Antibiotics

Time dependant: beta-lactams and vanco (little post-abx effect or dose dependant kill)

Concentration dependant abx: fluoroquins and aminoglycosides

in septic pts, gfr may be raised due to CO and inotropes, especially in the young. need higher beta-lactam dosings, prob aminoglycosides as well

 

 

Review Article on ABX dosing in sepsis

 

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Updates now include a prompt for weight and serum creatinine in order to appropriately dose these antibiotics based on the Cockcroft-Gault formula.  The TDS Calculator will compute the GFR to guide appropriate dosing.

 

Pulse (once daily) aminoglycoside dosing is usually preferred unless the GFR is less than 40 mL/min/1.73m2 or otherwise contraindicated.  Monitoring should be done with a random level drawn 8 hours after the end of the infusion and interpreted using the Hartford nomogram below:

 

http://intranet1.mountsinai.org/tds/aminoglycoside_lis.htm

 

Please reserve peak and trough for traditional aminoglycoside dosing only.  Please monitor vancomycin using troughs only or order random levels if renal failure is present (routine monitoring of vancomycin peaks is not recommended).

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Sepsis

Immunocompetent – Antipseudomonal PCN/Ceph + (aminoglycoside or fluoroquinolone) or Carbapenam + (amino or fluoro)

 

Anaerobic-add flagyl or clinda

MRSA-add vanco

HIV-timentin+tobramycin

Pneumonia-ceph + macrolide or fluoro

ABD-AMP/GENT/FLAG or Zosyn/Genta

Urinary-Fluoro or Amp/Genta

CSF-Ceph + Vanco if old, add genta

 

 

1) Genta : Best method of administration is “extended interval dosing” 5-7mg/kg initially per day and adjust according to a nomogram on a serum level taken 14hrs after dose. Nomogram from New Zealand which we use all the time – I think the reference is Barclay ML, Duffull SB, Begg EJ, Buttimore RC. Experience of once-daily aminoglycoside dosing using a target area under the concentration-time curve. Aust N Z J Med. 1995; 25:230-5. Or another nomogram that could be used particularly for dysfunction is from Nicolau et al Antimicrob Agents Chemother 1995; 39:650-655 2) Vanco : “Jury still out” as to best method of administration ie divided doses or continuous infusion. Target levels probably should be – trough 20 or greater. Note present day vanco MUCH safer than the older constituted drug. Apart from speed of infusion causing “red man (some people call red neck) syndrome” vanco is amazingly safe ie side-effect free. Predisposition to resistance is a different issue.

 

5-15 for line infections; 15-20 for everything else

Penicillins

B-lactam ring structure conveys the antibiotic activity; various side chain affect activity.

Bactericidal, as are cephalosporins.  Work against the cell wall of organisms.

Only get good CSF penetration when meninges are inflamed

Renally eliminated for the most part

 

Natural:  Benzylpcn (IV), Procaine pcn g (IM), benzathine pcn G (IM), pcn V (PO)

Penicillinase-resisant:  methicillin (no longer available), oxacillin, nafcillin, cloxacillin, dicloxacillin

Extended Spectrum

Aminopcns:  ampicillin, amoxicillin

Anti-pseudomonal carboxypcns:  carbenicillin, ticarcillin

Anti-pseudomonal ureidopcns:  mezlocillin, piperacillin

B-Lactam/B-Lactamase inhibitor combinations:  amox/clavulanate (PO), ampicillin-sulbactam (IV), ticarcillin/clavulanate (IV), piperacillin/tazobactam (IV)

Cephalosporins

Cephalosporins are ineffective against enterococci and MRSA

Cefotaxime, Ceftriaxone, Ceftazidime penetrate the CSF when meninges are inflamed

Cross-sensitivity in PCN Allergic

Cephalosporin use is contraindicated in penicillin-allergic patients only if an IgE-mediated reaction such as urticaria, angioedema, or anaphylaxis occurs. Estimates of cross-sensitivity of cephalosporins and penicillins vary widely, ranging between 2% and 16%.112 However, even in patients with a stated penicillin allergy, true anaphylaxis to cephalosporins is extremely rare (< 0.02%).113 In fact, cross-reactions appear limited to patients given first-generation cephalosporins. Studies of second- and third-generation cephalosporins show no increase in allergic reactions in patients who have a history of penicillin allergy  (Ann Allergy Asthma Immunol 1995;74(2))

 

AAP cephalosporins in the pen allergic patient (Pediatrics 2005;115(4):1048)

Most recent article from JEM (Volume 42, Issue 5, May 2012, Pages 612–620)

Prescribing Cephalosporins in the Setting of a Penicillin Allergy:  What is the Truth? Conventional wisdom holds that there is a significant risk of an allergic reaction if a cephalosporin is prescribed to a patient with a history of a PCN allergy (2007 PDR: “cross-hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy”).

Key Background Facts:

• Early studies on this topic were very flawed because the penicillin test compounds had been contaminated with cephalosporins; until 1982, penicillin was produced commercially using the cephalsoporium mold (1,2).  Furthermore, these early studies upon which the frequently quoted 10% cross-reactivity is based did not routinely confirm the allergy by skin testing, and at least some of the reactions were not immune-mediated (3).
• When patients with a history of PCN allergy receive 1st generation cephalosporins – which share a side chain similar to penicillin – they may exhibit an increased risk of an allergic reaction. However, 2nd and 3rd generations cephalosporins are different enough structurally from PCN that they do not increase the risk of allergic cross-reactivity (1).

Most patients who give a history of PCN allergy are not so allergic:  The most frequent reactions are non-pruritic, non-urticarial rashes; for most the mechanism is idiopathic and not a contraindication to future use. The term “penicillin allergy” is often misused: although studies vary, perhaps 10% of patients who state they are truly “allergic to penicillin” are truly allergic (4-6).

Much of the literature advises skin testing prior to administration of cephalosporins in a patent who describes a penicillin allergy, but skin testing is not practical in the ED.  In fact, penicillin skin tests do not predict the likelihood of allergic reactions to cephalosporins in patients with histories of penicillin allergy (1,7). It is also important to note that extensive post-marketing studies of 2nd and 3rd generation cephalosporins showed no increase in the number of allergic reactions in patients with penicillin allergy (7).  To further emphasize this point, it should be pointed out that the AAFP recently released an evidence-based clinical practice guideline on the treatment of acute otitis media recommending the use of 2nd/3rd generation cephalsoporins for patients allergic to penicillin (1). Several studies indicate that cephalosporin-induced anaphylaxis occurs no more frequently among patients with known PCN allergy than among those without such allergy (1,2). Furthermore, PCN allergy is most likely simply a marker for an allergic individual in general as opposed to a marker of cross-reactivity with cephalosporins:  A recent retrospective study of a huge database of over 3 million patients who received penicillin revealed that 1.1% of the patients who had an allergic-like event (ALE) after penicillin also had an ALE after a cephalosporin BUT 1.6% of the patients who had an ALE after penicillin also had an ALE after a sulfonamide! (8)

Conclusion:  “For patients truly allergic to penicillin, the risk of reaction from a cephalosporin with side chains that differ from penicillin is so low that use is justified and medico-legally defensible by the currently available evidence” (1).  A reasonable approach is that cephalosporins can safely be given to a penicillin-allergic patient who did not experience anaphylaxis to the penicillin.References: (1) Pichichero ME. Cephalosporins can be prescribed safely for penicillin-allergic patients  J Fam Pract  2006;55(2):106-12. (2) Kelkar PS, Li JT. Cephalosporin allergy  N Engl J Med  2001345: 804-9. (3) Gruchalla RS, Pirmohamed M.  Clinical practice. Antibiotic allergy  N Engl J Med  2006;354: 601-9. (4) Graff-Lonnevig V, et al.  Penicillin allergy – a rare paediatric condition?  Arch Dis Child  1988;63(11):1342-6. (5) Surtees SJ, et al.  Allergy to penicillin: fable or fact?  BMJ  1991;302: 1051-2. (6) Salkind AR, et al.  The rational clinical examination. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy  JAMA  2001;285: 2498-2505. (7) Anne S, Reisman RE.  Risk of administering cephalosporin antibiotics to patients with histories of penicillin allergy  Ann Allergy Asthma Immunol  1995;74: 167-70. (8) Apter AJ, et al.  Is there cross-reactivity between penicillins and cephalosporins?  Am J Med  2006;119: 354.e11-19. (EMEDHOME.com)

