Antibiotic Resistance to Community-Acquired Infections: Clinical Impact on Medical Practice
Antibiotic Resistance to Community-Acquired Infections: Clinical Impact on Medical Practice
Author: Laura Pimentel, MD, Assistant Professor, Division of Emergency Medicine, University of Maryland School of Medicine, Baltimore.
Peer Reviewers: Sandra Schneider, MD, FACEP, Professor and Chair, Department of Emergency Medicine, University of Rochester, Rochester, NY; and Robert D. Powers, MD, MPH, Professor of Emergency Medicine, University of Connecticut School of Medicine, Farmington.
Bacterial resistance to antibiotic treatment has concerned the medical community since the introduction of the first antibiotics in the 1920s. Development of new anti-infective agents has been precipitated by increasing resistance to older agents and classes of agents. While high rates of resistant organisms have been particularly problematic in hospital intensive care units, serious resistance now is being encountered in community-acquired infections. This review will focus on the clinical aspects of antibiotic resistance in community-acquired respiratory infections, pharyngitis, skin infections, and urinary tract infections. The most common organisms causing each infection will be reviewed with respect to clinical presentation, mechanisms and rates of resistance, and current treatment guidelines.
The Editor
Respiratory Infections
Acute respiratory tract infections, including pharyngitis, epiglottitis, bronchitis, and pneumonia are the leading infectious causes of death in the world.1 Among ambulatory patients, respiratory infections are the most common causes of visits to physician offices and emergency departments (EDs). Most acute infections are viral in etiology. Common respiratory viruses include influenza A and B, parainfluenza virus, rhinovirus, coronavirus, adenovirus, and respiratory syncytial virus.2 Pfaller and colleagues cultured infectious sputum or nasopharyngeal secretions from patients presenting to office-based practices in the United States with clinically suspected community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis, and sinusitis. Pathogenic bacteria grew from one-third of the specimens. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis were the three most frequently occurring organisms.3 Antibiotic resistance has been documented in each of these organisms.4,5
Streptococcus Pneumoniae. Streptococcus pneumoniae is a Gram-positive organism that is morphologically identified by its characteristic diplococcus configuration. Invasive pneumococcal disease is a leading cause of morbidity and mortality among those with community-acquired infections.
Haemophilus Influenzae. Haemophilus influenzae is a small, nonmotile respiratory pathogen with a morphologic appearance ranging from coccobacilli to long filaments. Its varied appearance and inconsistent dye uptake makes Gram stain interpretation difficult. The organism has been isolated only in human hosts. H. influenzae has six capsular types, A to F, that have been described. The capsular distinctions are important because they confer virulence properties to the bacteria. Strains that lack a capsule are designated nontypeable.6 Type B H. influenzae, a virulent pathogen in infants and young children, is practically eliminated in those individuals and countries vaccinated with the H. influenzae type B (Hib) conjugate vaccine.7 Nontypeable H. influenzae colonizes 80% of healthy individuals and is not affected by the vaccine. It often is found in the pharynx and occasionally the conjunctiva. Those with chronic obstructive pulmonary disease (COPD) frequently are colonized with H. influenzae in the lower respiratory tract. Transmission among persons is by airborne droplets.
Moraxella Catarrhalis. Moraxella catarrhalis is a Gram-negative diplococcus that resembles Neisseria organisms on Gram stain. Until the 1970s it was not recognized as a pathogen but thought to harmlessly colonize the respiratory tract. Convincing evidence now exists that M. catarrhalis is a common pathogen. Humans are the only known hosts. Rates of colonization differ with age and geographic location. Infants harbor M. catarrhalis at much higher rates than do adults. Presence of the bacteria in the nasopharynx of young children is associated with recurrent otitis media. It is estimated that 1-5% of healthy adults are colonized in the upper respiratory tract. Those with chronic lung disease harbor the organism at a higher rate.
