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Keywords:

  • Antimicrobial resistance;
  • Canine;
  • Epidemiology;
  • Risk factors

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. References

Background: Extraintestinal infections caused by multidrug-resistant (MDR) Escherichia coli and Enterobacter are becoming more common in veterinary medicine.

Objective: To generate hypotheses for risk factors for dogs acquiring extraintestinal infection caused by MDR E. coli and Enterobacter, describe antimicrobial resistance profiles and analyze treatment and clinical outcomes.

Animals: Thirty-seven dogs diagnosed with extraintestinal infection caused by MDR E. coli and Enterobacter spp. between October 1999 and June 2006.

Methods: Retrospective case series assembled from hospital records data, including clinical history before 1st MDR isolation and treatment outcome. Identity and antimicrobial susceptibility profiles were confirmed by standard microbiological techniques for 57 isolates.

Results: Most dogs had an underlying disease condition (97%), received prior antimicrobial treatment (87%), were hospitalized for ≥3 days (82%), and had a surgical intervention (57%). The urinary tract was the most common infection site (62%), and urinary catheterization, bladder stasis, or both were common among dogs (24%). Some dogs were treated with high doses of co-amoxyclavulanate (n = 14) and subsequently recovered even though the isolates showed in vitro resistance to this antimicrobial. Other dogs were successfully treated with chloramphenicol (n = 11) and imipenem (n = 2).

Conclusion and Clinical Importance: Predisposing disease condition, any prior antimicrobial use rather than a specific class of antimicrobial, duration of hospitalization, and type of surgical procedure might be risk factors for acquiring MDR extraintestinal infections. Whereas culture and sensitivity results can indicate use of last-resort antimicrobials such as imipenem for MDR infections, some affected dogs can recover after administration of high doses of co-amoxyclavulanate.

Escherichia coli and Enterobacter spp. are common causes of extraintestinal opportunistic infections in humans.1 Isolates that are resistant to 3rd-generation cephalosporins and ciprofloxacin are becoming more common in health care facilities and the general community.1,2 Multidrug-resistant (MDR) E. coli and Enterobacter have a similar role in opportunistic infections in dogs.3,4 Recently, there has been an increased frequency of infections in veterinary settings,3–9 possibly because of greater use of intensive care facilities, newer generation antimicrobials, and longer hospitalization periods.4

A cluster of extraintestinal infections caused by MDR E. coli occurred in hospitalized dogs at The University of Queensland Veterinary Teaching Hospital (UQVTH) between 2000 and 2001. Clonal expansion of 2 distinct genetic groups of E. coli was confirmed, with each clonal group showing differences in plasmid carriage and resistance profile. However, they shared a common plasmid-mediated AmpC gene blaCMY7, responsible for resistance to 3rd-generation cephalosporins and β-lactam/β-lactamase inhibitor combinations.7 MDR Enterobacter were also isolated at the same time and were more genetically diverse, with 3rd-generation cephalosporin resistance attributed to the presence of plasmid-mediated blaSHV−12 extended-spectrum β-lactamase in 9 isolates and an AmpC blaCMY−2 in the remaining isolate.5

There are few published studies describing risk factors for nosocomial infections caused by MDR bacteria in veterinary medicine.3,4 In human medicine, identified risk factors include underlying condition, age (pediatric or geriatric), immunosuppression, concurrent chemotherapy or radiation therapy, introduction of medical and surgical devices, prolonged hospitalization, and antimicrobial treatment. These could also be clinically relevant factors for MDR nosocomial infections in veterinary hospitals, which may be less common because companion animals are not kept in aged care facilities and immunocompromised/chronically ill animals are often euthanized.3,4

The objective of this case series was to generate hypotheses for risk factors for dogs acquiring extraintestinal infection caused by MDR E. coli and Enterobacter by describing the frequency of exposure to putative risk factors for 37 dogs diagnosed with extraintestinal infection. The study also aimed to describe antimicrobial resistance profiles of the isolates and treatment and clinical outcomes of the cases.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. References