Go to source: eud6B.htm

 

 

 

 

3rd gen ceph breed resistance of acino

There is no doubt overuse of third generation cephalosporins is directly related to the rise of such ‘unique’ ICU bugs as multiresistant Acinetobacter. We are struggling (and failing) to stop the emergency department from giving ceftriaxone to every patient they admit with a possible chest infection. One my colleagues refers to ceftriaxone as “the antibiotic for the intellectually bereft”!!!!! [I am not disputing the many valid indications for third generation cephalosporins]

 

The definitive study on this was by Apter AJ etal:Is There Cross-Reactivity Between Penicillins andCephalosporins?The American Journal of Medicine (2006) 119, 354.e11-354.e20They looked at over 3,000,000 patients! Read this carefully. 500,000 also received a cephalosporin. Approximately 4000 of these had documented allergic reactions to penicillin. Only 43 (1.1%) also were allergic to cephalosporin ( none had a severe reaction). But 1.6% of the penicillin allergic patients reacted to the alternative antibiotic, sulfonamide! Yes, that is a 45% higher risk than the cephalosporins. Therefore:Penicillin allergy patients are at increased risk of allergy to ALL antibioticsThe risk is actually LOWER for cephalosporins than for “alternative” antibioticsNone of the penicillin allergic patients had a severe reaction to cephalosporin”Cross reactivity” – a unique increased risk specifically to cephalosporins – does not exist.

 

Dosing

Give Q12 ceftriaxone in critically ill (The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. J Antimicrob Chemother. 2001 : 47 : 421-429.)

Carbapenems

Impenem / Meropenem

anaerobic coverage as good as flagyl or clindamycin

Meropenem has better gram negative rod activity and penetrates the CSF; imipenem is slightly superior against gram positives

while there have been previous reports of high cross reactivity in the case of pcn allergic patients, the real number is probably <1% cross-reactivity (Ann Pharmacother. 2009 Feb;43(2):304-15. Allergic cross-sensitivity between penicillin, carbapenem, and monobactam antibiotics: what are the chances?)

Monobactams

Aztreonam

only gram negative activity, slightly less active against pseudomonas than ceftazidime

 

Oxazolidinones

Linezolid

synthetic oxazolidinone

Quinupristin/Dalfopristin

Synercid

Combination of two streptogramins

Aminoglycosides

Bactericidal, if high concentration causes killing of bacteria.  Post antibiotic effect is bacteriostatic

Peak Levels

Genta, Tobra, and Netilmicin:  6-8 mcg/cc for serious infections, 8-10 for life threats

Amikacin 20-25 and 25-30 respect.

Trough Levels

0.5 to 1.0 for serious 1-2 in life threats for Genta, Tobra, and Netilmicin

1-4 and 4-8 in amikacin

Single daily dose

Genta 6 mg/kg/dose

draw peak 60 minutes after end of infusion, draw trough 30 minutes before infusion

drug levels in bronchial secretions are only 2/3 of serum

 

Typical Dosing

A.    Initial dosing for gentamicin and tobramycin and timing of measurements of serum concentrations

1.      Initial dose: 3 mg/kg ideal body weight (IBW)

a.     Men: IBW (kg) = 48.2 + (2.3 × height in inches >5 feet)

b.     Women: IBW (kg) = 45.5 + (2.3 × height in inches >5 feet)

c.      If actual body weight (ABW) exceeds 125% of IBW, use the following adjustment for dosing weight:Adjusted body weight = IBW + 0.4 × (ABW − IBW)

2.     Subsequent serum measurements

a.     Obtain 2 serum concentrations: one sampled 30 minutes to 1 hour after initiation of the 30-minute infusion, and one sampled approximately 1.5 half-lives later

b.     t1/2 = 0.693 / (0.0026 × Clcr + 0.014)

c.      Definitions: t1/2 = half-life (hr); Clcr = creatinine clearance (mL/min)

B.    Estimate pharmacokinetic parameters after first dose.

1.     

2.    

3.    

4.     Definitions: IT = infusion time (hr); T1 = time (hr) since the end of infusion; C1 = concentration (mg/L) obtained 30 minutes to 1 hour after the initial dose; C2 = concentration (mg/L) obtained 1.5 half-lives after the first dose; k = elimination rate constant (hr−1 ); Vd = volume of distribution (L); Δt = time elapsed (hr) between drawing C1 and C2

C.    Individualizing dosing regimens

1.      Select a dosing interval of at least 2 half-lives, but no more frequent than every 12 hours.

2.     If 12 hours is too frequent, increase to 24 hours.

3.     If 24 hours is too frequent, increase by 24-hour increments.

4.     For gentamicin and tobramycin, determine a regimen that produces AUC of 75 to 100 mg·hr/L.

5.     For serious or life-threatening Gram-negative infections, select AUC at the higher end of the range.

6.     24-hour dose = total dose (mg) to be given in a 24-hour interval, determined by: 24-hour dose = AUC × k × Vd

7.     If dosing interval is not 24 hours, divide the 24-hour dose by the number of doses given per day to determine the dose per dosing interval.

D.   Predicting peak and trough

1.      Unnecessary to predict the peak and trough when dosing per AUC

2.     If predicted true peak and trough at steady state are desired, use:

a.     True peak = dose × (1 − e−k×IT ) ÷ k × Vd × IT × (1 − e−k×τ )

b.     Trough = true peak × e−k × (τ − IT)

c.      Definitions: true peak = concentration (mg/L) at the end of infusion; trough = drug concentration (mg/L) just before the next dose; τ = dosing interval (hr)

E.    Subsequent monitoring

1.      Frequency of subsequent serum measurements is based on clinical response, physiologic changes, and risks for toxicity.

Repeat above steps to determine the 24-hour dose; adjust as needed.  (Saunder’s Manual of Critical Care)

 

Once-daily administration (ODA) of aminoglycosides has been a dosing strategy in use for several years.[1,2] The rationale behind ODA administration is to optimize the pharmacodynamic properties of the aminoglycosides; more specifically, ODA results in a higher peak serum concentration than traditional multiple daily dosing can achieve, which enhances the concentration-dependent bactericidal killing activity of the compound. Additionally, aminoglycosides exhibit a postantibiotic effect which is exerted during the drug-free interval at the end of the ODA interval. During the postantibiotic effect, the organism is essentially stunned and does not replicate.[1,2]

Dosing recommendations for gentamicin/tobramycin for ODA range from 5 to 7 mg/kg, using the higher dose for select critically ill patients, and a multiple of 4 for amikacin (20-28 mg/kg, again using the higher dose for select critically ill patients).[1,3,4]

 

Fluoroquinolones

inhibit bacterial topoisomerase and DNA gyrase

 

Factive™ (gemifloxacin) – short for fast and active active against double mutant resistance

Macrolides

bacteriostatic, inhibit bacterial RNA

 

azithromycin:  atypicals and gram negatives

clarithromycin:  MAC, less h. flu activity

erythromycin:  poor h. flu coverage.  also enhances GI motility

Vancomycin

Distributes to CSF when meninges inflamed

Trough should be 10-12 in normal situations and 15-20 for CSF

need vanco trough>20 for lung, but this leads to greater renal tox

From Bryan Hayes:

• For bacteremias/endocarditis: if the S. aureus MIC ≥ 1.5 mcg/mL, don’t use vancomycin!
• For all other MRSA infections: if the S. aureus MIC ≥ 2 mcg/mL, don’t use vancomycin!