Mechanisms of Antibiotic Resistance to Respiratory Pathogens
S. Pneumoniae. The primary microbiologic basis for penicillin resistance to S. pneumoniae is alteration in the pattern of penicillin-binding proteins (PBPs). Resistance is a gradual and stepwise process introduced into the bacteria; PBPs develop a pattern consistent with progressively higher penicillin resistance as genetic transformation occurs.8,9 This mechanism confers some resistance to other beta lactam antibiotics. Macrolide resistance occurs by one of two mechanisms. The first is enzymatic alteration of the target site, which confers high-level resistance. Bacteria harboring this property usually are resistant to all macrolide, lincosamide, and streptogramin antibiotics.10 The second type of resistance, an efflux mechanism, preserves sensitivity to clindamycin and the streptogramin antibiotics. M phenotype isolates exhibit the efflux mechanism resulting in moderate levels of resistance to erythromycin, clarithromycin, and azithromycin.11 Resistance to fluoroquinolones is dependent upon DNA mutation. Low-level resistance occurs with a single mutation, but two sequential mutations are necessary for high-level resistance.12
The extent of resistance to S. pneumoniae is well documented. The SENTRY Antimicrobial Surveillance Program, global in scope, has been monitoring resistance of bacterial pathogens to commonly prescribed antibiotic agents from 1997 to the present. Gordon and colleagues reported results of SENTRY data (1997-2001) from North American surveillance centers collected from patients with community-acquired respiratory tract infections and hospitalized patients.13 Table 1 shows percentages of community-acquired S. pneumoniae demonstrating in vitro sensitivity to individual antimicrobials.13
| Table 1. Community-Acquired S. Pneumoniae Susceptibility to Commonly Prescribed Antibiotics Based on SENTRY Program, 1997-2001 |
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The implications of in vitro resistance to antibiotic therapy of pneumonia are not clear. Comparatively few studies correlate antibiotic resistance and clinical patient outcomes. Co-infection with typical and atypical pathogens, common in CAP, confounds outcome studies; distinguishing colonizing from pathogenic bacteria in non-sterile respiratory samples creates further methodological problems. Beta lactam antibiotics may remain clinically effective when resistant in vitro because higher antibiotic concentrations are achieved in pulmonary tissue than in blood. One study reviewed 15 clinical outcome studies of beta lactam resistance in patients with pneumococcal pneumonia.14 Twelve of the 15 found no statistically significant impact of penicillin resistance on mortality. One study that found a significant difference only compared highly resistant isolates (MIC > 4.0 mcg/mL) with susceptible isolates.15 The author concludes that first-line antibiotics for treatment of CAP continue to remain effective. Current evidence only supports a clinical impact in the small percentage of patients infected with highly resistant S. pneumoniae.
At this time, clinical outcome data suggest minimal impact from macrolide resistance in patients with pneumococcal pneumonia. Both morbidity and mortality data are similar in patients with macrolide resistant pneumococcal strains compared to macrolide susceptible strains.16,17 The only evidence documenting clinically important fluoroquinolone resistance in patients with pneumococcal disease are scattered case reports.18,19
H. Influenzae. Beta lactamase production is the primary mechanism of antibiotic resistance employed by H. influenzae. The beta lactam antibiotics include four groups: the penicillins, cephalosporins, carbapenems, and monobactams. Structurally, all of the antibiotics within these groups contain a beta lactam ring. Beta lactamases are a group of enzymes that inactivate the drugs by hydrolyzing the ring. Other mechanisms of antibiotic resistance are utilized by H. influenzae; beta lactamase negative ampicillin resistance (BLNAR) has been identified. Resistance to amoxicillin/clavulanate is present in some of these strains. The proposed mechanism is alteration of PBPs.20
SENTRY program data from North American surveillance centers demonstrate a 24.5% resistance rate of H. influenzae to ampicillin through 2001. Amoxicillin/clavulanate, however, remained almost universally effective against the bacteria.13 See Table 2 for susceptibility percentages of H. influenzae to commonly prescribed antibiotics.13 Richter and colleagues found a 31%-33% rate of beta lactamase production in H. influenzae in a 1997-1998 United States national surveillance study. This was down from a peak of 36.4% documented in 1994-1995.
