Review What are the factors to be considered in choosing an antimicrobial agent?
Mẹo về What are the factors to be considered in choosing an antimicrobial agent? 2022
Hä tªn bè đang tìm kiếm từ khóa What are the factors to be considered in choosing an antimicrobial agent? được Cập Nhật vào lúc : 2022-10-11 23:38:04 . Với phương châm chia sẻ Mẹo Hướng dẫn trong nội dung bài viết một cách Chi Tiết 2022. Nếu sau khi tham khảo tài liệu vẫn ko hiểu thì hoàn toàn có thể lại Comments ở cuối bài để Tác giả lý giải và hướng dẫn lại nha.Pneumonia and Other Respiratory Infections
Nội dung chính- Pneumonia and Other Respiratory Infections Skin and Soft Tissue Infections Gastrointestinal Infections Infectious Diarrhea C. difficile-Associated Diarrhea Bone and Joint Infections
Osteomyelitis Septic Arthritis Prosthetic Joint Infection Central Nervous System Infection Meningitis Encephalitis Healthcare-Associated Infections Healthcare-Associated Pneumonia Skin and Soft Tissue Infections Urinary Tract Infection BacteremiaWhat three factors should be considered in selecting an appropriate antimicrobial drug?What are the 5 characteristics of an ideal antimicrobial agents?What factors are responsible for the effectiveness of antimicrobial agents?
The physiology, microbiology, and management of pneumonia in older patients are discussed greater length in Chapter 126. A limited discussion of the specific factors that influence the selection of antimicrobial therapy for older patients with respiratory infection is offered here in order to demonstrate the application of the paradigm for antimicrobial selection outlined in Table 125-1.
Anticipation of the causative pathogen is central to the appropriate selection of empiric antimicrobial therapy for older patients with respiratory infection. To this end, a number of clinical features have been associated with specific causative pathogens. However, these associations generally do not stand up to more rigorous scrutiny, especially in older patients. Of greater utility in predicting the causative pathogen in community-acquired pneumonia are the epidemiological features that distinguish one patient from the next, including nursing home residence and recent hospitalization.
In the absence of unique clinical or epidemiological features to suggest chronic respiratory infection (such as that cause by M. tuberculosis) or viral pneumonia, clinicians caring for older patients must make every effort to optimize their management of community-acquired pneumonia. For older patients, as for younger patients with pneumonia, there are a number of suitable therapeutic options to address the suspected pathogens (Table 125-4). These regimens are generally well tolerated, although clinicians must be alert to common toxicities, such as gastrointestinal distress caused by macrolides or mental status changes caused by fluoroquinolones.
Table 125-4 Common Pathogens and Optimal Treatments for Older Patients with Community-Associated Pneumonia
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Table 125-4 Common Pathogens and Optimal Treatments for Older Patients with Community-Associated Pneumonia
CLINICAL SETTING
COMMON PATHOGENS
RECOMMENDED EMPIRICAL REGIMEN
Community-acquired, not hospitalized
S. pneumoniae, atypical bacteria (M. pneumoniae, C. pneumoniae), viral pathogens
Respiratory fluoroquinolone, or azithromyc in plus high-dose amoxicillin
Community-acquired, hospitalized
S. pneumoniae, atypical bacteria (M. pneumoniae, C. pneumoniae)
Ceftriaxone plus azithromycin, or respiratory fluoroquinolone
Community-acquired, hospitalized in ICU
S. pneumoniae, Legionella spp.
3rd generation cephalosporin plus respiratory fluoroquinolone
Community-acquired, LTCF resident
S. pneumoniae, influeza, enterobactereciae, P. aeruginosa
3rd generation cephalosporin plus respiratory fluoroquinolone plus vancomycin (if S. aureus or MRSA suspected)
Hospital-acquired
P. aeruginosa, enterobactericiae
Imipenem or piperacillin/tazobactam plus respiratory fluoroquinolone plus vancomycin (if S. aureus or MRSA suspected)
The most appropriate duration of therapy for community-acquired pneumonia in the older patient has not been rigorously assessed. Conventionally, most patients will receive between 10 and 14 days of treatment.
Skin and Soft Tissue Infections
The skin of older patients is especially vulnerable to infection with a wide range of microorganisms as a result of the physiologic and physical changes to the integument that accompany aging. As is true for younger patients, the majority of skin and soft tissue infections in the older adults are caused by the gram-positive bacteria that normally colonize the skin. Streptococcal and staphylococcal species predominate. However, it is important to recognize the potential for disruption of the native skin flora as a result of certain comorbidities, such as diabetes mellitus, or recent antimicrobial therapy which may lead to a greater proportion of cutaneous infections caused by other less common pathogens. In such patients, cellulitis, furunculosis, or folliculitis may be caused by gram-negative bacteria, including Escherichia coli and Klebsiella spp. Less commonly, Pseudomonas aeruginosa may be isolated as the cause of skin infection in an older patient.