Clindamycin

Clindamycin Clindamycin resistance rates in vitro for worldwide isolates of S. aureus ranged from 23.4–35.5% in one report.[69] However, in vitro activity often differs significantly in isolates that are methicillin resistant. [41, 42] For example, in one report, 96.3% of 888 MSSA isolates were susceptible compared with only 39.8% of 334 MRSA isolates.[41] In vitro susceptibility rates of CA-MRSA isolates are higher than those seen in nosocomial isolates. In one report, in vitro susceptibility was reported in 81% and 19% for community and nosocomial isolates, respec-tively. [70] However, as with fluoroquinolones, wide geographic variations in CA-MRSA resistance rates have been reported. Susceptibility of CA-MRSA to clindamycin has been reported as high as 94% in south Texas,[71] 97% in Atlanta,[6] and 100% in Detroit,[72] whereas others have reported resistance rates for this pathogen exceeding 20–25%.[73, 74] Clindamycin has limited activity against h-VISA; 98% of isolates were resistant to clindamycin in one report. [48] Caution should be used in interpreting the potential utility of clindamycin based on in vitro testing, since infections due to clindamycin-susceptible, erythromycin-resistant isolates would be inappropriately treated with clindamycin in the setting of inducible macrolide-lincosamide-streptogramin B (MLS Bi) resistance reported in S. aureus. A phenotypic method for detecting such inducible resistance has been described with use of a double-disk diffusion assay.[75, 76] In one series examining 14 patients with 15 episodes of CA-MRSA, 8 ( 53.3%) episodes were erythromycin resistant and clindamycin susceptible; however, all of these isolates exhibited inducible resistance to clindamycin.[77] Other institutions have reported MLSBi resistance ranging from less than 10% [78] to 56%[79] of their erythromycin-resistant, clindamycin-susceptible S. aureus isolates. Clindamycin-inducible resistance can also vary over time within the same institution. For example, a Dallas pediatric hospital reported that CA-MRSA isolates susceptible to clindamycin increased from 77.9% to 88.9% in 1999 and 2002, respectively.[80] Most published experience with the use of clindamycin is in the treatment of skin and skin structure infections.[81, 82] Case reports cite varying degrees of success for invasive S. aureus infections treated with clindamycin (including refractory cases of endocarditis). Recent reports reviewed the use of clindamycin for the treatment of invasive CA-MRSA and CA-MSSA infections in children. [71, 83] Infections in these series included bacteremia, osteomyelitis, septic arthritis, pneumonia, and lymphadenitis.

Metronidazole

 

Cubicin (daptomycin)

is the first in a new class…cyclic lipopeptides. It works by depolarizing bacterial cell membranes.       It’s for complicated skin infections due to gram-positive bacteria…including methicillin-resistant Staph aureus (MRSA).       MRSA now accounts for nearly 60% of staph infections in hospitals and is also increasing in the community.       Cubicin works about as well as vancomycin, oxacillin, or nafcillin for treating complicated skin infections.       Cubicin is also being tested for other uses…bacteremia, endocarditis, and vancomycin-resistant enterococci.       Cubicin is given once a day IV…costs about $135 a vial.       Cubicin can increase serum CPK levels and therefore might cause myopathy. Check CPK levels once a week during treatment and tell patients to report muscle pain or weakness.

 

 

Crop Rotation

rotating antibiotic schedule reduces resistance (Crit Care Med 2004;32:1,p.53)

 

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Antibiotic Resistance from Anesthesia Audiodigest

ANTIBIOTIC RESISTANCE—Douglas B. Coursin, MD, Professor of Anesthesiology and Internal Medicine, University of Wisconsin School of Medicine, Madison Centers for Disease Control and Prevention (CDC) Web site: “superb” information; www.cdc.gov/drugresistance/healthcare Incidence: 750,000 patients have life-threatening infections yearly; overall mortality about one third of patients, 215,000 deaths per year; significant number developing infections with antibiotic resistance Magnitude of problem: “infection shadows the patient in the ICU [intensive care unit] and also shadows them very closely in the operating room [OR]”; 1 in 10 patients develops nosocomial infection during stay in hospital; community and nosocomial infections major contributory factor to fatal outcome in >50% of ICU patients; in early 1990s, approximately 30% of Staphylococcus aureus resistant to methicillin, now approaches 60% to 65%; Enterococcus now fourth most common nosocomial infection in ICU; Klebsiella and quinolone resistance in Pseudomonas also increasing Case 1: woman admitted with history of general malaise, cough, fever, and delirium; history of spinal fusion approximately 2 mo prior, with rods placed at lower lumbar spine; hypotensive despite fluids and vasopressors; tachycardic and markedly febrile; confused; active cough; abnormal breath sounds bilaterally consistent with consolidation; well-healed scar on back, and no obvious lesions or surgical abscess; examination symmetric; laboratory data revealed leukocytosis with marked shift, mild coagulopathy, and gram-positive cocci “too numerous to count” with “tons” of polymorphonuclear leukocytes in sputum; tap of large pleural effusion revealed empyema, lancet-shaped diplococci, and gram-positive cocci; altered mental status suggested need for lumbar puncture (LP; computed tomography [CT] necessary only with signs of neurologic distress, eg, coma, papilledema, abnormal asymmetric examination); LP revealed thousands of white blood cells (WBC) and gram-positive cocci, protein >500 mg/dL and glucose <3 mg/dL; diagnosis of gram- positive bacteremia; presumptive diagnosis of pneumococcus; treated empirically with vancomycin, ceftriaxone, and rifampin Pneumococcus: most common cause of community-acquired pneumonia; number-one cause of meningitis in immunocompetent patients in United States; increasing resistance in previously readily treatable organism; resistance to penicillin >40% in southeastern United States; increasing resistance to macrolide antibiotics (eg, clarithromycin) and quinolones; in vivo resistance may vary greatly from in vitro, may require DNA mapping or other testing; current recommendations to include vancomycin with ceftriaxone to ensure adequate treatment Case 2: man 65 yr of age removed one canine tooth with pliers; seen in emergency department (ED) on several occasions with fever alone, then with fever and lethargy; red streaking into right chest, seen on CT going into pleural and pericardial spaces; blood cultures in first 36 hr positive for vancomycin-intermittent S aureus (VISA); required teams of surgeons to drain head and neck abscess and abscesses under scapula, in chest, in pericardium; methicillin-resistant S aureus (MRSA), VISA, and vancomycin-resistant S aureus (VRSA) increasing problems; MRSA overwhelmingly common in United States (60% of isolates in hospitals); VISA and VRSA also increasing; linezolid and Synercid (quinupristin/dalfopristin) “the two treatments for this” (reports of resistance to even these drugs) Influence of antibiotic-resistant organisms in ICU: for patient with resistant organisms, increased mortality, prolonged length of stay in ICU and hospital, prolonged mechanical ventilation, and greater incidence of and need for tracheostomy; requires use of more expensive antibiotics, multiple antibiotics, and prolonged duration of therapy to treat difficult infections; overuse of specific antibiotics may diminish efficacy for other organisms in other patients; “in addition, you have to isolate and manage these patients differently, and that costs more money”; antimicrobial resistance more common in patients who have been in hospital and ICU for longer periods, who have had prior antibiotics, who are sicker, who are older, and who have invasive therapeutic devices in place Development of antibiotic resistance: clinicians use antibiotics unnecessarily for outpatient procedures; use in cattle of antibiotics that may be unnecessary; antibiotic-fed chickens may “not be a wise move”; organisms able “to do things vertically and horizontally with their genetic material that allows them to become increasingly resistant” in short time; tendency to use excessive amounts of antibiotics for prolonged periods, particularly in ICU; resistance occurs not only in bacteria, but also in fungi and viruses Bacterial antibiotic resistance: appears more frequently in critically ill; encountered more commonly in ICU; can be overcome by “having a pretty good guess what the infection is, depending on whether it’s a pneumonic process, intra- abdominal, GU [genitourinary], or postsurgical”; clinicians frequently use inadequate antibiotic doses and improper durations or excessive and prolonged empiric antibiotics; antibiotic resistance develops with some specific agents, but not always related to class; some resistance intrinsic to antibiotic; intrinsic resistance attributable to particular species (eg, vancomycin ineffective for gram-negative rod infections; useful only in aerobic and anaerobic gram-positive organisms) Acquired resistance vs intrinsic resistance: reflects true change in genetic composition of organisms; degrees of resistance may range from relative to frank resistance; development of resistance occurs because organism develops mechanism to remove drug faster than it arrives, outer membrane becomes impermeable, cytoplasmic target unavailable, or target becomes unavailable; adaptation of organisms may occur through chromosomal, plasmid, or transposon (subnucleic acid material) method Primary prevention: maintain high index of suspicion with patient at risk; control dose and duration of drugs (use sufficient and proper amount, but not for extended time); do not “shotgun” everyone in ICU who has fever or leukocytosis but does not have obvious infection or source of infection; wash hands between patients (single most important action to limit nosocomial infections); other ideas from CDC include vaccinations, removing catheters, attacking specific pathogen, practicing good antibiotic control, using local data on sensitivities, consulting experts, treating infection and not contamination, treating infection and not colonization, knowing when “to say no to vancomycin,” stopping therapy when patient cured, isolating pathogen when resistant, and containing contagion; prevalence of resistance can vary from one location to another; treat infection and not contamination (Corynebacterium and Propionibacterium tend to be noninfectious; coagulase-negative Staphylococcus may or may not be infectious; in blood cultures, Staphylococcus, Streptococcus , Enterobacteriaceae, Pseudomonas, and Candida tend to be infectious) Case 3: woman with vancomycin- and ampicillin-resistant Enterococcus (VAREC); resistance varies between species (Enterococcus faecium becoming highly resistant, Enterococcus faecalis not yet); treat with linezolid (less toxic than Synercid; associated with thrombocytopenia; reports of resistance) or Synercid (inhibits protein synthesis; reports of resistance); older therapies used in many cases (eg, tetracyclines, trimethoprim–sulfamethoxazole, colistin, chloramphenicol); hope for new drugs against Enterococcus “pretty limited” Rotation of antibiotics: controversial; some suggest removal of antibiotics from armamentarium for transient period ( less than or equal to 6 mo) may help them to “become active again”; others advocate formulary restrictions Incorrect antibiotics: first, consider likely infection for septic patient in ICU; avoid problems of resistance by using prophylaxis properly (single dose or less than or equal to 24 hr of antibiotic); determine location (eg, urinary tract, gastrointestinal tract, lungs); take into account length of hospital stay, presence of catheters, and likelihood of unusual or resistant organism Catheter-related blood stream infection: speaker uses chlorhexidine in every procedure; several situations have occurred in which someone has placed central line without disinfecting skin; except for high-risk patient, speaker does not use antibiotic-impregnated catheter Vaccination against newer strains of organisms:bioengineers working with pneumococcal strains in production of pentavalent vaccines that are “fairly active” against intermediate-resistant and, possibly, even resistant strains