Case Definition and Selection of Cases

All dogs with an extraintestinal infection yielding at least 1 MDR E. coli or Enterobacter isolate cultured by The University of Queensland Veterinary Diagnostic Laboratory between October 1999 and June 2006 were enrolled. Dogs were from 1 of 3 veterinary referral hospitals in southeast Queensland, UQVTH (n = 20), and Brisbane referral veterinary hospitals 1 (n = 15) and 2 (n = 2). Isolates were considered MDR if they were resistant to 4 or more of 6 antimicrobials (tetracycline, gentamicin, enrofloxacin, amoxicillin/clavulanic acid, sulfonamide/trimethoprim, and cephalothin) on the basis of disk diffusion susceptibility testing.10

Clinical Data Collection

Signalment, underlying disease condition, clinical history, prior treatments and interventions, hospitalization histories, and outcomes were analyzed from hospital records for each dog from 6 weeks before the 1st isolation of MDR E. coli or Enterobacter from an extraintestinal site (defined as the preisolation period). Dogs were categorized as having 1 of 3 outcomes: (1) recovery based on clinical assessment alone or in combination with negative cultures or radiographic evidence, (2) euthanasia or death, or (3) unknown outcome because the dog was lost to follow-up.

Bacterial Isolates and Antimicrobial Susceptibility Testing

E. coli and Enterobacter isolates were identified from specimens by standard veterinary diagnostic techniques, including the Microbact 24E system,a and by species-specific polymerase chain reaction amplification of E. coli uspA.11Enterobacter spp. were further identified as either E. hormaechei or E. cloacae by 16S rRNA gene sequencing.5 All isolates were stored in Lauria-Bertani broth with 15% (v/v) glycerol at −80 °C. They were confirmed to be MDR via Clinical and Laboratory Standards Institute disk diffusion susceptibility testing for 20 antimicrobials (Table 1).10 For 3 dogs, MDR infection had first been demonstrated by a private veterinary diagnostic laboratory during the 6-week preisolation period, and these original MDR isolates were not available for further bacteriological analysis. For these dogs, isolate information and resistance profiles were extracted from case records and diagnostic reports.

Table 1.   Antimicrobial resistance profiles of 57 multidrug-resistant Escherichia coli and Enterobacter spp. isolates obtained from extra-intestinal infection in 37 dogs.
Resistance ProfileNumber of IsolatesDisk Diffusion Susceptibilitya
AMCAMPKFCAZCPDCTXCROCXMCHLCIPENRFOXGENMARSXTTICTETTIMIPMAMK
  • a

    AMC, amoxycillin/clavulanic acid 20/10 μg; AMP, ampicillin 10 μg; KF, cephalothin 30 μg; CAZ, ceftazidime 30 μg; CPD, cefpodoxime 10 μg; CTX, cefotaxime 30 μg; CRO, ceftriazone 30 μg; CXM, cefuroxime 30 μg;CHL, chloramphenicol 30 μg; CIP, ciprofloxacin 5 μg; ENR, enrofloxacin 5 μg; FOX, cefoxitin 10 μg; GEN, gentamicin 10 μg; MAR, marbofloxacin 5 μg; SXT, sulfamethoxazole/trimethoprim 1.25/23.75 μg; TIC, ticarcillin 75 μg; TET, tetracycline 30 μg; IPM, imipenem 10 μg; TIM, timentin; AMK, amikacin 30 μg.

  • b

    b 2 I.

  • c

    c 1 I

  • d

    d 2 S.

  • e

    e 1 S.

  • f

    f 3 S.

  • g

    g 1 R.

  • S, sensitive; I, intermediate; R, resistant.