The increased breadth of pathogens associated with skin and soft tissue infections among older patients is further complicated by the challenge of obtaining definitive microbiological diagnosis in such cases. Cultures of blood, skin swabs, and even skin biopsies are likely to be of low yield in establishing the causative pathogen of nonsuppurative infections like cellulitis. As a result, empiric therapy is the rule for treating patients with skin infection. When there is abscess material to be sampled, it is critical that specimens be collected as quickly as possible, preferably prior to the institution of antimicrobial therapy. Providing further rationale for incision and drainage of a furuncle is the fact that antimicrobial therapy may be unnecessary in the setting of adequate drainage. However, the decision to withhold antimicrobial therapy for furunculosis should only be contemplated in a stable patient with good baseline health without extensive soft tissue inflammation.
Once empiric therapy is started, the older patient with skin and soft tissue infection should be monitored closely for signs of improvement, as delayed recovery may be indicative of clinical failure as a result of inadequate antimicrobial coverage. Clinicians should monitor the patient for improvement in systemic signs of infection within the first 24 to 48 hours of antibiotic therapy and consideration should be given to modifying therapy for patients who appear to be failing.
Older patients, whether because of the phenomenon of immunosenescence, comorbid conditions, or immunosuppressive drug therapy, may be increased risk for rapidly-progressive skin and soft tissue infection, including necrotizing fasciitis. In general, an older patient evaluated in the acute care setting for skin and soft tissue infection should be followed closely for early evidence of rapid spread of infection. Skin infection that measurably expands within the first hours of evaluation represents a potentially life-threatening emergency. In addition to broadening antimicrobial coverage, urgent surgical consultation is warranted.
The management of skin and soft tissue infections among all patients has been complicated in recent years by the emergence of strains of Staphylococcus aureus-resistant to methicillin in individuals without prior contact with the healthcare system or exposure to antibacterial agents. So-called community-associated methicillin-resistant S. aureus (MRSA) appears to be associated with particularly severe and recurrent skin infections. While the extent to which this emerging pathogen specifically affects older patients is not yet known, clinicians must be aware of this new epidemiological trend and adjust the choice of empiric therapy accordingly.
Despite concerns for gram-negative or antimicrobial-resistant pathogens, initial antimicrobial therapy active against streptococci and staphylococci remains appropriate for older patients with skin and soft tissue infection. Commonly-selected regimens include antistaphylococcal penicillin such as dicloxacillin (oral) or oxacillin (parenteral), or a first-generation cephalosporin such as cephalexin (oral) or cefazolin (parenteral). The rationale for choosing parenteral rather than oral therapy is based on the assessment of severity of illness. While penicillin offers adequate coverage for streptococcal infection, the typical absence of a confirmed microbiological diagnosis precludes this approach given the lack of activity of penicillin against nearly all staphylococci. For patients with allergy to β-lactam agents, clinicians may elect to treat with clindamycin, a macrolide or a tetracycline derivative (such as doxycycline). Antimicrobial agents active against MRSA are discussed in greater detail in the section on healthcare-associated infection.
Possible regimens for skin and soft tissue infection are generally well tolerated in older patients. There are limited drug interactions between these antibiotics and the pharmaceutical agents commonly prescribed to older adults. The duration of therapy should be approximately 2 weeks; however, there are limited data available comparing the effectiveness of different durations of therapy. In all cases, incision and drainage of any purulent collection offers not only the opportunity for microbiological diagnosis, but also improved likelihood of clinical resolution.
Gastrointestinal Infections
Infectious Diarrhea
As in other age groups, infectious diarrhea may represent nothing more than a harmless nuisance to the older patient. However, by some estimates 50–85% of the mortality associated with diarrheal illness in developed nations occurs in geriatric populations.
Certain epidemiologic factors may increase an elderly patient's risk for gastrointestinal infection with certain pathogens—such residence in a nursing home, known to be loci of norovirus outbreaks, or recent hospitalization or antimicrobial use, which should bring consideration of Clostridium difficile to mind. Clinical and epidemiological clues as to the causative pathogen may also be gained by inquiring about: how the illness began; stool characteristics (frequency and quantity); symptoms or signs of hypovolemia; travel history; whether the patient has ingested raw or undercooked meat, raw seafood, or raw milk; whether the patient's contacts are ill; the patient's sexual contacts, medications, and other medical conditions if any.
An older patient presenting with fever, tenesmus, and bloody stools should be evaluated for inflammatory or invasive diarrhea caused by Salmonella, Shigella, Campylobacter, Yersinia, or C. difficile. For this group, antimicrobial therapy may be appropriate. While clinicians may choose to treat empirically and not perform stool cultures, the utility of confirmatory testing for a microbiological diagnosis may be especially high in an institutional setting in which a number of individuals appear to have similar complaints. In addition, stool cultures can be beneficial to the care of the individual patient by identifying etiologic agents that do not require antimicrobial therapy (such as viral pathogens), thus avoiding unnecessary antibiotic use. Lastly, antimicrobial resistance has been observed in a number of enteric pathogens, including fluoroquinolone resistance in Campylobacter and multidrug resistance in Salmonella. As a general rule, it is probably wise to obtain stool testing from patients with diarrhea that has lasted longer than 1 day, is accompanied by fever, hematochezia, systemic illness, or dehydration, or in individuals who have recently been hospitalized or have received recent antimicrobials.
