Empirical antimicrobial therapy: making decisions without a culture (Proceedings)
The first step in empirical antimicrobial therapy is to first critically ask whether there is good evidence of a bacterial infection. Too often, antimicrobials are prescribed on a 'just in case' basis or because an owner resists additional diagnostics.
Is there good evidence of bacterial infection?
The first step in empirical antimicrobial therapy is to first critically ask whether there is good evidence of a bacterial infection. Too often, antimicrobials are prescribed on a "just in case" basis or because an owner resists additional diagnostics. There are several very real drawbacks of "just in case" antimicrobials: they add to the cost of the visit or hospitalization, without contributing to a diagnosis; they may lead to diarrhea, inappetance, or vomiting that obscure the underlying problem; they can cause adverse reactions or drug interactions; and importantly, they encourage the selection of resistant bacteria, both globally, in your hospital, and in that patient.
Fever alone is inadequate criteria for prescribing an antimicrobial. If the probable source of fever cannot be localized during a physical exam, it is not possible to choose an appropriate spectrum of bacterial coverage or decide how long to treat. Physical exam findings that support the use of antibiotics without additional diagnostics are usually straightforward, such as a carnasial tooth root abscess, skin pustules or epidermal collarettes, or a traumatic wound with purulent exudate. Cytology should be performed on all exudates in all areas endemic for Blastomycosis or other fungal infections, prior to considering antibacterials.
Leukocytosis alone is not a good justification for antimicrobials, since leukocytosis can result from stress, inflammation, glucocorticoid administration, or hyperadrenocorticism. If a left shift and toxic change are present with leukocytosis, then a source of infection or significant inflammation should be pursued. Fever with neutropenia, however, is an established indication for empirical antimicrobials, at least in humans. Meta-analyses of studies in humans suggest that the benefit of antibacterials in neutropenic patients, even prior to fever, outweighs the negative effects of selecting for bacterial resistance. A beta lactam and fluroquinolone combination is recommended in humans, which provides coverage against gut flora to include anaerobes and Enterococcus (beta lactam) and gram negatives (fluoroquinolone).
Antimicrobials are inappropriate in most cats with lower urinary tract signs. There is a < 5% incidence of positive urine cultures in cats with lower urinary tract disease overall. Clients' money is better spent on a urinalysis and bladder imaging for stones. Cats at higher risk for bacterial urinary tract infections are those with diabetes mellitus (13% prevalence), perineal urethrostomies, CRF, or in older cats with dilute urine.2 For these cats, urine culture is a good investment.
For cats with upper respiratory infections, there are no good studies comparing antimicrobials to placebo. Although Mycoplasma is commonly isolated from pharyngeal swabs, underlying viral infection is typical, and cats have similar recovery rates whether antimicrobials with and without activity against Mycoplasma are used. When active Mycoplasma or Chlamydia infection are documented or suspected, doxycycline remains the drug of choice. Suspension is preferable to capsules to decrease the risk of esophagitis.
Diarrheas in dogs and cats are usually not caused by pathogenic bacteria. For example, in dogs with acute diarrhea, the prevalence of Salmonellosis (2%), Campylobacter (5%), and Clostridium difficile toxin (10%) is low. Empirical antimicrobials, such as amoxicillin or fluoroquinolones, are not indicated for acute diarrheas. Fiber, probiotics, or Pepto-Bismol, along with a short-term diet change, may be a better approach.
Finally, pancreatitis is usually sterile in dogs and cats. Antimicrobials are not indicated unless peritonitis, pancreatic abscess, or loss of intestinal mucosal integrity (bloody diarrhea with mucosal sloughing) develops. In humans, antimicrobials in severe (necrotizing) pancreatitis do not reduce the incidence of secondary pancreatic infection or decrease mortality.
Helpful diagnostics in lieu of culture
Pyuria with bacteria in a urine sediment provides a strong indication for antimicrobials, although bacteriuria can be overdiagnosed. If cocci are frequently diagnosed in your in-house urine sediments, be cautious; stain precipitates can mimic cocci. The majority of urinary pathogens in dogs are gram negative rods. In cats, gram positive and gram negative pathogens occur at approximately the same rate; however, urinary tract infections are much less common in cats overall.