| Table 2. Community-Acquired H. Influenzae Susceptibility to Commonly Prescribed Antibiotics Based on SENTRY Program, 1997-2001 |
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The clinical relevance of H. influenzae resistance is unclear. At this time, no controlled studies have demonstrated treatment failures in patients with CAP infected with this organism.14
M. Catarrhalis. Beta lactamase production is almost ubiquitous among strains of M. catarrhalis. BRO-1 and BRO-2 are the enzymes that hydrolyze penicillin, ampicillin, and amoxicillin. Richter and colleagues documented a beta lactamase positive rate of 94.6% of M. catarrhalis strains collected in the United States in a 1997-1998 study.21 This should preclude use of single-agent penicillins against this organism. Addition of clavulanic acid to amoxicillin, however, almost completely eliminated M. catarrhalis resistance. Multiple studies have found excellent susceptibility to the cephalosporins, macrolides, fluoroquinolones, and tetracycline.21-23 Up to 10% of isolates demonstrate resistance to trimethoprim-sulfamethoxazole (TMP-SMX).21,23
Respiratory Infections
S. Pneumoniae. S. pneumoniae has been identified as the etiologic agent in 30% of ED patients diagnosed with pneumonia when an organism could be identified.24 Demographic studies of patients with invasive pneumococcal disease suggest an annual incidence ranging from 9.6 per 100,000 in adults younger than 65 years of age, to nine times that rate in the elderly.25 Human Immunodeficiency Virus (HIV) infection confers a relative risk of invasive pneumococcal disease 41.8 times that of similarly aged non-infected counterparts.25 Factors that increase risk of infection with antibiotic-resistant pneumococci are the following: age older than 65 years, beta lactam therapy within three months, alcoholism, immune suppressive illness, corticosteroid use, medical co-morbidities, and exposure to a child in a day care center.26
Clinical pneumonia is contracted by aspiration of S. pneumoniae that has colonized the nasopharynx. Illness classically is heralded by abrupt onset of a rigor; this is followed closely by a high fever, cough productive of rust-colored sputum, and shortness of breath. A chest x-ray usually will reveal a lobar infiltrate.27
Intrapulmonary complications of invasive pneumococcal disease include ARDS, empyema, and lung abscess. Bacteremia occurs in 12% of hospitalized patients. Meningitis, endocarditis, septic arthritis, and peritonitis are secondary complications in 10% of patients with bacteremic disease.28 The overall mortality is 12%29 but ranges to 28% in hospitalized patients.30
H. Influenzae. Nontypeable H. influenzae has the ability to exist intracellularly within macrophages; this is possibly the reason it persists within the respiratory tract. It typically is found in the mucous layers of nonciliated epithelial cells and extracellularly in respiratory tract epithelia. Local defense mechanisms control the constantly multiplying organism in healthy individuals. Factors such as chronic smoking or previous viral infections damage ciliated epithelia, diminish resistance to the bacteria, and predispose to infection. Unlike H. influenzae type B that spreads hematogenously, nontypeable H. influenzae infects mucosal surfaces and spreads locally within the respiratory tract. Contiguous spread may produce infection within the middle ear, sinuses, or lower respiratory tract.
In nonvaccinated children, H. influenzae type B may cause devastating and fatal illness. Meningitis, epiglottitis, pneumonia, cellulitis, and septic arthritis are potential manifestations of the pathogen. Nontypeable H. influenzae can and does infect children and adults regardless of vaccination status. While generally less virulent than type B disease, sepsis may occur in hosts with predisposing risk factors.6 H. influenzae is a leading bacterial cause of chronic obstructive pulmonary disease (COPD) exacerbation and community-acquired pneumonia encountered in the office setting; it is the second most commonly identified organism (21.7%) in office patients with sinusitis.3,31,32 In children with otitis media, this organism is responsible for about 25% of cases.