Having identified inflammatory diarrhea in an older individual and developed a suspicion about the likely pathogen based on epidemiologic clues, the next step is to determine whether or not to initiate antimicrobial therapy all. Individuals with diarrhea caused by the E. coli O157:H7 strain may be more likely to develop hemolytic uremic syndrome after therapy with certain antimicrobials. Treatment of diarrhea caused by Salmonella spp. with fluoroquinolone agents can lead to a prolonged carrier state or relapse of symptoms. The decision to initiate antimicrobial therapy should be guided by an assessment of the patient's severity of illness as well as their comorbid medical conditions. Empiric recommendations are detailed in Table 125-5. Duration of therapy may range from 3 to 14 days depending upon the enteric pathogen, as outlined in Table 125-5. Anticipated toxicities may include exacerbation of intestinal distress by doxycycline or rash secondary to trimethoprim-sulfamethoxazole.
Table 125-5 Antimicrobial Recommendations for Enteric Pathogens
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Table 125-5 Antimicrobial Recommendations for Enteric Pathogens
ORGANISM
OPTIONS FOR THERAPY
SPECIAL CONSIDERATIONS
Aeromonas/Plesiomonas
Trimethoprim-sulfamethoxazole
Fluoroquinolone
Campylobacter spp.
Erythromycin
C. difficile
Metronidazole
Discontinue antimicrobial therapy, if possible
Oral vancomycin
Recurrences can be managed with repeat courses of metronidazole
E. coli spp.
Enterohemorrhagic (STEC)
Role of antimicrobials unclear, avoid administration. Avoid antimotility agents
Enteroinvasive
Trimethoprim- sulfamethoxazole
Fluoroquinolone
Enteropathogenic
Trimethoprim-sulfamethoxazole
Fluoroquinolone
Enterotoxigenic
Trimethoprim-sulfamethoxazole
Fluoroquinolone
Giardia lamblia
Metronidazole
Salmonella, non-typhi spp.
Trimethoprim-sulfamethoxazole
Be aware of possibility of trimethoprim-sulfamethoxazole and fluoroquinolone resistance
Fluoroquinolone
Ceftriaxone
Shigella spp.
Trimethoprim-sulfamethoxazole
Fluoroquinolone
Ceftriaxone
Azithromycin
C. difficile-Associated Diarrhea
Advanced age is a well-established risk factor for C. difficile-associated diarrhea (CDAD). The vulnerability to CDAD in the geriatric age group is felt to be explained by age-related changes in the fecal flora, immunosenescense, and the presence of other comorid medical conditions.
Symptoms of CDAD can range from several loose stools a day without fever or clinical instability to a debilitating watery diarrhea associated with abdominal cramping, fever, leukocytosis with consequent dehydration and electrolyte losses. In advanced disease, a dangerous ileus may develop and the most severely ill patients may require colectomy. The range of manifestations highlights the need to remain vigilant for the possibility of C. difficile infection in patients recently treated with antimicrobials.
Contact with the healthcare system is a known risk for acquiring C. difficile colonization, which can then progress to infection following the administration of antibiotics. Nearly every antimicrobial agent has been implicated as a risk factor for CDAD and outbreaks have been seen both in acute care hospitals as well as long-term care facilities.
The initial approach to the management of CDAD includes discontinuing all precipitating antimicrobial agents (if possible), replacement of fluid and electrolyte losses, and avoidance of antimotility agents. Conservative management will not be sufficient for the majority of patients, and therapy with either metronidazole or vancomycin is needed. Although oral vancomycin is the only FDA-approved agent for treating CDAD, most guidelines recommend initiating therapy with oral metronidazole. This is because of the higher cost of vancomycin, the concern that use of vancomycin will lead to selection of vancomycin-resistant enterococci, and the fact that vancomycin was not been shown to be superior to metronidazole in head-to-head studies. Vancomycin may be considered for individuals who cannot tolerate oral metronidazole or for those patients who fail to improve with metronidazole therapy. Duration of therapy of 10 to 14 days is recommended.
It is estimated that recurrence of CDAD following the completion of therapy occurs in as many as half of cases. It is recommended that recurrence be managed with a repeated course of oral metronidazole of standard duration.
Probiotics such as Sacharomyces boulardii and Lactobacillus rhamnosus are microorganisms of low pathogenicity that may be used to re-populate the normal bowel flora that has been eliminated through the use of antimicrobial agents. Unfortunately, they have not been shown to be of great benefit. Use of probiotics should be avoided in immunocompromised individuals because of the possibility of invasive infection caused by these organisms.
Bone and Joint Infections
Osteomyelitis
Bone infection presents both diagnostic and therapeutic challenges in all patient populations, but especially in older patients. Because manifestations of disease may be nonspecific, the first step in making the diagnosis of bone infection is the timely recognition of predisposing factors, such as loss of overlying skin and soft tissue integrity. The forms of osteomyelitis typically seen in older patients are vertebral osteomyelitis, generally secondary to bacteremic seeding, and contiguous osteomyelitis, which may or may not be associated with vascular insufficiency. In all forms of osteomyelitis in this population, identification of the causative pathogen greatly improves the likelihood of administering appropriate antimicrobial therapy. In most cases of spine infection as well as in cases of contiguous osteomyelitis, bone biopsy is almost always necessary to establish the pathological diagnosis and to identify the causative organisms so that appropriate therapy may be chosen. See Table 125-6 for anticipated pathogens and recommended regimens for treatment of osteomyelitis.