The finding of intracellular bacteria on cytology is a strong rationale for antimicrobials. A gram stain, which is immediate and cheap, narrows the spectrum to gram positive, gram negative, or mixed. Gram stains are underutilized in companion animal practice. This simple technique is described at: http://www.life.umd.edu/classroom/bsci424/LabMaterialsMethods/GramStain.htm
Deciding about cultures
Cultures are not, in the practical sense, necessary for first time empirical treatment of many routine bacterial infections, to include acute contaminated wounds, carnasial tooth abscess, infectious tracheobronchitis, superficial pyoderma, cat bite abscess, or first time bacterial cystitis in an adult dog.
Cultures are very important for any second line antimicrobial treatment, to include lack of response to empirical treatment, relapse after treatment discontinuation, or waxing and waning signs. Examples of this include suspected bacterial bronchopneumonia, urinary tract infections, or non-responding pyoderma. Avoid antibiotic roulette in these cases! With recurrent urinary tract infections, serial cultures can be very helpful. Repeated culture of the same organism suggests inadequate clearance (e.g. poor compliance, uroliths, pyelonephritis, or accompanying prostatitis with inadequate drug penetration). Repeated culture of different organism suggests new (usually ascending) infection (e.g. an anatomic defect such as an ectopic ureter or urethral incompetence, vulvar fold pyoderma, or poor perineal hygiene in debilitated or obese animals).
Cultures and cytology are also important for first time treatment of long-standing infections, such as fistulous tracts, possible chronic foreign bodies, or non-healing wounds, as well as for serious or life-threatening infections, such as pyothorax, suspected endocarditis, osteomyelitis, joint sepsis, renal failure with suspected pyelonephritis, or suspected sepsis. Cultures are also recommended for suspected hospital-acquired infections (those developing > 72 hours after admission), since nosocomial bacteria may have multi-drug resistance patterns, and hospitalized patients may be more susceptible to sepsis because of IV lines, urinary catheters,invasive procedures, and immunocompromise.
Practical culture techniques
For aerobic culture, our microbiologist at UW-Madison (Faye Hartmann) recommends BBL CultureSwab Plus (Amies gel formulation without charcoal; available from Fisher Scientific). This system is not ideal for anaerobes in our hands (despite the label). Urine is ideally set up for culture within 15 to 30 minutes of collection, but this is impractical in many settings. Alternatively, a sterile syringe containing urine can be capped and refrigerated immediately, for up to 12 hours prior to culture. While some fastidious bacteria may not survive storage > one hour, this approach is adequate in most situations, and also allows quantitative culture by the laboratory. Fluids for culture should not be placed in heparin or EDTA.
For anaerobic (along with aerobic) cultures, which are recommended for bile, body fluid, and pus, transport media should be used. A.C.T. II agar tubes (Remel) contain a nonnutritive semi-solid medium to which you can add fluid, or, if using swabs, insert one swab each for aerobic and anaerobic culture. Organisms should be stable for 24 hours for both aerobic and anaerobic culture set up. Mycoplasma cultures, which are recommended for tracheal wash samples, can be run from either BBL CultureSwab Plus (without charcoal) or A.C.T. II agar tubes.
If your available laboratory does not provide cultures at an affordable price or with a useful turnaround time, talk to the laboratory manager about your concerns. In-house cultures are also an option, and may not require an incubator. One author recommends inoculation of blood agar and McConkey plates with a sterile calibrated loop or pipette, followed by incubation eleven cm under a 60 watt bulb for 24 hours. Positive plates are submitted for identification and susceptibility, while negative plates are discarded. This can reduce costs to the client and make cultures an affordable habit in your practice.
Common isolates from bacterial infections in dogs
Empirical first line regimens
There are several principles to follow when using empirical antimicrobials. First, use the narrowest spectrum drug for the suspected organism. For example, choose amoxicillin or penicillin, instead of amoxicillin-clavulanate, for a cat abscess, and doxycycline, rather than a fluoroquinolone, for suspected Bordetella infectious tracheobronchitis. Fluoroquinolones are over-used as first line antimicrobials in both human and veterinary medicine. Common reasons for misuse in humans include the wrong disease indication and the availability of narrower spectrum first line agents.
