanic acid 500mg twice daily for 3 daysGatifloxacin 400mg twice daily for 7 days
What would be the most probable causative organism in the above recurrence?Strep. PneumoniaeE. coliPseudomonas aeruginosaKlebsiella
The same patient returns with mild pyelonephritis two days after her second visit. Which would be the most appropriate regimen, based on this information?TMP 100mg twice daily for 10 to 14 daysClarithromycin 500mg twice daily for 10 to 14 daysAmoxicillin/clavulanic acid 500mg twice daily for 10 to 14 daysGatifloxacin 400mg once daily for 7 days
Vesicular enanthem between uvula and tonsils may be which of the following?Acute retroviral syndromeAdenovirusEpstein-Barr virusCoxsackie herpangina
Which is the most likely causative organism in otitis media?VirusH. influenzaeStrep. PneumoniaeM. catarrhalis
Which is the most likely causative organism in acute bacterial maxillary sinusitis?M. catarrhalisH. influenzaeStrep. PneumoniaeStaph. Aureus
Which is the most likely causative organism in acute exacerbation of chronic bronchitis?H. influenzaeStrep. PneumoniaeStaph. AureusVirus
The young adult patient with persistent cold, fatigue, rales, arthritis, rash, and hemolytic anemia is most likely infected with which of the following?H. influenzaeStrep. PneumoniaeStaph. AureusMycoplasma pneumoniae
Which of the fluoroquinolones is associated with QTC prolongation?MoxifloxacinGatifloxacinTrovafloxacinLevofloxacin
Answer Key
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