 

 

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Patterns of Resistance in Specific Organisms

 

• Escherichia coli E. coli is a common hospital pathogen. ß-lactamases are now almost the norm! Chromosomal ß-lactamases (also called Type I) are common, but plasmid-mediated ß-lactamases (notably ESBLs – extended spectrum beta lactamases) are also widespread. ESBL spread is thought to be related to excessive use of later-generation cephalosporins, now being further promoted by use of quinolones (and co-trimoxazole). The spread of ESBLs is made worse by their common association (on the same plasmid) with multiple other resistance genes. Many laboratories are unreliable in reporting the presence of ESBLS. If E coli is reported as resistant to ceftazidime or the MIC is 2 or more, you should assume the organism has ESBLs, and avoid the use of all cephalosporins, and all penicillins. Associated resistance may be to aminoglycosides and fluoroquinolones! The best test for ESBLs is perhaps to test for synergy between ceftazidime and clavulanic acid (Drusano, 1998).If you’re going to use beta-lactamase inhibitors for organisms with ESBLs, you mustgive high doses, or the inhibitor will be overwhelmed! Carbapenems are perhaps best as initial therapy if the patient has serious infection with an ESBL-producing organism.
• Klebsiella The same points made for E. coli carrying ESBLs appy to Klebsiella, another common pathogen that has picked up the ESBL habit! Klebsiella species with ESBL-gene containing plasmids are now common in European ICUs. Plasmids rapidly spread between different species of bacterium, for example moving between Klebsiella, E. coli and Serratia. This spread is made worse by transposons – “jumping genes” that move from site to site, even jumping from plasmids to bacterial chromosomes. (We have only recently realised the importance of integrons, which are discussed below).
• Proteus Proteus mirabilis may still be sensitive to ampicillin, although in some centres resistance is present in ~50% of isolates, often due to production of penicillinase. ESBLs in P. mirabilis have now become a cause for concern [Int J Antimicrob Agents 2001 Feb;17(2):131-135] Such organisms may respond to high dose piperacillin + tazobactam, or carbapenems, ± amikacin. Inhibitor resistantbeta-lactamases may also be found in some clinical isolates of P. mirabilis!Other Proteus species may respond to a 3rd generation cephalosporin + aminoglycoside, or perhaps piperacillin + tazobactam, or a quinolone.
• Enterobacter Enterobacter cloacae may account for up to one quarter of ventilator-associated pneumonias in some studies, although one must remember that criteria for ventilator-associated pneumonia vary from centre to centre. Third-generation cephalosporin treatment of Enterobacter infections (especially pneumonia) has been associated with rapid selection of “de-repressed mutants”. These organisms produce vast amounts of beta-lactamase all the time, because (simplistically) they lack the “switch” that normally turns off the ß-lactamase gene when there are no beta-lactams in the environment. (A similar phenomenon has been seen with Serratia and Citrobacter). ‘Epidemic’ spread of the organism may then occur. Treatment of such organisms may be limited to carbapenems, cefepime, or possibly high-dose piperacillin+tazobactam. (Cefepime still works in many, even if chromosomally mediated stably derepressed ‘Amp C’ cephalosporinases are present).
• Pseudomonas aeruginosaIn some ICUs, this is the major pathogen causing ventilator-associated pneumonia! Resistance to multiple antibiotics is common, including piperacillin, ceftazidime, quinolones; and imipenem (due to the D2 porin being dropped). Treat according to the sensitivity profiles from your unit – one usually has to choose between cefepime, a carbapenem, or piperacillin+tazobactam. Combination therapy (+ aminoglycoside) is still controversial.
• Stenotrophomonas maltophilia This organism is inherently resistant to imipenem. It usually attacks debilitated or immunosuppressed individuals. Treatment is controversial. Co-trimoxazole may be a treatment option, (despite it being only bacteriostatic), or possibly ticarcillin+clavulanate. A superb review is [Clin Microbiol Rev 1998 Jan;11(1):57-80].
• Acinetobacter anitratus, baumanni and friendsResistance to quinolones and cephalosporins is prevalent. Other resistance is variable. It is often difficult to decide if the Acinetobacter is merely a coloniser, or causing harm. Treatment should be based on sensitivity profiles of the organisms commonly present in your unit, or the organism itself (if you’ve isolated it). Quinolone resistance seems to be on the increase.
• Serratia marcescensWhere appropriate, this organism may respond to beta lactams, aminoglycosides, or fluoroquinolones. Hejazi and Falkiner have reviewed S. marcescens well [J Med Microbiol 1997 Nov;46(11):903-12]. As with Pseudomonas and Acinetobacter, quinolone resistance is not uncommon.
• Staphylococcus aureus and MRSAMethicillin-resistant Staphylococcus aureus (MRSA) is now a major pathogen in many ICUs, and in some accounts for over a third of ICU pneumonias! This pathogen is resistant to all beta lactams, as well as quinolones, so glycopeptides are the drug of choice in institutions where such resistance is common. Recently we have seen the emergence of S. aureus with reduced susceptibility to vancomycin (a great worry).
• Methicillin resistant coagulase-negative staphylococci(CNS) Resistant to beta lactams (and a few to teicoplanin too). CNS are commonly associated with intravascular catheters.
• Streptococcus pneumoniae (and penicillin-resistant S. pneumoniae) Unfortunately, S. pneumoniaeresistant to penicillin are becoming more common. Where they are not prevalent, penicillin G is still the drug of choice; otherwise use cefotaxime. There has been international dissemination of several penicillin-resistant clones of S. pneumoniae (from serotypes 6, 9, 14, 19 and 23). In the USA ‘SENTRY’ study, 1/3 of S. pneumoniae isolates were at least partially resistant to penicillin. Multidrug resistance is on the increase, with significant levels of resistance to ceftriaxone, tetracycline, and (commonly) co-trimoxazole.
• Enterococci (and VRE)Enterococcal infections are on the increase in ICU, perhaps explained by excessive cephalosporin use, as these bacteria are inherently resistant to cephalosporins, including later cephalosporins such as ceftriaxone. A lot of the patients are very sick, and one is often not sure whether the Enterococcus is actually causing disease, or just a coloniser! E faecalis is commonly resistant to ampicillin, and E faecium resistance to vancomycin is on the increase.A few enterococci are intrinsically resistant to vancomycin, but most of the current ‘VREs’, especially E. faecium, have acquired resistance to glycopeptides. This was probably related to the outrageously silly, extensive use of vancomycin in the USA in the 1980s. If your patient has VRE infection, you have a biiig problem. (Consider high dose ampicillin+sulbactam if the MIC is under 64 µg/ml, with an aminoglycoside if still sensitive to this; otherwise streptogramins which may be difficult to obtain and do NOT work against E. faecalis; or possibly linezolid).
• Enterobacter cloacaeCommonly resistant to all cephalosporins; rarely to imipenem and/or fluoroquinolones. Some recommend combination therapy for E. cloacae. Cefepime is usually still active against this organism.
• Bacteroides fragilis We have briefly reviewed B. fragilis elsewhere. The organism is interesting because some isolates contain carbapenemases!
• Cl. difficileThis common ICU pathogen can cause diarrhoea or even life-threatening pseudomembranous enterocolitis. Prior antibiotic therapy (often with third-generation cephalosporins, other beta lactams, or clindamycin) is almost invariable. Treatment is metronidazole. (Avoid oral vancomycin because of its potential for promoting vancomycin resistance). Recurrences are common but respond to re-treatment.
• Other agentsThere is marked variation between ICUs as regards pathogenic bacteria. For example, in some instututions (with contaminated water) Legionella has turned out to be an important pathogen; in others Haemophilus influenzae is a major cause of pneumonia!
• Neisseria meningitidis Patients with meningococcal septicaemia often die rapidly despite adequate antibiotic therapy and heroic measures. There is a superb review in Clinical Microbiology Reviews [Clin Microbiol Rev 2000 Jan;13(1):144-66] Decreased senstivity to penicillin has been widely reported, (due to poor PBP-2 binding), so broad-spectrum cephalosporins such as ceftriaxone are now recommended, started as soon as possible. Chloramphenicol resistance has occasionally been reported.