COPD exacerbations are characterized by increases in cough, sputum production, and dyspnea. Low-grade fevers are common, and sputum usually is purulent. H. influenzae pneumonia causes similar symptoms. It is a common complication in patients with underlying COPD. The clinical presentation is indistinguishable from pneumonia of other bacterial etiologies. Sinusitis will present with facial pain, purulent nasal discharge, and headache. Purulent conjunctivitis from H. influenzae occurs in outbreaks and presents with purulent ocular discharge and conjunctival hyperemia.6
M. Catarrhalis. M. catarrhalis causes local mucosal infections. The bacteria spread contiguously from the nasopharynx to the middle ear, sinuses, and lower respiratory tract. An estimated 15-20% of cases of otitis media are caused by this organism. Lower respiratory infections occur in adults with increased risk in those with COPD. M. catarrhalis is believed to be the second most common cause of COPD exacerbations.33 The organism caused 31% of COPD-related infections in one study.34 Ten percent of cases of pneumonia in the elderly may be caused by this pathogen.35 Co-morbidities including COPD, congestive heart failure, and diabetes mellitus predispose to M. catarrhalis pneumonia. Fulminant illness is rare, though severe illness does occur. Bacteremia, while uncommon, has been reported.33
Antibiotic Treatment of Acute Respiratory Infections
The evolution of bacterial resistance to antibiotic therapy has important implications for treatment of respiratory infections. The CDC convened a panel of experts from the disciplines of internal medicine, family medicine, emergency medicine, and infectious disease to develop therapeutic principles for treatment of acute respiratory tract infections in adults.36 The panel noted that "previous antibiotic use is an important risk factor for carriage and infection with antibiotic-resistant S. pneumoniae." This fact highlights the importance of reducing unnecessary antibiotic use for routine, self-limited upper respiratory infections. Documented benefits of this strategy include major reduction in the prevalence of antibiotic resistance in targeted bacterial infections.37 Risks of allergic reactions, unpleasant side effects, and drug-drug interactions are avoided. Noting that most of these infections are nonbacterial in origin, the panel outlined criteria for initiation of antibiotic therapy.36
Most cases of rhinosinusitis are viral in origin. Hickner et al. postulate that no more than 13% of patients with rhinosinusitis presenting for care have a bacterial etiology.38 Clinically, bacterial and viral diseases are difficult to differentiate. Criteria indicating the need for antibiotic therapy are: symptoms lasting seven days or more, pain overlying the maxillary sinuses, tenderness in the face or teeth, and purulent nasal secretions.38 Antibiotic treatment of uncomplicated acute bronchitis in the absence of COPD rarely is efficacious. Generally healthy adults with normal vital signs, normal lung exam, and normal oxygen saturation should not be treated with antibiotics regardless of cough duration. If pneumonia or pertussis is identified, antibiotics are indicated.39
Principles of antibiotic treatment for patients with pneumonia depend upon illness severity; host factors including age, co-morbidity, and recent treatment with antibiotics; and outpatient, inpatient, or intensive care unit (ICU) management. The two main schools of thought in the United States are represented by the Infectious Disease Society of America (IDSA) and the American Thoracic Society (ATS). The IDSA emphasizes tailoring treatment to organisms identified by sputum Gram stain and blood and sputum cultures.40 The ATS emphasizes empiric treatment with antibiotics chosen to cover likely pathogens.26 Both guidelines incorporate core management concepts for the initial empiric treatment of pneumonia patients:41
1. All patients should be covered with an antibiotic or combination that covers the most common bacterial etiologies and atypical pathogens (M. pneumoniae, C. pneumoniae, and Legionella pneumophila).
2. Macrolide monotherapy may be used in patients without major co-morbidity or risk factors for drug-resistant S. pneumoniae (DRSP). (The IDSA recommends doxycycline or tetracycline as an alternative in this group).
3. Patients with risk factors for DRSP or major co-morbidity require therapy with a beta lactam/macrolide combination or an antipneumococcal quinolone.
4. Antipseudomonal beta lactam antibiotics should be limited to patients with severe disease and risk factors for Pseudomonas aeruginosa.
5. Vancomycin therapy should be limited to patients with severe pneumonia and suspected meningitis.
Both the IDSA and the ATS support combination therapy for ICU-admitted patients. Monotherapy with an antipneumococcal fluoroquinolone is inadequate. Initial choices may include a beta lactam in combination with either a macrolide or an antipneumococcal fluoroquinolone.26,40 Tetracycline and quinolones are relatively contraindicated in children younger than 8 years.
The prevalence of resistant respiratory pathogens is dynamic. Most strains of S. pneumoniae continue to respond to the outlined regimens. Antipneumococcal fluoroquinolones remain active against 98% of S. pneumoniae isolates in the United States.40 Vancomycin, virtually 100% effective against this organism, should be restricted to patients with coexistent meningitis or selected critically ill children.41,42 New antibiotic agents holding promise for treatment of resistant respiratory pathogens include telithromycin, gemifloxacin, ertrapenem, and linezolid.40 The cost of these drugs, particularly linezolid, is extremely high. At the present time, there is no indication for empiric treatment in the ED setting.