E. coli
17RRRRRRRRRRRRRRRRRRSS
219RRRRRRbRcRSRRRRdRReRReRSS
313If,gRRSSSSISgRRSRRRRRSSS
43SSRSSSSISRRSRRSSRSSS
53RRISSSSSSRRSSRRRRSSS
Enterobacter spp.
Ec18RRRRRIgIgRRRRRRcRRRRIe,gSS
Ec22RRRRRIRRSSRRRSRRRScSS
Ec32RRRRRIgRbRRSScRRSRRRIgSS

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. References

Source of Cases

Thirty-seven dogs were diagnosed with MDR E. coli or Enterobacter extraintestinal infection over the 6-year study period. The dogs were divided into 2 groups: (a) dogs that were diagnosed with infection after surgery (postsurgical dogs) and (b) dogs that were diagnosed with an infection after medical treatment or immediately before surgery (medical dogs) (Table 2). These could be further subdivided by specimen type (urinary tract infection [UTI] versus other extraintestinal sites).

Table 2.   Description of the specimen and underlying condition for postsurgical and medical dogs and the resistance profiles of the MDR Escherichia coli or Enterobacter spp isolates.
CategorySpecimenUnderlying Conditions/SurgeryNo. of DogsDog No.Resistance ProfileNo. of Isolates
Postsurgical dogs (n = 16)UrineOrthopedic (n = 5)86, 11, 17, 18, 23, 26, 29, 3112
 Urogenital (n = 2)  25
 Abdominal (n = 1)  Ec15
Orthopedic implant/screw or swabOrthopedic (n = 5)52, 3, 10, 22, 3411
    22
    Ec14
    Ec22
Wound aspirateAural (n = 1)28, 911
 Abdominal (n = 1)  22
BloodAbdominal (n = 1)12721
Medical dogs (n = 21)UrineNeoplasia (n = 2)151, 7, 12–16, 19–21, 28, 32–33, 35, 37  
 Diabetes mellitus (n = 2)    
 Pyelonephritis (n = 3)  14
 Chronic cystitis (n = 5)  215
 Urinary incontinence (n = 3)  35
 Trauma (n = 1)  42
 Immune-mediated thrombocytopenia (n = 2)  53
 Discospondylitis (n = 1)  Ec13
 Inflammatory bowel disease (n = 2)  Ec31
 Pancreatitis (n = 2)    
 Granulomatous meningioencephalitis (n=1)    
Vaginal swabCystitis, endometritis12438
EpididymisAutoimmune haemolytic anemia, epididymitis1522
Skin swabAbscess (n = 1)24, 3021
 Myelodysplastic syndrome (n = 1)  Ec11
Joint fluidImmune-mediated thrombocytopenia13651
Bullae fluidOtitis media/externa12541
Total  37  72

Antimicrobial Resistance Profiles

Seventy-two MDR E. coli (55 isolates from 27 dogs) or Enterobacter (17 isolates from 12 dogs) were obtained from the 37 dogs. Two dogs yielded both E. coli and Enterobacter isolates. Because 15 isolates were unavailable for study, full-resistance profiles were obtained for 57 isolates from 31 dogs (Table 1). E. coli resistance profile 1 (chloramphenicol R) and 2 (chloramphenicol S) corresponded with the previously described clonal group 1 and clonal group 2, respectively.6E. coli resistance profiles 3, 4, and 5 were similar to profile 2, except that they were susceptible to 3rd-generation cephalosporins and cefoxitin. Three profiles were generated for the MDR Enterobacter (Table 1), and have been reported previously for a subset of the isolates.5

Seventeen of the 37 dogs had multiple isolates taken from the same site at various time intervals after the date of 1st isolation (range 0–330 days, median 49 days). In general, multiple isolates from each dog had the same resistance profile, but there were a few notable exceptions, including a dog with osteomyelitis (dog 2) and dogs with recurrent cystitis (dogs 13, 14, 26, 28, and 29) (Table 2).

