1.Cell wall permeability to antibiotics is decreased by changes in porin channels (especially important for gram-negative bacteria with complex cell walls, affect- ing aminoglycosides,-lactam drugs, chloramphenicol, sulfonamides, tetracy- clines, and possibly fluoroquinolones).
2.Production of specific antibiotic inactivating-enzymes by either plasmid- mediated or chromosomally mediated mechanisms affects aminoglycosides, -lactam drugs (-lactamases), chloramphenicol, and macrolides.
a. -lactamases. Members of the family Enterobacteriaceae express plasmid- encoded -lactamase enzymes commonly, which modify or destroy the -lactam nucleus central to penicillins, cephalosporins, and carbapenems.
3.Alteration of the target for antibiotic binding in the cell wall (e.g., penicillin- binding proteins, which are important enzymes for formation of the peptidogly- can matrix of the cell wall of gram-positive bacteria) affects-lactam drugs and vancomycin, whereas alteration of target enzymes can affect-lactam drugs, sulfonamides, fluoroquinolones, and rifampin.
4.Drugs that bind to the bacterial ribosome (i.e., aminoglycosides, chlorampheni- col, macrolides, lincosamides, streptogramins, and tetracyclines) are also sus- ceptible to alteration of the receptor on the ribosome.
5.Antibiotics may be extruded actively by efflux pumps once entry to the cell is achieved, in the case of macrolides, lincosamides, streptogramins, fluoro- quinolones, and tetracyclines.
B.The bacterial species of greatest clinical concern for development of resistance may be recalled as the “ESKAPE” pathogens (Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter calcoaceticus-baumannii complex, P. aeruginosa, and Enterobacter spp.).
Chapter 14rInfections, Antibiotic Prevention, and Antibiotic Management 147 1.Certain antibiotic classes are highly associated with emergence of resistance as compared with other antibiotic classes. In the case of MRSA, coloniza- tion and infection have been associated with prior exposure to glycopeptides, cephalosporins, and fluoroquinolones. Colonization with C. difficile has been associated with cephalosporins, fluoroquinolones, and clindamycin in particu- lar (although any antibiotic, even a single dose of a first- or second-generation cephalosporin used appropriately for surgical prophylaxis and those used for treatment of C. difficile infection [CDI], may lead to CDI).
a. GPC.GPC cause most infection following injury. These include infections following neurosurgery (e.g., ventriculitis following invasive monitoring of intracranial pressure), sinusitis, CLABSI, device/implant-associated infec- tions, and complicated skin and skin structure infections (cSSSI). Respiratory tract and UTIs may also be caused by GPC.
i. S. aureus is the most important pathogen among the GPC. Sixty per- cent of hospital-acquired isolates of S. aureus are resistant to methicillin (MRSA), whereas up to 50% of community-acquired strains are now resistant (CA-MRSA) in some regions of the US. Staphylococcal resistance to vancomycin remains rare and is induced only after prolonged expo- sure to vancomycin among debilitated patients (e.g., dialysis patients).
S. aureus is a major pathogen in sinusitis, catheter-related bloodstream infections (CR-BSI), cSSSI, and pneumonia.
ii. S. epidermidis is usually resistant to methicillin (MRSE, 85%) and is the major pathogen in CLABSI and device/implant-associated infections.
iii. Enterococcus spp. can cause cSSSI, CR-BSI, and infections of the urinary tract. About 30% of enterococci are resistant to vancomycin (VRE), but the pattern is species-specific. Whereas 70% of E. faecium isolated are VRE, the same is true for only 3% of Enterococcus faecalis isolates. VRE poses a threat primarily to debilitated patients after prolonged hospi- talization. Colonization of the feces with VRE usually precedes invasive infection, and cannot be eradicated. Risk factors for the acquisition of VRE include prolonged hospitalization, readmission to the ICU, and ther- apy with vancomycin or third-generation cephalosporins.
iv. Because of the high prevalence of MRSA, vancomycin remains the most prescribed antibiotic for resistant GPC despite poor tissue penetration and the risk of toxicity.