Streptococcus Pyogenes. Organism and Resistance. Streptococcus pyogenes (S. pyogenes) or Group A Beta hemolytic Streptococcus is the most common bacterial cause of acute tonsillopharyngitis requiring antibiotic therapy.43 The organism is a Gram-positive coccus that appears in chains. To date, this organism remains uniformly susceptible to penicillin, which is the drug of choice.
Infections. Fifteen percent to 30% of pharyngeal infections in children and 5-10% of infections in adults are caused by S. pyogenes. Patients present with tonsillopharyngeal exudate, anterior cervical lymphadenitis, and fever. Pharyngitis caused by Neisseria gonorrhoeae, also requiring antibiotic therapy, presents a similar clinical picture. Therapeutic goals of antibiotic treatment include prevention of suppurative complications such as abscess formation, sinusitis, and mastoiditis; rheumatic fever prevention; and shortening illness duration.43
In addition to pharyngeal infections, S. pyogenes is a skin pathogen causing erysipelas, a subtype of cellulitis. Patients present with a sharply demarcated erythematous, tender skin lesion. Fever and systemic symptoms are common. In rare cases, a devastating necrotizing fasciitis develops. Manifestations include fascial and subcutaneous tissue destruction commonly occurring in an extremity. This toxin-mediated pathologic process is rapidly progressive and frequently fatal. The initial symptom is pain out of proportion to physical findings. The diagnosis may be suggested by findings on magnetic resonance imaging (MRI), computed tomography (CT), or plain films and confirmed by deep incisional biopsies.44 When complicated by the streptococcal toxic shock syndrome, multiorgan system failure, circulatory collapse, and high mortality result. Surgical debridement is the hallmark of treatment.
Antibiotic Treatment of S. pyogenes Infections. Because of the persistent sensitivity of S. pyogenes to it, penicillin remains the first-line drug for infections caused by this pathogen. For treatment of bacterial pharyngitis, a 10-day course is recommended. Adolescents and adults may be treated with a twice-daily regimen of 500 mg. Azithromycin is effective in a 5-day regimen; however, rapid resistance to macrolides has been documented.37 Cooper et al. recommend clinically screening adult patients with pharyngitis using the Centor criteria: history of fever, tonsillar exudates, absence of cough, and tender anterior cervical lymphadenitis.45,46 Those patients having none or one criterion should be neither tested nor treated. If available, test patients with two, three, or four criteria with a rapid antigen test and treat if positive. If a test is unavailable, treat patients with three or four criteria.
When treating erysipelas, penicillin or another beta lactam antibiotic is effective. In cases of necrotizing fasciitis caused by S. pyogenes, penicillin remains the antibiotic of choice. Clindamycin often is co-administered because increased efficacy has been documented; intravenous immunoglobulin also has been recommended.47-49
Staphylococcus Aureus. Staphylococcus aureus is a Gram-positive coccus that occurs singly, in pairs, or in short chains that form characteristic clusters. The organisms are among the hardiest bacteria and intermittently colonize the skin and nasopharynx.