Table 125-6 Subtypes of Bacterial Osteomyelitis Among Older Patients
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Table 125-6 Subtypes of Bacterial Osteomyelitis Among Older Patients
TYPICAL CLINICAL SETTING
COMMON PATHOGENS
RECOMMENDED EMPIRICAL REGIMEN
Spinal osteomyelitis
Bacteremic spread from other source of infection
S. aureus (including MRSA), streptococci
Vancomycin
Osteomyelitis from contiguous spread with vascular insufficiency
Diabetic foot ulcer
S. aureus, streptococci, enterococci, gram-negative pathogens, anaerobes
IV: ertapenem, ampicillin/sulbactam, vancomycin (if MRSA suspected)
Orally: amoxiciilin/clavulanate, fluoroquinolone plus clindamycin
Osteomyelitis from contiguous spread without vascular insufficiency
Pressure ulcer
S. aureus, streptococci, enterococci, gram-negative pathogens, anaerobes
Imipenem, piperacillin/tazobactam, vancomycin (if MRSA suspected)
Vertebral osteomyelitis generally presents subacutely with fever and back pain; other constitutional symptoms such as night sweats or weight loss may also be present. The presentation in an elderly individual may be subtle or atypical and the presence of preexisting back pain may delay recognition of a new infectious process this site. Knowledge of a primary site of infection from which the bone has been seeded is a clue to the pathogen, although frequently the primary site is unknown. Skin and soft tissue pathogens, particularly S. aureus, are most commonly involved, but genitourinary and respiratory infections, infected intravenous catheters, postoperative wounds, endocarditis, and dental sources are all considerations. In a patient with known or suspected exposure to tuberculosis, Pott's disease (tuberculosis of the spine) is a concern.
Because of the more chronic nature of the infection, empiric antimicrobial therapy may be safely withheld from the older patient with suspected vertebral osteomyelitis until cultures have been performed in order to increase the likelihood of identifying the infecting pathogen. A caveat to this is that patients experiencing neurological deficits, including new lower extremity sensory or motor deficits or bowel or bladder dysfunction, should receive prompt treatment with antimicrobials, as well as neurosurgical evaluation. While awaiting culture results once specimens have been collected, it may be reasonable to cover broadly for gram-positive skin and soft tissue organisms, particularly S. aureus, with a first-generation cephalosporin or an antistaphylococcal penicillin. In a patient with a history of MRSA or risk factors for MRSA, vancomycin is an appropriate addition. In a patient with known urinary tract infection or prostatitis, gram-negative coverage with a third-generation cephalosporin or a fluoroquinolone should be added. Once the infecting organism is identified, coverage can be narrowed and is generally continued for 4 to 6 weeks in intravenous or highly orally bioavailable form. Adverse effects associated with therapy for osteomyelitis include the complications of long-term intravenous access, such as line infection or thrombosis caused by the foreign body toàn thân. Long-term β-lactam use may be associated with bone marrow suppression or hepatic toxicity. Prolonged vancomycin use may also result in bone marrow suppression or, infrequently, renal toxicity. Regular monitoring of blood counts and liver and kidney function is advised with prolonged use of any intravenous antimicrobial therapy, especially in older patients.
Osteomyelitis caused by contiguous spread of infection with vascular insufficiency generally refers to diabetic ulcers of the lower extremity, but may also occur in individuals with severe peripheral vascular disease. Patients typically present with a long-standing ulcer of the foot, possibly with concurrent cellulitis or purulent drainage. Polymicrobial infection is the rule; S. aureus, streptococci, enterococci, gram-negatives, and anaerobes are frequently seen. Bone biopsy for culture is valuable in identifying the causative organisms, as well as confirming the pathological changes of acute osteomyelitis, and is not associated with exacerbation of the infection. This infection may be slow to respond to antimicrobial therapy, particularly if underlying issues of blood glucose control and vascular supply are not addressed. In many cases, the goal of therapy is to suppress infection and maintain functional status. Wound care and surgical management are equal partners to treatment with antimicrobial agents. Antimicrobial therapy is generally prolonged, but can often be administered orally, owing to the availability of oral agents with superior bone penetration, such as amoxicillin/clavulanate, trimethoprim-sulfamethoxazole, clindamycin, and ciprofloxacin.
Osteomyelitis caused by contiguous spread of infection without vascular insufficiency is most often associated with trauma, but pressure ulcers are a particular concern in bed-bound elderly individuals. These infections are generally polymicrobial in cause and may include staphylococci and streptococci. In the case of sacral pressure ulcers, Gram-negatives and anaerobes may be present given the proximity to the rectum and the likelihood of stool contamination of broken skin. Recommended empiric therapy should be broad, but can later be narrowed on the basis of cultures from deep tissue biopsy or debridement. Antimicrobial-resistant organisms are a concern, particularly in institutionalized patients, and culture-guided therapy may need to be administered for MRSA, VRE, or resistant gram-negatives. Surgical management is a critical component of therapy, the purposes of which include: drainage, debridement, obliteration of dead space, and wound protection. Proper wound care is also necessary, as is well described in Chapter 124.