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Sites and types of infection

“Blood borne infections”

As we said above, it’s always a good idea to look diligently for the site of origin of microbes in the blood. Karam & Heffner have summarised the common causes of blood borne infection, based on CDC and other data. Coagulase negative staphylococci come out tops {how many of these were contaminants?}, followed by Staph. aureus and Enterococci, a surprisingly high percentage are Candidal (5 to 11%), and E. coli and Klebsiella make up some of the remainder. If there is no other source for infection, think about that intravenous catheter you have left in for “just one more day”!

Pneumonia

Patients that end up in ICU with community acquired pneumonias may be infected with a variety of organisms, including S. pneumoniae, Haemophilus, Klebsiella, Legionella, and even Mycoplasma, Chlamydia, and so on. ICU- and ventilator-associated pneumonias (VAP) are difficult to diagnose and manage, and are commonly due to multiresistant gram-negative organisms, although recently, resistant gram positives have become prominent. VAP is by far the most important infection in ICU. Think Pseudomonas, Klebsiella, Acinetobacter, and also S. aureus. One possible solution to overuse of antibiotics is short course quinolone therapy, with reassessment at 3 days [Am J Respir Crit Care Med 2000 Aug;162(2 Pt 1):505-11]. There is scant evidence that invasive assessment of VAP alters outcome. See for example [Am J Respir Crit Care Med 2000 Jul;162(1):119-25]. Gram stain of sputum in VAP is of mimimal value. Causative organisms of VAP vary widely from ICU to ICU.

Urinary tract infection

While community-acquired UTIs are often due to E. coli, in hospital the usual nosocomial gram negatives are also often responsible.

Intra-abdominal infections

Here too, E. coli is important, but a host of other gram negatives may participate, enterococci often add to the problem, and anaerobes are extremely important, especially Bacteroides fragilis. Remember that infections are often polymicrobial.

Surgical wound infection

Both staphylococci and gram negatives (often hospital-acquired) are important.

Meningitis

In adults the main organisms are Neisseria meningitidis, and Streptococcus pneumoniae. Long-term neurological sequelae are common, if the patient survives. If the person is immune compromised, think Gram -ve bacilli, Listeria monocytogenes, fungal infection, and mycobacteria. It is not uncommon for doctors to mis-diagnose tuberculous meningitis as an acute bacterial meningitis because (a) they haven’t taken a decent history and (b) the initial leukocytosis in the CSF may confuse them. Pseudomonas meningitis is uncommon but difficult to treat, and outcome is often poor. Imipenem should be avoided as it may cause seizures, but meropenem is safe, although an antipseudomonal penicillin (such as ceftazidime) is perhaps preferable, unless resistance is suspected.

Immune compromise

We will not here discuss the immune-compromised patient in any detail. Suffice it to say that many ICU patients are subtly or even overtly immune compromised, due to their poor nutritional status. There are others who may be on corticosteroids, and a small subset on potent immunosuppressives, or with underlying disease (such as AIDS) which predisposes to attack by a host of ‘normal pathogens’, as well as numerous fungi (like Pneumocystis and Candida), parasites, and opportunistic bacteria. In neutropaenic sepsis, aggressive and above all urgent management for presumed Gram negative infection will be life-saving.

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Topics of Interest

What is an integron?

 

Integrons are very important, because they are the mainmechanism for dissemination of resistance genes in Gram negative bacteria. Let’s start by describing the structure of an integron. An integron has:

• A strong promoter site;
• A gene coding for an enzyme called an integrase (the ‘intl’ gene);
• A ‘recombination site’ (the fancy abbreviation for this is attI).

The basic idea is that the integrase catalyzes insertion or deletion of resistance genes, and these are then vigorously expressed due to the strong promoter site. Resistance genes can spread aggressively between bacteria. These genes that can be clipped out of one integron and inserted into another are called gene cassettes (Something like taking a tape recorder cassette and playing it on somebody else’s tape deck)! The cassettes are inserted at the attI site, which is recognised by the integrase. Up to five (or possibly even more) resistance genes may be contained in a single integron. There are over 60 gene cassettes described, including those that code for ESBLs and carbapenemases. Other cassettes code for resistance to aminoglycosides, trimethoprim, chloramphenicol, and even antiseptic agents such as quaternary ammonium compounds and mercury!

Different intl genes have been described. There are at least six, with classes 1, 2 and 3 being considered most important in spread of antibiotic resistance. Integrons have been around for a long time – we just haven’t been really aware of them until recently. (See the review in [Clin Chem Lab Med 2000 Jun;38(6):483-7] ).

Most integrons have been reported from gram negatives (especially Enterobacteriaceae). “Super-integrons” have also been described, harbouring hundreds of genes, for example in Vibrio species.

Thoughts about predisposition to development of resistance

It makes sense that the larger the population of bacteria, and the longer they are exposed, the more likely they are to develop resistance to a particular antimicrobial. Remembering that the largest natural reservoir of bacteria in man is the bowel, it then comes as no surprise that agents that are extensively excreted into the bowel should promote ready resistance, especially if they persist for long periods of time (eg. rifampicin). Likewise, oral administration of vancomycin, a silly idea which should be avoided if at all possible, will probably promote vancomycin resistance, while intravenous administration should be far less likely to do so, as the drug is then renally excreted.

Mechanisms of Resistance

We have discussed this elsewhere.

Do ICUs export resistant bugs?

There is some evidence suggesting this is the case. See for example [ Clin Infect Dis 1999 29 1411-18 Lucet et al ]. ICUs are often jam-packed with resistant micro-organisms, accounting for up to a quarter of all nosocomial infections (despite constituting under 5% of beds in most hospitals).

Does initial appropriate therapy lower mortality?

Yes. See [ Chest 1999 115 462-74, Kollef et al].

Does good empiric therapy prevent drug resistance?

Yes. See [ Ann Intern Med 1996 124 884-90, Pestotnik et al].

Bactericidal vs bacteriostatic antibiotics?

It is often recommended (without support from a vast amount of research) that bactericidal antibiotics are preferable to bacteriostatic ones, with severe ICU infections. Examples of bactericidal antibiotics are penicillins, cephalosporins, aminoglycosides, carbapenems, and fluoroquinolones.

Endotoxin release by antibiotics

We know that gram negative bacteria release endotoxin from their cell walls when proliferating and when dying, and it is this endotoxin that initiates many cellular events (such as cytokine production) that cause morbidity and mortality. An attractive hypothesis (with little current substantiation or refutation) links administration of some antibiotics, massive bacterial killing, endotoxin release, and patient deterioration. We are not convinced that such endotoxin release is clinically significant.

If I stop using an agent, will resistance to it disappear?

No. Resistance will be suppressed, but the chances are that the resistant organism will still lurk in the background, and reappear quickly in large numbers, once it is encouraged to appear by suppression of the competition (when you start using the agent enthusiastically once more).

Dosing considerations – infusions and stat doses

Aminoglycosides kill bacteria based on high concentrations, and because (unlike most other agents) they have a post-antibiotic effect(PAE) that may last several hours, should probably be given in high doses once a day, rather than smaller doses twice or more per day. Although quinolones don’t have a PAE, they too kill depending on concentration, and so area under the plasma concentration-time curve is important in determining bacterial kill rates.