Mechanisms of Antibiotic Resistance to S. Aureus. S. aureus resistance to antibiotics has evolved since the early days of penicillin use. Resistance was reported shortly after its introduction and is the result of beta lactamase production.50 This led to the development of the semisynthetic penicillinase-resistant antibiotics: methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, etc. Beta lactamase production does not confer resistance against these antibiotics nor most cephalosporins. Resistance to chloramphenicol, erythromycin, and the tetracyclines was reported in the 1950s.51
Methicillin resistance first was reported in the early 1960s.52 While methicillin-resistant S. aureus (MRSA) initially was a nosocomial organism, it rapidly has emerged in the community.53-55 Methicillin resistance is conferred by the mecA gene, approximately 30-50 kb of additional chromosomal DNA not present in non-resistant strains. MecA, which encodes PBP2a, is carried on a large genetic element referred to as the staphylococcal cassette chromosome (SCC). S. aureus produces four major PBPs that catalyze a reaction necessary for the synthesis of the bacterial cell wall. PBPs 1, 2, and 3 have high affinity for the beta lactam antibiotics proving lethal to the bacterium. In MRSA, PBP 2a, having low affinity for the beta lactam antibiotics, substitutes for the high-affinity PBPs, allowing survival of the bacterium at antibiotic levels that would otherwise prove lethal.56 In nosocomial MRSA, mecA is carried on a large SCC that codes for methicillin and non-beta lactam antibiotic resistance. Of four known SCC types, types I-III are associated with nosocomial MRSA. SCC type IV carries mecA mediating community-acquired MRSA; it differs in that the SCC is small and does not confer resistance to non-beta lactam antibiotics.57 Increased virulence of the bacterium is associated with community-acquired MRSA strains carrying genes for Panton-Valentine leukocidin (PVL); PVL is a virulence factor found in many strains that encodes a potent toxin associated with necrotizing pneumonia and skin infections.58-60
The glycopeptide antibiotics vancomycin and teicoplanin work against S. aureus by binding to the D-alanyl-D-alanine residues of the murine monomer of the cell wall. In 1996, the first report of vancomycin-resistant S. aureus (VRSA) emerged from Japan.61 An initial report of a VRSA isolate occurring in the United States was identified in June 2002.62 The postulated mechanism of resistance is abnormal cell wall thickness in the VRSA strains. Thirty to 40 extra layers of peptidoglycan and murein monomers have been identified by biochemical and transmission electron microscopy. These extra layers are thought to trap vancomycin molecules. The molecules then destroy the mesh structure of the outer layers of peptidoglycan preventing further vancomycin penetration. This is referred to as the "clogging phenomenon."63
Infections. Skin breaches from trauma or surgery provide opportunity for establishment of characteristic infection. S. aureus infection takes many forms from superficial and relatively benign skin lesions to overwhelming toxin-mediated sepsis syndromes. (See Table 3.) Necrotizing fasciitis, clinically indistinguishable from that caused by S. pyogenes, has been reported.64
| Table 3. Clinical Manifestations of S. Aureus Infections |
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Toxin-mediated skin syndromes include the staphylococcal scalded skin syndrome occurring primarily in children younger than 5 years of age; it responds well to localized skin care and fluid and electrolyte management. Toxic shock syndrome was described in 1980 in menstruating women and was associated with use of hyperabsorbable tampons. Nonmenstrual toxic shock syndrome occurs in association with vaginal infections, use of contraceptives, childbirth, abortion, and the postpartum state. Forty percent, however, are post-operative complications in wounds that do not appear overtly infected. This multisystem disorder presents with fever, intense myalgias, vomiting, diarrhea, conjunctivitis, and an erythematous rash. Organ involvement may include renal failure, hepatic inflammation, and adult respiratory distress syndrome. Aggressive critical care including treatment with a beta lactamase-resistant antistaphylococcal antibiotic and clindamycin has reduced the mortality of the disorder to the 3-5% range.64
Community-acquired MRSA is a clinically important pathogen in medical practice. Skin infection, particularly furunculosis, is the most common manifestation. The organism directly invades skin and surrounding soft tissues, producing abscesses and/or cellulitis.65 Skin infections usually remain localized, but bacteremia and other systemic complications have been reported.60,66 Necrotizing pneumonia is a potentially deadly manifestation of community-acquired MRSA.58,67 Preceding influenza infection is common. The clinical presentation is characterized by high fevers, hemoptysis, and hypotension. Multilobar pulmonary infiltrates develop that progress into abscesses. Septic shock and respiratory failure are common, and mortality is high.
Empiric Antibiotic Treatment of Skin Infections
In geographic regions with high percentages of community-acquired MRSA, the approach to empiric antibiotic coverage in ED patients with suspected S. aureus infections is changing. Life-threatening infections should be treated empirically with intravenous vancomycin. Optimal antibiotic treatment of less serious skin infections has not been determined by clinical outcome studies. Data from clinical trials are demonstrating high rates of in vitro resistance to beta lactam antibiotics in S. aureus cultured from skin infections in ED patients in some regions.59,68 It now is difficult to justify the use of beta lactam antibiotics in these communities. Adequate surgical drainage of skin abscesses is most important. In cases where adequate drainage is achieved and the patient manifests no evidence of cellulites or systemic illness, no antibiotic treatment is necessary.