Septic Arthritis
Septic arthritis is an infection with high morbidity and mortality. Elderly patients are particularly risk, by virtue of pre-existing joint disease caused by rheumatoid arthritis, osteoarthritis, and gout, which are known risk factors for septic arthritis. Patients typically present with fever, pain, warmth, swelling, and decreased range of motion the infected joint, although these may be absent in older patients. Gonococcal arthritis is common in young adults, but fairly infrequent in the elderly population, although it should be considered in the setting of appropriate risk factors. Gram-positive organisms are prominent, both because of the pathogenesis of bacteremic seeding from compromise of the skin and because of the proclivity of these organism to adhere to the connective tissue and extracellular matrix proteins of the joints. As such, S. aureus is the most commonly implicated organism and is associated with notably poor outcomes. Group B beta-hemolytic streptococcus (S. agalactiae) is seen in association with diabetes, cirrhosis, advanced age, and neurologic disease. S. pneumoniae may occur following invasive pulmonary infection, but also occasionally in the absence of pneumonia. Gram-negative infections may occur following genitourinary infection, and are also associated with intravenous drug use, particularly P. aeruginosa. Coagulase negative staphylococci may be seen following joint arthroscopy.
Joint aspiration is necessary both to confirm the presence of septic arthritis and identify the causative organism. Gram stain of fluid is not particularly sensitive, so empiric therapy should be instituted before cultures results are available. Because the infection is rapidly destructive and has a high mortality, therapy should be initiated rapidly. If Gram stain is negative, an antimicrobial agent that covers staphylococci and streptococci as well as gram-negatives should be initiated, such as ceftriaxone. Many would also advise initial vancomycin therapy for the possibility of MRSA. Intravenous therapy is typically used for a 3-week duration. Surgical therapy is an important component of management, and joint drainage and irrigation should be performed to allow for decompression of the joint, improvement in blood flow, and removal of bacteria, toxins, and proteases. Open drainage should be considered in the case of a slow clinical response or inaccessible joint, such as the shoulder joint. See Table 125-7 for common pathogens and suggested empiric treatment for septic arthritis.
Table 125-7 Common Pathogens and Optimal Treatments for Older Patients with Septic Arthritis
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Table 125-7 Common Pathogens and Optimal Treatments for Older Patients with Septic Arthritis
CAUSATIVE PATHOGEN
EPIDEMIOLOGICAL CLUES AND RISK FACTORS
OPTIMAL THERAPY
S. aureus
Usually bacteremic spread from other site of infection
Vancomycin if MRSA is suspected. Otherwise nafcillin or oxacillin
N. gonorrhea
Sexually active patient
3rd generation cephalosporin
S. pneumoniae
May follow pulmonary infection
3rd generation cephalosporin
Group B streptococcus
Diabetes, cirrhosis, neurological disease
Penicillin G or 3rd generation cephalosporin
Prosthetic Joint Infection
This issue is covered in more detail in Chapter 116, but certain points will be highlighted here as they serve to illustrate key issues of antimicrobial management in the elderly population. One of the foremost of these is the well-established association between timing of infection relative to surgery and likely organisms isolated, an excellent example of how epidemiologic clues can help guide empiric antimicrobial therapy in older patients. The presentation of prosthetic joint infection is typically divided into 3 stages based on how soon after joint implantation the infection occurs (see Table 125-8). Early infections occur within the first 3 months following joint implantation and are typically caused by highly pathogenic organisms, such as S. aureus or Gram negatives that were inoculated during the original surgery. Delayed infections, occurring 3 to 24 months followings surgery, are also felt to have been inoculated during the original surgery, but involve less virulent pathogens, such as coagulase negative staphylococci and Propionobacterium that present in a subacute manner. Late infections, occurring more than 24 months after surgery, are felt to arise through hematogenous seeding of the prosthetic material, and, as such, involve virulent organisms typically associated with bacteremias, such as S. aureus from skin sources, and the appropriate organisms from respiratory, dental, and genitourinary sources.
Table 125-8 Bacteria Associated with Prosthetic Joint Infection by Time of Presentation
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Table 125-8 Bacteria Associated with Prosthetic Joint Infection by Time of Presentation
TIMING
MOST COMMON PATHOGEN(S)
Early
0–3 months postoperative
S. aureus (including MRSA), gramnegative bacteria
Delayed
3–24 months postoperative
Coagulase-negative staphylococci, Proprionobacterium spp.