v. Alternatives for therapy of MRSA include linezolid, tigecycline, dapto- mycin (butnot for pneumonia), ceftaroline (indicated only for acute bacterial skin and skin structure infections) and quinupristin/dalfopristin (used seldom because of multiple toxicities).
b.GNB.GNB are less common as pathogens than GPC but are important in the pathogenesis of cSSSI (particularly after inoculation of a wound), lower respiratory tract infection, and intra-abdominal infection. Although E. coli or Klebsiella spp. predominate in intra-abdominal infection, P. aeruginosa is the second most common ICU pathogen overall and the bacterium most closely associated with death from HAI. P. aeruginosa can infect virtually any tissue, including synovium and vitreous humor. P. aeruginosa bacteremia can cause or complicate pneumonia, and other metastatic infections can follow.
Antimicrobial resistance is a major problem with P. aeruginosa, Acinetobacter spp., and Klebsiella spp., and increasing among Enterobacteriaceae other than Klebsiella.
i. Although resistance to cephalosporins can occur by several mechanisms, the appearance of chromosomally mediated-lactamases has been iden- tified as a consequence of the use of third-generation cephalosporins.
Resistance rates decline when use is restricted. The mutant bacte- ria develop resistance rapidly to both cephalosporins and entire other classes of-lactam antibiotics. It is justifiable therefore to restrict the use of ceftazidime, especially when grappling with an ESBL-producing bacterium.
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148 The Trauma Manual: Trauma and Acute Care Surgery
ii. Carbapenems and aminoglycosides generally retain useful microbici- dal activity against ESBL-producing strains, but ESBL-producing strains can cause fatal infections because of delayed recognition and con- sequent delayed empiric antimicrobial therapy. Unfortunately, routine antimicrobial susceptibility testing does not detect ESBL-producing strains. When in doubt, the laboratory now has a bias to label an organism non-susceptible, so as to direct therapy to another agent of a different class.
iii. The resistance problem in GNB is not limited to cephalosporin resistance.
Metalloproteinases and carbapenemases threaten the utility of carbapen- ems to treat Pseudomonas and Acinetobacter.
iv. The fastest-growing resistance problem for GNB in the US. is quinolone resistance, particularly against Pseudomonas and Enterobacteriaceae.
Quinolone resistance is chromosomally mediated for the most part, pri- marily by changes in the target sites (DNA gyrase or topoisomerase IV) for the antibiotic.
v.Resistance to one quinolone may also increase the MIC for other quinolones against the organism, so a highly active agent given in ade- quate dosage is essential for empiric therapy with quinolones.
c. Fungi and yeast
i. Most fungi and yeast are avirulent opportunistic pathogens that do not threaten healthy patients. However, such infections should also be unusual in the “typical” critically ill or injured patient. Unless occur- ring in a profoundly immunosuppressed patient (i.e., cancer chemother- apy with neutropenia, bone marrow transplant or non-renal solid organ transplant) fungal infections are usually the result of antibiotic overuse.
Prolonged broad-spectrum antibiotic therapy suppresses host flora, and creates the opportunity for overgrowth of commensal flora. The most common health care–acquired fungal infections are caused by Candida spp., which are part of gut flora in approximately one-quarter of patients.
ii. Although colonization with Candida does precede invasive infection, the utility of antifungal prophylaxis remains controversial and unsupported by evidence. However, most surgical patients do not manifest fungemia, the prototypical invasive infection.
iii. Widespread prescribing of fluconazole has led to emergence of resistance among Candida spp.
iv. Empiric therapy of suspected invasive fungal infections is probably not necessary in most units that have a low incidence of such infections, but must address the possibility of resistant Candida if administered.