MDR E. coli antimicrobial resistance profiles also changed over time. Of the MDR E coli isolated between 1999 and 2002, 29% (7/24) were profile 1, 58% (14/24) were profile 2, and 13% (3/24) were profile 3. In contrast, for isolates obtained between 2003 and 2006, 0% were profile 1, 24% (5/21) were profile 2, and 76% (16/21) were profiles 3, 4, or 5. MDR Enterobacter were sporadically isolated between February 2001 and March 2006.

Signalment

No single breed predominated. Age at the time of the 1st isolation ranged from 4 months to 17 years, with a median of 7.5 years. For postsurgical dogs, the median age was 4.5 years (range 4 months–8 years) and for medical dogs, the median age was 11 years (range 3–17 years). The dogs that developed an MDR UTI after medical treatment were older, with a median age of 10.5 years. Twenty-one dogs were female (15 spayed) and 16 were male (8 castrated).

Underlying Condition

Forty-three percent (16/37) of dogs were diagnosed with extraintestinal MDR infection after surgery. The type of surgery varied from orthopedic (10 dogs, 5 with a postoperative UTI and 5 with osteomyelitis), urogenital (2 dogs with UTI), abdominal (3 dogs; 1 with a UTI, 1 with peritonitis, and 1 with septicemia), and aural (1 dog with an infection post ear canal resection). Fifty-seven percent (21/37) of dogs were diagnosed with MDR E. coli or Enterobacter infection on 1st presentation or while undergoing medical treatment. These dogs presented with a number of underlying conditions (Table 2). Eleven dogs had some form of urinary tract disease, including 3 with upper urinary tract disease, 6 with lower urinary tract disease, and 2 with incontinence. Other conditions included immune-mediated/inflammatory (9); infectious disease (4); neoplasia (3); and diabetes (2). Seven dogs had multiple unrelated underlying conditions.

Antimicrobial Use Before Isolation of MDR E. coli or Enterobacter

Five dogs with primary medical infections had no prior history of antimicrobial use, but 9, 14, and 9 dogs had received 1, 2, and 3 or more antimicrobials in the pre-isolation period, respectively. Antimicrobials used in the pre-isolation period included penicillin (ampicillin), cephalosporins (1st generation), β-lactam/β-lactamase inhibitor combinations (co-amoxyclavulanate), fluoroquinolones (enrofloxacin), nitromidazoles (metronidazole), and trimethoprim/sulfonamide (Table 3). Before confirmation of MDR infection, all dogs except 5 with primary medical infections, for whom antimicrobial treatment history could not be determined from case records, were treated with co-amoxyclavulanate, cephalosporins, or fluoroquinolones alone or in combination with another drug. Forty-six percent (17/37) of dogs had been treated with cephalosporins, 49% (18/37) with fluoroquinolones, and 57% (21/37) with co-amoxyclavulanate.

Table 3.   Antimicrobials prescribed in the preisolation period for dogs with MDR Escherichia coli or Enterobacter spp. extraintestinal infection.
CategorySpecimenNo. of Dogs Prescribed (%)
AMCAMPENRKFMTZSXT
  • a

    Specimen was obtained from either orthopaedic implant/screw or swab (n = 5), wound aspirate (n = 2), or blood (n = 1).

  • b

    Specimen was obtained from vaginal swab (n = 1), epididymis aspirate (n = 1), skin swab (n = 2), joint fluid (n = 1), or bullae fluid (n=1).

  • MDR, multidrug resistance; AMC, amoxycillin/clavulanic acid; AMP, ampicillin; ENR, enrofloxacin; KF, cephalothin; MTZ, metronidazole; SXT, sulfamethoxazole/trimethoprim.