Late
>24 months postoperative
S. aureus (including MRSA), other pathogens from bacteremic spread
Identification of the infecting organism may be facilitated by blood cultures, but often requires direct culture of joint fluid or tissue obtained from operative debridement or prosthetic removal. In the case of delayed infection, which is generally subacute, it is appropriate to withhold antimicrobial therapy until after cultures are obtained or if therapy has been initiated to stop therapy 2 to 4 weeks prior to obtaining operative cultures to improve the diagnostic yield of these cultures. Multiple tissue cultures are useful to confirm the pathogen status of organisms of low virulence like coagulase negative Staphylococcus or Propionobacterium. Empiric choice of antimicrobials should include coverage for resistant gram-positive organisms like MRSA or coagulase negative staphylococci—generally, vancomycin is used. Gram-negative coverage with a third-generation cephalosporin may be utilized if these less common culprits are suspected.
Once the causative organism is identified and directed therapy is chosen, it is necessary to consider addition of an agent like rifampin for its ability to penetrate biofilms. Bacteria growing on prosthetic material often form a biofilm—a community of bacteria growing within a polymeric matrix. Antimicrobials diffuse poorly through biofilms and bacteria within them assume a stationary growth phase that makes them less susceptible to antimicrobials with activity against dividing bacteria. Antimicrobial therapy for prosthetic infections must be prolonged in order to counter the resistance to therapy imparted by the biofilm. While intravenous agents such as antistaphylococcal penicillins, first-generation cephalosporins, or vancomycin are typically used along with rifampin, several older studies found that oral combinations of fluoroquinolones and rifampin also successfully treated prosthetic joint infections. Unfortunately, resistance to fluoroquinolones has become so prevalent in staphylococci that this is no longer a reliable combination. Rifampin should be used cautiously given its effect on hepatic metabolism and numerous consequent drug–drug interactions.
The most appropriate duration of therapy for prosthetic joint infection is typically prolonged and may range from several months to life-long therapy depending upon whether the infected prosthesis is removed.
Central Nervous System Infection
The manifestations of infection of the central nervous system (CNS) among both older and younger patients range from self-limited and benign to abrupt and lethal. Careful review of the patient's presenting complaints, history, examination and initial laboratory and radiographic data should permit a clear distinction between the infectious syndromes of the nervous system, including meningitis, encephalitis, and brain abscess. Figure 125-2 outlines the approach to managing an older patient with suspected CNS infection.
Figure 125-2.
Approach to the older patient with suspected CNS infection.
Meningitis
Signs and symptoms of bacterial infection of the CNS must be recognized in a timely manner in order to ensure the best possible clinical outcome. Unfortunately, the classical signs and symptoms of meningitis may be masked among older patients, contributing to a delay in diagnosis. Generally speaking, clinicians caring for older patients are well advised to have a low threshold to aggressively pursue the diagnosis of meningitis with early lumbar puncture and cerebrospinal fluid (analysis whenever confronted with a patient with the constellation of fever and headache or mental status change. While it is optimal to collect cerebrospinal fluid for Gram stain and culture prior to the administration of the first dose of antibiotic, therapy should not be delayed for an undue period while lumbar puncture is performed or radiological evaluation is completed.
In the setting of suspected meningitis in an elderly patient, empiric antimicrobial therapy should be selected that has sufficient coverage to address all clinically relevant pathogens. While meningococcal meningitis occurs less frequently in elderly patients than in young adults and children, pneumoccocus remains a concern, and, in fact, is the most-commonly-isolated bacterial pathogen in this population. Older patients appear to be increased risk for CNS infection with strains of pneumococcus that are resistant to penicillin. While third-generation cephalosporins may be effective against penicillin-resistant S. pneumoniae infection other sites, these agents may not be adequate for therapy of meningitis in this setting. As a result, supplemental therapy with vancomycin should be included in the initial empirical regimen to ensure coverage of resistant pneumococci.
Elderly patients are particularly susceptible to meningeal infection with Listeria monocytogenes. While a number of epidemiological clues can point to infection with L. monocytogenes, including exposure to specific contaminated food, such clinical risk factors need not be present to raise the concern for this infection. High dose ampicillin is the most appropriate choice for CNS infection with L. monocytogenes. Because the clinical signs and symptoms of CNS infection with Listeria overlap considerably with those attributable to infection with S. pneumonia and N. meningitidis, ampicillin should be included in the empiric regimen for all older patients even before microbiological identification and susceptibility testing has been completed.
Once the results of microbiological cultures and other laboratory studies are available, antimicrobial therapy for meningitis can be narrowed to focus on the causative pathogen while limiting toxicity and interactions with other pharmacological agents. The duration of therapy for pneumococcus should be approximately 2 weeks and for Listeria 3 weeks or longer depending upon clinical response.
If no causative bacterial pathogen is isolated despite the timely collection of CSF specimens and the clinical presentation (including clinical signs and symptoms as well as CSF cell counts, protein and glucose levels) is consistent with viral meningitis, antibacterial therapy should be discontinued so as to minimize the exposure to these potentially toxic drugs.
Encephalitis
In an older patient with fever and focal neurological signs and/or change in sensorium who lacks definitive clinical, physical examination or laboratory evidence for meningeal infection, the diagnosis of encephalitis must be considered swiftly. As was true for meningitis, prompt initiation of antimicrobial therapy may be critical to the recovery of affected individuals.