Community-acquired MRSA remains highly susceptible to clindamycin, trimethoprim-sulfamethoxazole, rifampin, and tetracycline. Treating patients with a combination of trimethoprim-sulfamethoxazole and rifampin should be considered in patients thought to be nasal carriers of MRSA.69 Physicians should cover S. pyogenes in patients with cellulitis, the more likely pathogen in patients without abscess formation. Penicillin and beta lactam antibiotics remain active against S. pyogenes. Use of the combination of cephalexin and trimethoprim-sulfamethoxazole is a reasonable choice in cases where coverage of S. aureus and S. pyogenes is desirable. Clindamycin as a single agent is another option; however, potential drawbacks must be considered. These include cost, frequent dosing, adverse reactions (particularly pseudomembranous colitis), and the phenomenon of inducible resistance.59,69 The latter has been demonstrated in erythromycin resistant-clindamycin susceptible strains; the clinical relevance is not clear.70
Newer antibiotics may become important in the treatment of resistant strains of S. aureus. At this time, all have drawbacks including high cost and absence of clinical outcomes data showing advantage over less expensive drugs. Linezolid is effective in treating MRSA infections; toxicity with prolonged use and very high cost are major disadvantages at this time. Daptomycin is approved for treating Gram-positive skin and soft-tissue infections; it is very expensive and is thought to poorly penetrate alveolar secretions.55 Other agents are in Phase III clinical trial evaluation.
Escherichia coli. Escherichia coli (E. coli) is a Gram-negative bacillus that is the most frequent cause of urinary tract infections and one of the most common causes of bacteremia. Strains of the bacteria normally colonize the colon. Colonizing strains generally are less virulent than pathogenic isolates from infections of the urinary tract, blood, and meninges.71 Interestingly, Gram-negative bacteremia rarely occurred before the antibiotic era. Prior to the 1920s, fewer than 100 cases were reported in the medical literature. The influence of antibiotic introduction probably selected for Gram-negative bacteria. Factors that predispose to Gram-negative infection include advanced age, increasing prevalence of co-morbid illnesses, and increased numbers of patients with immunosuppressive illnesses.72
Mechanisms of Antibiotic Resistance to Escherichia coli. Antibiotic resistance to E. coli has developed through multiple mechanisms. All arise from changes in bacterial genes. Efflux pumps are particularly efficient resistance mechanisms utilized by E. coli and many other bacteria against an array of antibiotics. Drug molecules are captured and pumped out of the bacteria.73 E. coli resistance to beta lactam antibiotics occurs through three potential mechanisms: beta lactamase production (most common), PBP alterations, and decreased accumulation of the drugs by the bacterium. Sabate et al. found that hyper-production of chromosomal beta lactamase was the most frequent mechanism conferring resistance to broad spectrum cephalosporins.74
Urinary tract pathogen data were collated from the SENTRY Antimicrobial Surveillance Program for the year 2000.75 Isolates were obtained from hospitalized patients. E. coli were the most commonly identified bacteria, responsible for 43.3% of urinary tract infections in North America. The next three pathogens by frequency of occurrence were Enterococcus spp. (15.8%), Klebsiella spp. (12.0%), and P. aeuruginosa (7.2%). Table 4 lists percentages of antibiotic susceptibility of these organisms to commonly prescribed oral antibiotics in North America.75 Physicians should consider this information when treating patients ill enough to require admission.