Postsurgical dogsUrine (n = 8)5 (63)1 (13)4 (50)6 (75)00
Othera (n = 8)6 (75)3 (38)5 (63)5 (63)3 (38)0
Medical dogsUrine (n = 15)5 (34)1 (7)5 (34)4 (27)1 (7)1 (7)
Otherb (n = 6)5 (84)1 (17)4 (67)2 (34)1 (17)0
Total3721 (57)6 (16)18 (49)17 (46)5 (14)1 (3)

Hospitalization

Most (82%) of the dogs were hospitalized for ≥3 days before the 1st isolation of MDR E. coli or Enterobacter. All 16 postsurgical dogs were hospitalized within the pre-isolation period and the total duration of hospitalization varied from 3 to 33 days, with a median of 10 days. Eighty-five percent (18/21) of the medical dogs were hospitalized within the pre-isolation period (total duration 1–19 days, with a median of 7 days).

Invasive and Diagnostic Procedures

Fifty-seven percent (21/37) of dogs (including all 16 postsurgical dogs) had a general anesthetic and surgery within the pre-isolation period. Fifteen of the 16 postsurgical dogs also had at least 1 diagnostic imaging procedure (radiograph, ultrasound, or computed tomography scan), 62% (10/16) had more than 1 general anesthetic, and 44% (7/16) had more than 1 surgical procedure. Twenty-nine percent (6/21) of the medical dogs had a surgical procedure within the pre-isolation period, 38% (8/21) had a general anesthetic, and 48% (10/21) had diagnostic imaging performed.

UTIs

UTIs were most frequent, accounting for 62% (23/37) of dogs and 58% (42/72) of MDR isolations. All of these dogs had evidence of UTI on the basis of clinical history or physical examination. They had a variety of underlying conditions (Table 2), and 8 of the 23 dogs had a primary voiding dysfunction (Table 4). Urine was collected by cystocentesis in 87% (20/23) of dogs (Table 4), and MDR E. coli or Enterobacter was cultured at >103 bacteria/mL, indicative of UTI,13 in 88% (37/42) of urine specimens (Table 4). Four of 5 samples yielding bacterial counts of <103 bacteria/mL were collected by cystocentesis; the remaining sample was collected by a catheter at the time of removal because it contained a purulent discharge. For 1 dog with immune-mediated thrombocytopenia, only voided samples were considered. Twenty-eight urine specimens yielded MDR E. coli and Enterobacter in pure culture. In mixed infections, other bacteria isolated included E. coli (4) Streptococcus (1), Klebsiella pneumoniae (3), Proteus mirabilis (3), Staphylococcus intermedius (1), Candida sp. (1), Enterococcus (1), and Pseudomonas aeruginosa (1). Twenty-seven percent (10/37) of dogs had a urinary catheter in place. All but one of these dogs were given antimicrobials when catheterized before isolation of MDR E. coli or Enterobacter. Of the 23 dogs that developed an MDR UTI, 35% (8/23) had a urinary catheter in place during the preisolation period, for a median of 9.5 days (range 3–22 days).

Table 4.   Estimated bacterial count in urine and method of collection for 42 MDR Escherichia coli and Enterobacter isolates obtained from the urine of 23 hospitalized dogs.
Type of InfectionNo. of IsolatesCFU/mLaMethod of Collection
102–103103–104≥104≥105CystocentesisCatheterVoidedUnknown
  • a

    Colony forming units/mL of urine as defined.12

  • b

    Seven of 8 postsurgical UTI dogs had a primary voiding dysfunction (5 had spinal surgery, 1 had urinary stasis post cruciate surgery, 1 had prostatic surgery, and 1 had ectopic ureters). Six dogs had an indwelling urinary catheter before isolation of MDR E. coli or Enterobacter.

  • c

    c One of 15 medical UTI dogs had neurologic urinary bladder dysfunction. Two of 15 dogs had a urinary catheter before isolation.

  • d

    d Pure growth.

  • MDR, multidrug resistance; UTI, urinary tract infection.