HSV encephalitis remains a prevalent cause of CNS infection among older patients. Clinicians should remain vigilant for the diagnosis, even in patients without other evidence of herpes virus infection or a known history of prior cutaneous involvement. Suspicion for this etiology is strengthened by characteristic in the temporal lobes visualized on MRI. Confirmatory diagnosis requires detection of HSV DNA by PCR of the spinal fluid. Because this testing may take several days in some centers, therapy should be initiated upon first suspicion of infection. The optimal therapy is parenteral acyclovir, which should be continued for 2 to 3 weeks.
Healthcare-Associated Infections
The approach to antimicrobial therapy for the older patient infected as a consequence of hospitalization or other contact with the healthcare system is sufficiently unique to warrant separate consideration. The same general themes that have been discussed regarding the management of other infections in the older adults apply to the special case of healthcare-associated infections. Clinical features of the patient's presentation and epidemiological clues should be integrated to deduce the most likely causative pathogen. Specimens should be collected expeditiously for microbiological testing prior to the initiation of antimicrobial therapy if possible. Finally, the overall severity of infection, along with understanding of the unique pharmacological challenges of treating older patients should be considered prior to the final decision regarding antimicrobial treatment.
The goal in all cases of suspected healthcare-associated infection is to determine the likely pathogen responsible for the patient's signs and symptoms. For hospitalized patients, the anticipated microbiology will be influenced not only by the actual site of infection, but by the geographical and temporal trends in antimicrobial flora and susceptibility within the institution itself. Integrating epidemiological and microbiological data from the hospital antibiogram is critical to the selection of empirical therapy for the treatment of healthcare-associated infections in the older adults.
In general, the breadth and intensity of antimicrobial coverage for hospitalized older patients will tend to be greater than that provided to even debilitated older patients in the outpatient setting. This need for broader, more potent therapy is a consequence of the extensive comorbid conditions and generally poorer physiological reserve of hospitalized older patients.
In addition to their generally weakened physical condition, hospitalized older patients are commonly exposed to multiple medical interventions. As a result, the risk of complicated and potentially severe drug interactions is greatly increased in this population. Lastly, because of comorbid conditions or other therapies, the volume of distribution, renal and hepatic clearance and other pharmacokinetic parameters may be significantly altered when older patients are hospitalized.
Healthcare-Associated Pneumonia
The microbiology of respiratory infection among hospitalized patients is fairly distinct when compared to that associated with community-acquired pneumonia. Specifically, commensal gram-positive and anaerobic bacteria are replaced by Enterobacteriaceae, including E. coli and Klebsiella spp, after an older patient is hospitalized for several days. Such changes in the oral flora coupled with the possibility of aspiration of oral contents into the lower respiratory tract should lead to the inclusion of therapy active against Enterobacteriaceae in an empirical regimen for healthcare-associated pneumonia. Agents with activity against P. aeruginosa are generally included as well because of the relatively high incidence and clinical severity of nosocomial infection caused by this organism. MRSA is also seen increasingly commonly in healthcare-associated pneumonia. Finally, while patients with witnessed or high-risk for aspiration generally are prescribed an antimicrobial agent with activity against oral anaerobes, the available literature and recent guidelines do not specifically support this intervention.
The specific choice and breadth of antimicrobial therapy will be strongly influenced by the severity of the patient's pneumonia. Common choices include combination β-lactam/β-lactamase inhibitors such as piperacillin/tazobactam, ceftazidime, and combinations of third-generation cephalosporins with fluoroquinolones. Vancomycin or linezolid should be included when there is concern for MRSA involvement. Recent guidelines have recommended a 7-day course of therapy for healthcare-associated pneumonia not caused by P. aeruginosa. Extending therapy to 10 to 14 days may be reasonable in individuals with poor baseline health or particularly severe manifestations of pneumonia.
Skin and Soft Tissue Infections
For surgical wound infections in older patients, the approach is similar to that described earlier for cellulitis and other soft tissue infections in the outpatient setting. Anticipation of the causative organism is also comparable in that gram-positive bacteria predominate, specifically streptococcal and staphylococcal species. In the hospital, clinicians must be particularly vigilant for skin and soft tissue infections caused by MRSA, owing to the relatively high incidence and the risk of aggressive disease associated with this pathogen. Occasionally certain clinical features or epidemiological clues will suggest a less common pathogen (such as nontuberculous mycobacteria as a cause of chronic nonhealing surgical site infection).
As is always the case, systemic signs and symptoms, including evidence of sepsis, suggest the need for selection of broader empiric coverage and even consideration of less common pathogens, including Gram negatives. In addition, rapid progression of a skin or soft tissue infection may be evidence for a more complicated infection, such as necrotizing fasciitis. Management of this entity mandates rapid initiation of therapy that provides broad coverage for Gram positives, Gram negatives, and anaerobes. In addition, use of an antimicrobial that inhibits protein synthesis, such as clindamycin, is recommended in an attempt to disrupt the production of bacterial toxins responsible for this potentially life-threatening infection.