On the contrary, beta-lactam killing of bacteria depends on the amount of time the tissue levels are above the minimum inhibitory concentration (MIC), and (above this level) is concentration-independent. It is therefore logical to give penicillins by continuous infusion, and it is unclear to me why so many people are still giving their penicillins as intermittent push-ins! (Probably just a matter of convenience and tradition flying in the face of reason). See for example Craig & Ebert [Antimicrob Agents Chemother 1992 36 2577-83], and Drusano (1998).

Where can I get consensus guidelines on preventing spread of resistant micro-organisms?

Try:

• Goldmann et al [JAMA 1996 275 234-40]
• Shlaes et al [Clin Infect Dis 1997 25 584-99]

Weber et al also have a lot of detail, especially on management of MRSA outbreaks.

Crop Rotation

Kollef et al from St Louis [Crit Care Med 2000 28.10 3456-64], in the context of increasing incidence of microbial resistance, pursued the idea of scheduled changes in the class of antibiotics used for empirical therapy. (Some have called this “crop rotation”, or “heterogeneous antibiotic use”). They rotated (for periods of six months) from a baseline of ceftazidime, through ciprofloxacin, and then cefepime, showing a progressive decline in the primary outcome – incidence of inadequate antimicrobial treatment. This incidence was assessed by isolation of the causative organism, and sensitivity testing where appropriate. Approximately 3/4 of the 3668 patients received antibiotics, including about a quarter who received “post-operative prophylactic antibiotics”. 37% of patients had an identified infection, 90% of these being ventilator-associated or “bloodstream” infections. Inadequate antimicrobial therapy (use of a 3rd generation cephalosporin against a resistant organism, and to a lesser extent MRSA, Candida, VRE) was associated with increased in-hospital mortality. The study could perhaps be faulted because there was no simultaneous division of the study population into two groups – one group receiving therapy based on “the current crop”, and the other at the discretion of the attending physician. The limitations of the study are well-discussed in the article.

Also note the potential concerns about crop rotation, notably cross-resistance. See [ J Antimicrob Chemother 1992 29 307-12] and [Antimicrob Agent Chemother 1990 34 2142-7] for cross resistance between quinolones and imipenem!

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3. Most Commonly Encountered Protozoal And Fungal Infections.

 

Organism Treatment* Protozoa   Entamoeba Metronidazole, tinidazole, paromomycin Giardia Metronidazole, albendazole, tinidazole Plasmodia species (malarial) Chloroquine, primaquine, quinine, doxycycline, mefloquine, Fansidar®† Pneumocystis Trimethoprim-sulfamethoxazole, pentamidine, primaquine, clindamycin, dapsone† Toxoplasma Pyrimethamine/sulfadiazine, trimethoprim-sulfamethoxazole, clindamycin Trichomonas Metronidazole Fungi‡   Candida Clotrimazole§, miconazole§, fluconazole|| ¶ , amphotericin|| Cryptococcus Amphotericin B, fluconazole#, flucytosine** Dermatophyton Clotrimazole§, ketoconazole§, miconazole§††

*First choice appears in bold. †Only some of the available treatments listed ‡The most common in the ED §Topical ||IV treatment for bloodstream and other serious infections ¶Oral formulations available #Oral or IV **Adjunct to amphotericin ††Alternative and oral treatments available

 

Table 4. Brief Characteristics Of The Most Commonly Used Antibiotics.

 

Class Mechanism of Action Metabolism and Excretion Bacteria Covered Penicillins (natural) (penicillin G, pen VK) Bactericidal Inhibit cell wall synthesis Excreted in urine mostly in intact form Gram (+), except staph Some anaerobesN meningitides Penicillinase-resistant penicillins (methicillin, nafcillin, dicloxacillin) Bactericidal Inhibit cell wall synthesis Excreted in bile and urine Gram (+), used mostly for staph, but not MRSA Aminopenicillins (ampicillin, amoxicillin)

Aminopenicillins with beta-lactamase inhibitor (ampi/sulbactam, amoxi/clavulanate)

Bactericidal Inhibit cell wall synthesis Some bile excretion, but mostly kidney Gram (+), but not MRSA Some gram (-), not Pseudomonas Some anaerobes

Better staph coverage Better gram (-) and anaerobic coverage

Antipseudomonal penicillins(ticarcillin azlocillin, mezlocillin, pipracillin)

Anti-pseudomonal penicillins with beta-lactamase inhibitor (ticarcillin/clavulanate piperacillin/tazobactam)

Bactericidal Inhibit cell wall synthesis Excreted in bile and urine Gram (+), but not staph Some gram (-) Some anaerobes

Better staph coverage Better gram (-) and anaerobic coverage

Cephalosporins 1st-generation (cephalexin, cefazolin, cephradine) 2nd-generation(cefuroxime, cefoxitin, cefotetan, cefaclor, cefprozil

3rd-generation (ceftriaxone, cefotaxime, ceftazidime, cefixime)

4th-generation (cefepime)

Bactericidal Interfere with cell wall synthesis Excreted mostly intact in urine Gram (+), not MRSA Some gram (-) Some anaerobes

Gram (+), not MRSAGram (-), not PseudomonasAnaerobes

Gram (+), not MRSAGram (-), most are weak against Pseudomonas Some anaerobes

Gram (+), not MRSA or enterococcusGram (-)

Carbapenems (imipenem, meropenem) Bactericidal Inhibit cell wall synthesis Excreted mostly in urine Gram (+), not MRSAGram (-) Anaerobes Fluoroquinolones(ciprofloxacin, ofloxacin, norfloxacin)

Extended-spectrum fluoroquinolones (levofloxacin, gatifloxacin, moxifloxacin)

Bactericidal Inhibit DNA gyrase Some excreted by kidney, often metabolized in liver Some gram (+), Staph but not MRSAGram (-) Some atypicals

Gram (+) Gram (-) Atypicals Some anaerobic coverage

Macrolides (erythromycin, azithromycin, clarithromycin) Bacteriostatic Inhibit protein synthesis Metabolized in liver, excreted in bile and minimally in urine Gram (+), but not MRSA Some gram (-)Atypicals Some anaerobes Aminoglycosides (gentamicin, tobramycin, amikacin) Bactericidal Inhibit protein synthesis Excreted unchanged in urine Staph (combine with beta-lactams)Gram (-) Tetracyclines (tetracycline, doxycycline) Bacteriostatic Inhibit protein synthesis Excreted mostly in urine Some gram (+) Some gram (-)Atypicals Some anaerobes Clindamycin Bacteriostatic Inhibits protein synthesis Metabolized mostly in liver and excreted in bile Gram (+), not MRSAAnaerobes Vancomycin Bactericidal Inhibits cell wall synthesis and inhibits RNA synthesis Excreted in urine Gram (+) Some anaerobes Trimethoprim/ sulfamethoxazole Bacteriostatic Folate antagonist/inhibits folate synthesis Metabolized in liver, excreted in urine Some gram (+) Some gram (-) Some protozoans Metronidazole Bactericidal Toxic to cells by interfering with electron transport/producing free radicals Metabolized in liver Anaerobes Some protozoans and parasites Chloramphenicol Bacteriostatic Inhibits protein synthesis Metabolized in liver, excreted by kidney Gram (+) Gram (-) AnaerobesRickettsia Nitrofurantoin Bacteriostatic or bacteriocidal, depending on concentration Metabolized in liver, excreted by kidney Gram (+) Gram (-)Only in the lower urinary tract

 

 

 

Table 8. Antibiotics Of Choice

 

Pharyngitis124-127

First Choice Second Choice PCN VK 500 mg PO BID X 10 days*

Benzathine penicillin G 1.2 million units IM X 1 or C-R Bicillin IM

Erythromycin base 500 mg QID X 10 days†

1st- or 2nd-generation cephalosporin: cefuroxime axetil 250 mg BID X 4 days cefpodoxime proxetil 100 mg BID cefdinir 300 mg q 12 hour X 5-10 days cefprozil 500 mg QD X 10 d

Clindamycin 300 mg PO TID x 10 days‡

*Amoxicillin is used in young children because of better taste. †Other macrolides can be used as well, though the price may be prohibitive. ‡Mostly for patients with repeated episodes of pharyngitis

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Otitis Media118,128-130

First Choice Second ChoiceAmoxicillin 40-45 mg/kg/d div q12 or q8†

Amoxicillin 80-90 mg/kg/d div q12 or q8

Duration of treatment: < 2 years old X 10 days; > 2 yrs old X 5-7 days

 

Amoxicillin/clavulanic acid 90 mg/kg/d div BID‡

Oral 2nd- or 3rd-generation cephalosporin‡: Cefuroxime axetil 30 mg/kg/d div q12 Ceftriaxone 50 mg/kg IM x 1, followed by oral regimen

Trimethoprim/sulfamethoxazole 8 mg/kg/d div BID§

Macrolide§: Clarithromycin 15 mg/kg/d div q12h, azithromycin 10 mg/kg/d on day #1, then 5 mg/kg/d on days 2-5 or 30 mg/kg x 1 dose

 

*Children at low risk for complications may not require antibiotic treatment. This group consists of patients with mild symptoms who are older than 2 years, are not attending day care, and have not received antibiotics within the prior 3 months. †Lower-dose amoxicillin is recommended for children in the low-risk group, but with more severe symptoms. ‡Children with high fever, ill-appearing, and patients with prior treatment failure §High percentage of pneumococcus is resistant.