Second, consider tissue penetration. It should be assumed that urinary tract infections in male dogs involve the prostate, and antimicrobials with good prostatic penetration, such as fluoroquinolones, doxycycline, chloramphenicol, or potentiated sulfonamides, should be chosen. For bronchitis without pneumonia, drugs that achieve high concentrations in bronchial secretions should be prescribed, to include fluoroquinolones, doxycycline, azithromycin, or potentiated sulfonamides. For endophthalmitis or ocular trauma, azithromycin and fluoroquinolones show excellent ocular penetration. Beta lactams and aminoglycosides, which are relatively polar, have poor penetration into the prostate, eye, testes, or bronchial secretions.
Common isolates from bacterial infections in cats
Finally, treat for the shortest effective period possible. Shorter courses of appropriate antibiotics decrease the emergence of resistant organisms in humans, and there is a trend towards the use of shorter courses of antimicrobials, with equivalent efficacy compared to longer regimens, in human patients. For example, acute sinusitis, pneumonia, or uncomplicated urinary tract infections are treated effectively with only a 3 to 7-day course of antibiotics in humans. Bacterial otitis in children can be treated with a single dose of azithromycin (as effective as multiple dosing over 7 days), and for community-acquired pneumonia, treatment regimens are tailored to patient response, and are continued for only 2 to 3 days beyond resolution of fever. In veterinary medicine, the recommended duration of treatment for many infections is entirely empirical, and there has been little work to determine whether the longer courses that are recommended in textbooks are actually necessary. Consider using these shorter regimens, with a follow-up recheck and culture one week after discontinuation. Shorter treatment regimens are less expensive for clients (allowing more resources for diagnostics and follow-up), and are associated with better compliance. Most importantly, shorter courses of antimicrobials lead to significantly less bacterial resistance.
Typically effective antimicrobials for different microorganisms
Paul M, Leibovici L. Systematic reviews and meta-analysis of febrile neutropenia. Mayo Clin Proc 2005;80:1122-1125.
Bailiff NL, Westropp JL, Nelson RW, et al. Evaluation of urine specific gravity and urine sediment as risk factors for urinary tract infections in cats. Vet Clin Pathol 2008;37:317-322.
Bailiff NL, Nelson RW, Feldman EC, et al. Frequency and risk factors for urinary tract infection in cats with diabetes mellitus. J Vet Intern Med 2006;20:850-855.
Ruch-Gallie RA, Veir JK, Spindel ME, et al. Efficacy of amoxycillin and azithromycin for the empirical treatment of shelter cats with suspected bacterial upper respiratory infections. J Feline Med Surg 2008;10:542-550.
German AJ, Cannon MJ, Dye C, et al. Oesophageal strictures in cats associated with doxycycline therapy. J Feline Med Surg 2005;7:33-41.
McGrotty YL, Knottenbelt CM. Oesophageal stricture in a cat due to oral administration of tetracyclines. J Small Anim Pract 2002;43:221-223.
Trumble C. Oesophageal stricture in cats associated with use of the hyclate (hydrochloride) salt of doxycycline. J Feline Med Surg 2005;7:241-242.
Chase HP, Beck R, Tamborlane W, et al. A randomized multicenter trial comparing the GlucoWatch Biographer with standard glucose monitoring in children with type 1 diabetes. Diabetes Care 2005;28:1101-1106.
Hart PA, Bechtold ML, Marshall JB, et al. Prophylactic antibiotics in necrotizing pancreatitis: a meta-analysis. South Med J 2008;101:1126-1131.
Ball KR, Rubin JE, Chirino-Trejo M, et al. Antimicrobial resistance and prevalence of canine uropathogens at the Western College of Veterinary Medicine Veterinary Teaching Hospital, 2002-2007. Can Vet J 2008;49:985-990.
Ogeer-Gyles J, Mathews K, Boerlin P. Nosocomial infections and antimicrobial resistance in critical care medicine. J Vet Emerg Crit Care 2006;16:1-18.
Ogeer-Gyles J, Mathews K, Weese JS, et al. Evaluation of catheter-associated urinary tract infections and multi-drug-resistant Escherichia coli isolates from the urine of dogs with indwelling urinary catheters. J Am Vet Med Assoc 2006;229:1584-1590.
Chandler JC, Lappin MR. Mycoplasmal respiratory infections in small animals: 17 cases (1988-1999). J Am Anim Hosp Assoc 2002;38:111-119.
Bartges JW. Diagnosis of urinary tract infections. Vet Clin North Am Small Anim Pract 2004;34:923-933, vi.