While the optimal therapeutic regimen for patients with skin and soft tissue infection is subject to debate, a regimen with broad efficacy against gram-positive cocci and MRSA is requisite (see Table 125-9). Historically, the most common choice has been vancomycin. Familiar agents, such as clindamycin, trimethoprim-sulfamethoxazole, and minocycline, can be utilized for their activity against MRSA, but may have toxicities or limitations in coverage against streptococci, in the case of trimethoprim-sulfamethoxazole, that limit their use in all situations. The role to be played by newer agents such as linezolid and daptomycin remains to be seen. The toxicity and expense associated with these agents may preclude their use as the first choice of therapy. Additionally, it is recommended that linezolid not be used in combination with selective serotonin reuptake inhibitors (SSRIs) because of the concern for precipitating the serotonin syndrome. Duration of therapy typically mirrors that for nonhealthcare-associated skin and soft tissue infections—approximately 2 weeks—but in general, should be guided by the patient's response to treatment.
Table 125-9 Antimicrobial Agents with Activity Against MRSA
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Table 125-9 Antimicrobial Agents with Activity Against MRSA
ROUTE OF ADMINISTRATION
NOTES
Trimethoprim/sulfamethoxazole, clindamycin, doxycycline
Orally or IV
Effective against many strains of community-associated MRSA.
Ineffective against most hospital-acquired MRSA.
Vancomycin
Orally only (for systemic treatment)
Widely effective against nearly all MRSA strains isolated to date.
Requires therapeutic monitoring to ensure efficacy and avoid toxicity
Daptomycin
IV only
Not effective for primary pulmonary infections
Linezolid
Orally or IV
Demonstrated effectiveness in skin and soft tissue infections. Associated with thrombocytopenia when administered for extended duration
Urinary Tract Infection
Choosing antimicrobial therapy for healthcare-associated infections of the urinary tract presents several unique challenges. Standard culture methods enable detection of bacteria in the urine of hospitalized patients with a high sensitivity. In fact, the high sensitivity of culture results may even prove to be misleading. A large proportion of urine samples obtained from hospitalized older patients, particularly those with bladder catheters, may be found to be colonized with bacteria. In several studies, the prevalence of bacteriuria among catheterized patients has been found to approach 100% after 1 month with the catheter. As a result of these issues, in the setting of a sepsis-like syndrome occurring in an older hospitalized patient with bacterial growth in the urine as the sole evidence for the urinary tract as the primary site of infection, it is recommended that the search continue for a definitive source. Multiple cultures of the blood are essential to the informed management of such patients.
There are few unique clinical or epidemiological factors that influence appropriate selection of empiric antimicrobial therapy for older hospital patients with known or suspected urinary tract infection. For the most part, the antimicrobial regimen should include coverage for the Enterobacteriaceae that are most commonly associated with ascending urinary tract infections. Among the available agents, those that concentrate in the urine are particularly useful. Fluoroquinolones are frequently utilized in this capacity, although the rise of resistance to these agents mandates that therapy be guided by the bacterial susceptibility results obtained from urine cultures. A 3-day duration is appropriate for uncomplicated bladder infections. However, in older hospitalized patients, the urinary tract infection will often be considered “complicated,” necessitating a prolongation of therapy to 2 weeks.
Bacteremia
Bloodstream infection in hospitalized older patients can arise as a primary sự kiện affecting only the bloodstream or as a secondary manifestation of infection a specific body toàn thân site, such as bacteremic pneumococcal pneumonia. Among the former group, bloodstream infections complicating intravascular access devices remain most common. In all cases, the most common pathogens tend to be streptococci or staphylococci. However, when the endogenous flora that normally colonizes the skin and digestive tract of older patients are replaced by hospital-acquired pathogens, the diversity of pathogens causing bloodstream infection expands to include gram-negative bacteria and fungi.
Principal among the clinical and epidemiological factors that might influence the choice of empiric therapy is the detection of a primary site of infection in these patients. If infection of the lung, bladder, or a surgical wound is detected, therapy should be chosen to cover those pathogens most commonly associated with infection of that specific body toàn thân site. Alternatively, clinical evidence of infection of a vascular access device, such as drainage or inflammation a catheter insertion site, supports the diagnosis of a primary bloodstream infection. Most such cases, as has already been noted, will be caused by common gram-positive organisms.
Empiric coverage should generally be guided by the Gram stain or preliminary culture results. For gram positives, vancomycin should be used while awaiting identification and antimicrobial susceptibility testing, assuming that there is a high institutional prevalence of MRSA. For gram-negative pathogens, coverage should be informed by local antibacterial susceptibility trends as reported in an institutional antibiogram. The use of double coverage for gram-negative pathogens (and specifically for infection with P. aeruginosa) remains controversial. There is little direct evidence indicating a benefit of protracted coverage with more than one agent once final susceptibility results are available.
The optimal duration of therapy for bloodstream infection in the hospitalized older patient remains somewhat uncertain, but is influenced by whether or not the bacteremia is associated with a removable focus of infection. For patients with infected vascular access devices, best practice dictates the removal of the infected line. If this step is completed in a timely fashion, clinicians may opt to treat for as little as 7 to 14 days. However, this less intensive strategy would not be appropriate for patients with more complicated infection, including those with heart valve involvement or those with evidence of metastatic spread of infection, who may require several weeks of therapy.
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