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Acute Exacerbation of Chronic Bronchitis*104,118

First Choice Second ChoiceMacrolide: azithromycin 500 mg PO initial dose then 250 mg PO QD X 4 days

Fluoroquinolone†: levofloxacin 500 mg PO QD gatifloxacin 400 mg PO QD

Amoxicillin/clavulanic acid 875/125 mg PO BID or 500/125 mg PO TID‡

Tetracyclines§: doxycycline 100 mg PO BID 2nd- or 3rd-generation cephalosporin‡: cefaclor 500 mg q8h cefixime 400 mg PO QD cefpodoxime proxetil 200 mg PO q12 cefprozil 500 mg PO q12

trimethoprim/sulfamethoxazole: DS 1 tab (160 mg TMP) PO BID‡§

 

*Antibiotic therapy controversial; uncomplicated bronchitis is usually not treated in patients without COPD. †Extended-spectrum ‡Does not cover atypicals §Pneumococcus increasingly resistant.

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Community-Acquired Pneumonia118,131-134

First Choice Second Choice Ambulatory patients*Macrolide†: azithromycin 500 mg PO QD X 1 then 250 mg PO QD or clarithromycin 500 mg PO BID

Tetracyclines†: doxycycline 100 mg PO BID

Fluoroquinolone§: levofloxacin 500 mg PO QD or gatifloxacin 400 mg PO QD

Amoxicillin/clavulanic acid 875/125 mg PO BID‡

2nd-generation cephalosporin‡: Cefdinir 300 mg PO q 12, Cefpodoxime proxetil 200 mg PO q12 cefprozil 500 mg PO q12 cefuroxime axetil 250-500 mg PO q 12

Ambulatory patients > 60 yo§ Fluoroquinolone§: levofloxacin 500 mg PO QD or gatifloxacin 400 mg PO QD Amoxicillin/clavulanic acid 875/125 mg PO BID‡ Hospitalized patientsCeftriaxone 1-2 gm IV QD or cefotaxime 2.0 gm IV q4 – q8 +/- macrolide¶#

Beta-lactam/beta-lactamase inhibitor +/- macrolide¶

Fluoroquinolone: levofloxacin 500 mg IV QD or gatifloxacin 400 mg IV QD

 

Cefuroxime +/- macrolide

Azithromycin#**

 

*Course of treatment until patient is afebrile, usually 3-5 days, may require 7-10 days. †S pneumoniae increasingly resistant. ‡Does not cover atypicals. §Extended-spectrum ||Broad-spectrum antibiotics with low incidence of resistance suggested if sending these patients home. ¶Vancomycin can be added in ill patients requiring ICU admission. #Metronidazole or clindamycin should be added if aspiration is suspected. **IV

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Urethritis/Cervicitis*10,135-139

First Choice Second ChoiceAzithromycin 1 gm PO x 1 dose + ceftriaxone 125 mg IM x 1 dose

Doxycycline 100 mg PO BID X 7 days† + ceftriaxone 125 mg IM X 1 dose‡

Azithromycin 1 gm PO x 1 dose + cefixime 400 mg PO x 1 dose or ciprofloxacin 500 mg PO x 1 dose†

Amoxicillin‡ + ceftriaxone 125 mg IM x 1 dose or cefixime 400 mg PO x 1 dose

Ofloxacin 400 mg PO X 1 dose then 300 mg PO q12 X 7 days†

Erythromycin base 500 mg PO QID X 7 days + cefixime 400 mg PO x 1 dose or ceftriaxone 125 mg IM x 1 dose‡

Ciprofloxacin 500 mg PO x 1 dose† + azithromycin 1 gm PO x 1 dose or tetracyclines†§ or erythromycin

 

*Caused by N gonorrheae or C trachomatis; patients should have a test for syphilis performed. †Contraindicated in pregnancy ‡Treatment of chlamydia in pregnancy §7-day regimen

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Pelvic Inflammatory Disease135-139

First Choice Second Choice Outpatients*Ofloxacin 400 mg PO BID or levofloxacin 400 mg PO qd + metronidazole 500 mg PO BID

Ceftriaxone 125 mg IM/IV x 1 dose + doxycycline 100 mg PO BID x 14 days†

 

Azithromycin‡

 

Hospitalized patients Cefotetan 2 gm IV q12 or cefoxitin 2 gm IV q12 + doxycycline 100 mg IV/PO q12

Clindamycin 900 mg IV q8 + gentamicin 2 mg/kg IV loading dose then 1.5 mg/kg IV q8h, or 4.5 mg/kg x 1 dose, then doxycycline 100 mg PO BID X 14 days§

Ofloxacin 400 mg IV q12 + metronidazole 500 mg IV q8

Ampicillin/sulbactam 3 gm IV q6 + doxycycline 100 mg IV/PO q12

Ciprofloxacin 200 mg IV q12 + doxycycline 100 mg IV/PO q12 + metronidazole 500 mg IV q8

Azithromycin|| + metronidazole

*Temp < 38° C, WBC < 11,000/mm3, minimal evidence of peritonitis, active bowel sounds, able to tolerate oral nourishment. †May add metronidazole if anaerobes strongly suspected. ‡1st dose IV, followed by 6-day oral regimen. Consider adding oral metronidazole. §Followed by oral doxycycline ||IV

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Intra-abdominal Infections and Peritonitis8,10,118

First Choice Second ChoiceBeta-lactam/beta-lactamase inhibitor +/- aminoglycoside*: ampicillin/sulbactam 3 gm IV q6 or piperacillin/tazobactam 3.375 gm IV q6 or ticarcillin/clavulanate 3.1 gm IV

Cefotetan 2 gm IV q12 or cefoxitin 2 gm IV q 8h +/- aminoglycoside*

3rd-generation cephalosporin + metronidazole or clindamycin +/- aminoglycoside*

Fluoroquinolone + metronidazole or clindamycin: Ciprofloxacin 500 mg IV q6 + metronidazole 500 mg IV q6

Carbapenem +/- aminoglycoside:* Imipenim/cilastin 500 mg IV q6 or meropenem IV q8 +/- aminoglycosid

 

*Used less frequently as more drugs with gram (-) coverage available, mostly in very sick patients.

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Endocarditis*8,10,118

First Choice Second Choice Native Valves IVDU Non-IVDUNafcillin or oxacillin 2.0 gm IV q4 + gentamicin 1.0 mg/kg IM/IV q8

Penicillin G 20 mu IV QD or ampicillin 12 gm IV QD + nafcillin or oxacillin 2.0 gm IV q4 + gentamicin 1.0 mg/kg IM/IV q8

Vancomycin 15 mg/kg IV q12

Vancomycin 15 mg/kg IV q12 + gentamicin 1.0 mg/kg IM/IV q8

Prosthetic ValvesVancomycin 15 mg/kg IV q12 + gentamicin 1.0 mg/kg IM/IV q8+ rifampin 600 mg PO QD

 

 

*Empiric treatment before culture results available.