Speakman AJ, Dawson S, Corkill JE, et al. Antibiotic susceptibility of canine Bordetella bronchiseptica isolates. Vet Microbiol 2000;71:193-200.
Mean M, Pavese P, Vittoz JP, et al. Prospective assessment of fluoroquinolone use in a teaching hospital. Eur J Clin Microbiol Infect Dis 2006;25:757-763.
Dorfman M, Barsanti J, Budsberg SC. Enrofloxacin concentrations in dogs with normal prostate and dogs with chronic bacterial prostatitis. Am J Vet Res 1995;56:386-390.
Niederman MS. Principles of appropriate antibiotic use. Int J Antimicrob Agents 2005;26 Suppl 3:S170-175.
Falagas ME, Karageorgopoulos DE, Grammatikos AP, et al. Effectiveness and safety of short vs. long duration of antibiotic therapy for acute bacterial sinusitis: a meta-analysis of randomized trials. Br J Clin Pharmacol 2008.
Dimopoulos G, Matthaiou DK, Karageorgopoulos DE, et al. Short- versus long-course antibacterial therapy for community-acquired pneumonia: a meta-analysis. Drugs 2008;68:1841-1854.
Lutters M, Vogt-Ferrier NB. Antibiotic duration for treating uncomplicated, symptomatic lower urinary tract infections in elderly women. Cochrane Database Syst Rev 2008:CD001535.
Sykes JE, Kittleson MD, Pesavento PA, et al. Evaluation of the relationship between causative organisms and clinical characteristics of infective endocarditis in dogs: 71 cases (1992-2005). J Am Vet Med Assoc 2006;228:1723-1734.
Wagner K, Hartmann F, Trepanier L. Bacterial culture results from liver, gall bladder, or bile in 248 dogs and cats evaluated for hepatobiliary disease. J Vet Intern Med 2007;21:417-424.
Clements DN, Owen MR, Mosley JR, et al. Retrospective study of bacterial infective arthritis in 31 dogs. J Small Anim Pract 2005;46:171-176.
Marchevsky AM, Read RA. Bacterial septic arthritis in 19 dogs. Aust Vet J 1999;77:233-237.
Caywood DD, Wallace LJ, Braden TD. Osteomyelitis in the dog: a review of 67 cases. J Am Vet Med Assoc 1978;172:943-946.
Radhakrishnan A, Drobatz KJ, Culp WT, et al. Community-acquired infectious pneumonia in puppies: 65 cases (1993-2002). J Am Vet Med Assoc 2007;230:1493-1497.
Hagman R, Greko C. Antimicrobial resistance in Escherichia coli isolated from bitches with pyometra and from urine samples from other dogs. Vet Rec 2005;157:193-196.
Roy J, Messier S, Labrecque O, et al. Clinical and in vitro efficacy of amoxicillin against bacteria associated with feline skin wounds and abscesses. Can Vet J 2007;48:607-611.
Litster A, Moss S, Platell J, et al. Occult bacterial lower urinary tract infections in cats-Urinalysis and culture findings. Vet Microbiol 2008.
Walker AL, Jang SS, Hirsh DC. Bacteria associated with pyothorax of dogs and cats: 98 cases (1989-1998). J Am Vet Med Assoc 2000;216:359-363.
Oluoch AO, Kim CH, Weisiger RM, et al. Nonenteric Escherichia coli isolates from dogs: 674 cases (1990-1998). J Am Vet Med Assoc 2001;218:381-384.
Kraiczy P, Weigand J, Wichelhaus TA, et al. In vitro activities of fluoroquinolones against the spirochete Borrelia burgdorferi. Antimicrob Agents Chemother 2001;45:2486-2494.
Buckingham SC. Tick-borne infections in children: epidemiology, clinical manifestations, and optimal management strategies. Paediatr Drugs 2005;7:163-176.
Branger S, Rolain JM, Raoult D. Evaluation of antibiotic susceptibilities of Ehrlichia canis, Ehrlichia chaffeensis, and Anaplasma phagocytophilum by real-time PCR. Antimicrob Agents Chemother 2004;48:4822-4828.
Owen WM, Sturgess CP, Harbour DA, et al. Efficacy of azithromycin for the treatment of feline chlamydophilosis. J Feline Med Surg 2003;5:305-311.