| Table 4. Antibiotic Susceptibility for the Top 4 Urinary Tract Pathogens in North America Identified by SENTRY Program Data in 2000 |
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The impact of in vitro TMP-SMX resistance to urinary pathogens has been studied. Clinical outcome data show high correlation between laboratory resistance and treatment failure. Brown et al demonstrated that women with resistant strains of E. coli were greater than 17 times as likely as those with susceptible strains to fail treatment with TMP-SMX. They also noted that recent treatment with TMP-SMX conferred a 16-fold increase in likelihood of harboring a resistant organism.76 Other investigators have found similar results suggesting that TMP-SMX is no more effective than placebo in patients with resistant organisms.77,78 Table 5 quantifies resistance of community-acquired E. coli to commonly prescribed oral antibiotics.79
| Table 5. Trends in Resistance Rates of E. Coli Isolated from Female Subjects with Acute Uncomplicated Cystitis |
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Infections. The urinary tract is the most common site of E. coli infection. The normally sterile urinary tract may become infected at any point from the kidney to the bladder when invaded by bacteria. Uncomplicated cystitis commonly is experienced by otherwise healthy women predisposed to infection by a short urethra. In the outpatient setting, Staphylococcus saprophyticus is the second most common pathogen causing acute uncomplicated cystitis, responsible for 5-10% of infections. This organism typically infects young sexually active females.80,81 Classic symptoms include dysuria, urinary frequency, and urinary urgency. Pyelonephritis presents with flank pain, fever, chills, and other systemic symptoms such as vomiting. Bacteremia can complicate this infection. Host factors that predispose to urinary obstruction, including prostatic hypertrophy, kidney stones, congenital malformations, and Foley catheters, increase the likelihood of sepsis from urinary tract infections.82
Antibiotic Treatment of Urinary Tract Infections
Antibiotic treatment of urinary tract infections must be considered in light of local patterns of resistance to E. coli. Patient factors that predispose individuals to E. coli resistant to TMP-SMX include diabetes, recent hospitalization, current use of any antibiotic, and current or recent use of TMP-SMX.83 The most recent IDSA guidelines recommend 3-day therapy as the standard for treatment of acute uncomplicated cystitis.84 TMP-SMX should be used only in communities with rates of resistance lower than 10-20%. Trimethoprim alone may be used in patients allergic to sulfa. Where resistance rates exceed this level, fluoroquinolones should be considered first-line treatment. Hospital antibiograms provide readily available data on local patterns of resistance. When using these information sources, physicians must consider that inpatient and outpatient data often are collated together resulting in overestimation of resistance in community-acquired infections.
Amoxicillin and first-generation cephalosporins are treatment options for patients with contraindications to fluoroquinolones and TMP-SMX. Nitrofurantoin can be used for uncomplicated lower urinary tract infections. It is limited by poor tissue penetration and should not be used for upper tract infections.85
For treatment of pyelonephritis, the IDSA recommends 14 days of therapy; however, it acknowledges that 7 days of highly active treatment may be sufficient for mild or moderate cases. An oral fluoroquinolone is recommended unless the bacterial etiology is known to be susceptible to TMP-SMX. Talan et al. demonstrated the superiority of 7 days of ciprofloxacin to 14 days of TMP-SMX for treatment of uncomplicated pyelonephritis.78 Severely ill patients require hospitalization and parenteral treatment with fluoroquinolones, an aminoglycoside with or without ampicillin, or an extended-spectrum cephalosporin with or without an aminoglycoside.
Conclusion
Antibiotic resistance to community-acquired infections now influences patients, physicians, and pharmacists on a daily basis. An intelligent approach to treatment using evidence-based guidelines is necessary. Both individual patients and the community benefit from withholding antibiotics for minor respiratory infections. Knowledge of likely pathogens, local resistance patterns, and specialty society guidelines provide the basis for appropriate antibiotic choices in patients requiring treatment. Despite increasing documentation of resistance, community-acquired pneumonia continues to respond to common antibiotics. S. pyogenes manifests no penicillin resistance, though virulent toxin-producing strains produce devastating infections. Resistant S. aureus isolates, no longer limited to nosocomial infections, demonstrate increasing prevalence in the community. E. coli community-acquired urinary tract infections, increasingly resistant to in vitro measures of antibiotic susceptibility, still respond well to common oral antibiotics. New generations of antibiotics are on the horizon. Microbiologists and pharmacologists continue to study and defeat the mutations and adaptations of mankind's oldest and smallest foes.
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Bacterial resistance to antibiotic treatment has concerned the medical community since the introduction of the first antibiotics in the 1920s. Development of new anti-infective agents has been precipitated by increasing resistance to older agents and classes of agents. While high rates of resistant organisms have been particularly problematic in hospital intensive care units, serious resistance now is being encountered in community-acquired infections. This review will focus on the clinical aspects of antibiotic resistance in community-acquired respiratory infections, pharyngitis, skin infections, and urinary tract infections.Subscribe Now for Access
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