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Cellulitis8,10,118

First Choice Second Choice OutpatientsDicloxacillin 500 mg PO q6

Amoxicillin/clavulanic acid 500 mg PO TID*

Macrolide: Azithromycin 500 mg PO initial dose then 250 mg PO QD x 4 days

1st-generation cephalosporin: cephalexin 500 mg PO QID x 7-10 days

Hospitalized PatientsNafcillin or oxacillin 2.0 gm IV q4

Carbapenem†: Imipenem/Cilastin 0.5 gm IV q6 or meropenem 1.0 gm IV q8

Beta-lactam/beta-lactamase inhibitor†

Macrolide IV

1st-generation cephalosporin IV

Fluoroquinolone + clindamycin or metronidazole†:

Bite Wounds

Mild

Severe

 

Amoxicillin/clavulanic acid 500 mg PO TID*

Ticarcillin/clavulanate 3.1 gm IV q6 Ampicillin-sulbactam 3.0 gm IV q6

 

Fluoroquinolone + clindamycin or trimethoprim/sulfemethoxazole

Fluoroquinolone + clindamycin or trimethoprim/sulfemethoxazole

Diabetic Foot

Mild infection previously untreated Severe‡

 

1st-generation cephalosporin: cephalexin 500 mg PO QID x 14 days

clindamycin: 300 mg PO qid or 450-900 mg IV q8

Beta-lactam/beta-lactamase inhibitor: ampicillin/sulbactam 3.0 gm IV q6 piperacillin/tazobactam 3.375 gm IV q6 or 4.5 gm IV q8

Cefoxitin or cefotetan

Fluoroquinolone + clindamycin or metronidazole

 

 

Amoxicillin/clavulanic acid 875/125 mg PO q12 or 500/125 mg q8

 

Carbapenem: Imipenem Cilastin 0.5 gm IV q6 meropenem 1.0 gm IV q8

Nafcillin or oxacillin 2.0 gm IV q4 + gentamicin 1.0 mg/kg IM/IV q8 + metronidazole 500 mg IV q6

*Bite wounds †Skin infection with sepsis ‡Extensive involvement or failed prior treatment

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Meningitis10,118

First Choice Second Choice NewbornsAmpicillin + cefotaxime (dosage varies by age of patient and weight)

 

Ampicillin + gentamicin

 

Patients 2 Mos-60 Yrs Ceftriaxone 2 gm IV q12 or cefotaxime 2.0 gm IV q4-6 + /- vancomycin 500-750 mg IV q8* +/- rifampin*

Peds: Ceftriaxone 80-100 mg/kg div dose q12-24 +/- vancomycin 15 mg/kg IV q6

Meropenem¶ 1.0 gm IV q8+ /-vancomycin 500-750 mg IV q8*

 

Peds: Meropenem 40 mg/kg IV q8 + vancomycin 15 mg/kg IV q6

Patients older than 60 or immune compromised Ceftriaxone 2.0 gm IV q12 or cefotaxime 2.0 gm IV q6 +/- vancomycin* + ampicillin 2.0 gm IV q4† +/- gentamicin† Meropenem 1.0 gm IV q8 +/- vancomycin* Penicillin- allergic patients‡Chloramphenicol 50 mg/kg up to 1.0 gm IV q6 + vancomycin 500-750 mg IV q6 +/- rifampin* + trimethoprim Sulfamethoxazole 15-20 mg/kg/day div q6-8§ Aztreonam|| + vancomycin + trimethoprim/sulfamethoxazole§

*Depending on the prevalence of resistant strains †Add-on to other antibiotics for Listeria coverage ‡Cefotaxime and ceftriaxone may still be safe to use. §Covers Listeria ||Gram (-) coverage. In children > 1 mo of age, highly recommended to give dexamethasone 0.4 mg/kg q12 IV x 2 days. Give with or just before 1st dose of antibiotic to block TNF. ¶May not be used in penicillin-allergic patients.

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UTI10,18,142

First Choice Second Choice Uncomplicated Infection (Cystitis)Usual duration of treatment is 3 days Trimethoprim/sulfamethoxazole: 1 tab DS (160 mg TMP) PO BID X 3 days†

Fluoroquinolone†: ciprofloxacin 500 mg PO BID levofloxacin 250 mg PO QD gatifloxacin 200 or 400 mg PO QD x 3 days

1st-generation cephalosporin‡: cephalexin 500 mg PO QID

Nitrofurantoin 100 mg PO QID x 7 days‡

Pyelonephritis OutpatientsFluoroquinolone*§: ciprofloxacin 500 mg PO BID levofloxacin 250 mg PO QD gatifloxacin 200 or 400 mg PO QD x 7 days

Cephalosporin||: cephalexin 500 mg PO QID x 14 days

Amoxicillin/clavulanic acid 875/125 mg PO q12 or 500/125 mg PO q8 x 14 days||

Hospitalized Patients#

 

Trimethoprim/sulfamethoxazole*†||

Fluoroquinolone*: levofloxacin 500 mg IV QD gatifloxacin 400 mg IV QD

Ampicillin/sulbactam 3.0 gm IV q6 + gentamicin*

Beta-lactam/beta-lactamase inhibitor¶: ticarcillin/clavulanate 3.1 gm IV q6, piperacillin/tazobactam 3.375 gm q6 or 4.5 gm q8 IV

Carbapenem*#: imipenem 0.5 gm IV q6 or meropenem 1.0 gm IV q8

*Not in pregnancy †E coli increasingly resistant ‡In pregnancy, 7-10 day course §7–10-day regimen ||14 days ¶May need to add aminoglycoside, especially in septic patients. #In septic patients

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UTI on Children < 6 Years*142

< 2 weeks Ampicillin + gentamicin† 2 weeks-2 monthsAmpicillin + cefotaxime†

> 2 months

Hospitalized  

Oral regimens§

 

Cefotaxime† Ceftriaxone‡DOSAGES VARY BY WEIGHT AND AGE OF CHILD

Trimethoprim/sulfamethoxazole Cephalexin Cefixime Nitrofurantoin||

*Empiric treatment pending cultures †IV therapy until afebrile for 24 hours ‡Can also be used as IM therapy. §For use in older children with mild symptoms, or to complete therapy when IV treatment discontinued. ||For use in older children with mild symptoms.

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Sepsis Syndrome*8,10,118

First Choice Second Choice NeonatesAmpicillin 25 mg/kg IV q8 + cefotaxime 50 mg/kg q12

 

Ampicillin 25 mg/kg + ceftriaxone 50 mg/kg IV q24 IV/IM

Ampicillin 25 mg/kg + gentamicin or tobramycin 2.5 mg/kg IV q12

Children 3rd-generation cephalosporin: cefotaxime 50 mg/kg IV q8 ceftriaxone 100 mg/k q24 cefuroxime 50 mg/kg IV q8   Adults3rd- or 4th-generation cephalosporin†: cefotaxime 2.0 gm IV q4-8 ceftizoxime 2.0 gm IV q4 cefepime 2.0 gm IV q12

Beta-lactam/beta lactamase inhibitor: piperacillin/tazobactam 3.375 gm IV q4 ticarcillin/clavulanate 3.1 gm IV q4

Carbapenem: imipenem/cilastin 0.5 gm IV q6 meropenem 1.0 gm IV q8

vancomycin 1.0 gm IV q12+ aminoglycoside‡

aztreonam 2 gm q6§

Neutropenic (Absolute neutrophil count < 500/mm3)Beta-lactam/beta lactamase inhibitor: Piperacillin/tazobactam 3.375 gm IV q4, ticarcillin/clavulanate 3.1 gm IV q4 + Aminoglycoside: Gentamicin 2.0 mg/kg IV q8, Tobramicin 2.0 mg/kg IVq8, Amikacin 15 mg/kg IV q8 +/- Vancomycin 1.0 gm IV q12|| Carbapenem: imipenem/cilastin 0.5 gm IV q6, +/- vancomycin 1.0 gm IV q12||

3rd- or 4th-generation cephalosporin: cefotaxime 2.0 gm IV q4-8 + vancomycin 1.0 gm IV q12,

cefepime 2.0 gm IV q12, +/- vancomycin 1.0 gm IV q12||

In penicillin-allergic: Vancomycin 1.0 gm IV q12 + aminoglycoside +/- metronidazole 15 mg/kg IV then 7.5 mg/kg IV q6

*When source is unknown, the choice of treatment should be based on the most likely source of infection. †Cefotaxime and ceftriaxone are weak against Pseudomonas; ceftazidime should not be used against gram (+). ‡Use when MRSA is likely; if also suspecting anaerobes, need metronidazole or clindamycin. §For gram (-) sepsis only ||If MRSA or indwelling catheter

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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