Therefore, fluconazole should not be used until an organism that is likely to be susceptible to fluconazole is identified (most centers do not per- form fungal susceptibility testing). Empiric therapy choices include con- ventional amphotericin B, lipid formulations of amphotericin B, or the echinocandins, caspofungin or micafungin. Conventional amphotericin B is seldom used currently because of toxicity (e.g., febrile reactions, hypokalemia, renal insufficiency). The lipid formulations mitigate the toxicity, but at high cost. Echinocandins are broadly active against yeast and fungi including Candida spp. and Aspergillus spp., and a logical, choice for empiric therapy, but data are scant, particularly in surgical patients. Comparative studies suggest that the triazole agent voriconazole may be more effective than amphotericin B for invasive aspergillosis.
VII. NOSOCOMIAL INFECTIONS. Among nosocomial infections, pleuropulmonary infections (e.g., pneumonia, empyema) are more common than bacteremia, which in turn is more common than UTI.
A. Pneumonia.The most common HAI following critical illness or injury is pneumo- nia (HAP). Trauma patients may be at specific risk for development of pneumonia (or empyema, which complicates 5% of cases of post-traumatic pneumonia) for several reasons.
Chapter 14rInfections, Antibiotic Prevention, and Antibiotic Management 149 1.Chest wall injury (e.g., rib fractures) decreases thoracic compliance and impairs
pulmonary toilet.
2.Direct (e.g., penetrating injury, pulmonary contusion) or indirect (e.g., acute res- piratory distress syndrome, ARDS) pulmonary injury depresses local pulmonary host defenses directly.
3.TBI may impair airway reflexes, leading to an increased risk of aspiration of gastric contents.
4.Iatrogenic risk factors include prolonged bed rest, supine positioning, tracheal or nasogastric intubation, narcotic analgesics and sedatives, and prolonged mechanical ventilation. Even a single day of mechanical ventilation increases the risk of VAP.
5.Pneumonia can be prevented by careful adherence to the principles of infection control included in the “ventilator bundle.”
a. Positioning the head of the bed up 30 degrees at all times
b.Daily sedation holidays and assessment for liberation from mechanical ven- tilation
c. Prophylaxis of stress-related gastric mucosal hemorrhage d.Prophylaxis of venous thromboembolic disease
e. Daily oral hygiene with 0.12% chlorhexidine gluconate mouthwash 6.Some authors describe HAP or VAP asearly-onsetorlate-onset,with onset
more than 5 days after admission or intubation, respectively, being the defining time.
a. The microbiology ofearly-onset HAP/VAPdiffers, in that it is more likely to be caused by relatively antibiotic-susceptible bacteria such as S. pneumo- niae, H. influenzae, or methicillin-sensitive S. aureus (MSSA).
b.Late-onset HAPand especially VAP tend to be caused by MRSA, P. aerugi- nosa, Acinetobacter spp., and the Enterobacteriaceae (although E. coli pneu- monia is relatively uncommon).
7.The diagnosis of VAP in particular is controversial.
a. Routine sputum collection for culture and susceptibility testing by standard endotracheal suctioning can contaminate the specimen with these upper airway “colonists,” thereby leading to the over-diagnosis and consequent overtreatment of VAP.
b.To reduce this risk, quantitative microbiology testing of sputum obtained by a technique that minimizes the possibility of contamination has been advocated. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) or the use of a protected-specimen brush (PSB) catheter can reduce the risk of contamination of the specimen and increase the accuracy by increasing the specificity of the diagnosis, making antibiotic administration more accurate and affording the opportunity to withhold antibiotic therapy or truncate it.
8.The most common causative organisms for VAP are MRSA and P. aeruginosa;
effective initial empiric antibiotic therapy must account for both.Misdirected (against resistant pathogens) and delayed antibiotic therapy of VAP are major causes of therapeutic failure and death.Data suggest that the duration of therapy for VAP should be as brief as 8 days for most cases of VAP, with the possible exception of cases caused by non-fermenting GNB (e.g., P. aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia), which may require up to 2 weeks of therapy.
9.The mortality rate of pneumonia complicating trauma is approximately 20%, whereas it is approximately 35% for VAP in critically ill surgical patients.