Postsurgical dogsb (n = 8)122   11  
    109  1
Medical dogsc (n = 15)303   3   
  3  3   
   4 3 1d 
    2018 2d 

Clinical Outcomes and Antimicrobial Treatments after MDR Isolation

Sixty-eight percent (25/37) of dogs recovered (Table 5). Only dog 27, which developed MDR E. coli sepsis and endocarditis, was euthanized as a result of developing an extraintestinal MDR infection. However, 27% (10/37) of dogs either died or were euthanized at the discretion of the attending veterinary surgeon because of underlying medical conditions (renal or cardiac failure, neoplasia, or immune-mediated disease) or failure to respond to surgical treatment (continual paralysis after spinal decompression). The outcomes of 2 dogs (both orthopedic) were unknown; both were improving clinically and radiographically but were lost to follow-up while still on treatment.

Table 5.   Treatments prescribed for MDR Escherishia coli or Enterobacter spp. extraintestinal infections and the clinical outcomes for each dog.
CategorySpecimenNo. (%) of Dogs PrescribedOutcome—No. of Dogs (%)
AMCCHLENRIPMKFSXTOtherResolvedEuthanized or DiedUnknown
  • a

    Specimen was obtained from either orthopedic implant/screw or swab (n = 5); wound aspirate (n = 2); or blood (n = 1).

  • b

    Panalog Ointment® (nystatin, thiostrepton, neomycin sulfate, and triamcinolone acetonided).

  • c

    Otamax® (betamethasone valerate, gentamicin sulfate, and clotrimazoleb).

  • d

    Specimen was obtained from vaginal swab (n = 1), Epididymis aspirate (n = 1), skin swab (n = 2), joint fluid (n = 1), or bullae fluid (n = 1).

  • e

    Canaural Compositum® (diethanolamine fusidate, framycetin sulphate, nystatin, and prednisolonec).

  • MDR, multidrug resistance; AMC, amoxycillin/clavulanic acid; CHL, chloramphenicol; ENR, enrofloxacin; IPM, imipenem; KF, cephalothin; SXT, sulfamethoxazole/trimethoprim.

Postsurgical dogsUrine (n = 8)3 (38)2 (25)3 (38)002 (25) 5 (63)3 (37)0
Othera (n = 8)2 (25)3 (38)01 (13)00Topical aural preparationsb,c5 (63)1 (13)2 (25)
Medical dogsUrine (n = 15)8 (53)6 (40)2 (13)1 (7)1 (7)2 (13)Itraconzaole10 (67)5 (33)0
Otherd (n = 6)1 (17)01 (17)01 (17)0Topical preparationb,e Ovariohysterectomy Surgical drainage Castration5 (83)1 (17)0
Total3714 (41)11 (30)6 (16)2 (5)2 (5)4 (11) 25 (68)10 (27)2 (5)

All but one of the dogs involving an MDR E. coli UTI were treated with co-amoxyclavulanate (12.5–25 mg/kg PO q12h for 20–30 days) or chloramphenicol (50 mg/kg PO q8h for 11–33 days). The exception (dog 1) was treated with imipenem (IV) at 33 mg/kg q8h for 19 days, and the infection resolved. The 2 MDR Enterobacter UTIs that were sensitive to fluoroquinolones were treated with enrofloxacin (5–7 mg/kg PO q24h for 20–30 days). One dog with Enterobacter UTI, which was resistant to fluoroquinolones and trimethoprim/sulfonamide, received 70 days of treatment with a combination of these drugs (12 mg/kg PO q24h and 6 mg/kg PO q12h, respectively), and the infection resolved after this time. One Enterobacter UTI dog also had concurrent C. albicans infection, and was treated only with itraconazole. Follow-up urine cultures were negative for both Enterobacter and yeast. Four dogs had a urinary catheter in place at the time of diagnosis of MDR E. coli or Enterobacter UTI. For two of these dogs, the catheter was immediately removed on diagnosis, in 1 dog the indwelling urinary catheter remained in place for another 6 weeks (changed weekly), and 1 dog was euthanized shortly after diagnosis. The MDR infections associated with orthopedic surgery (5 dogs) were treated with co-amoxyclavulanate (25 mg/kg PO q12h for >21 days) or chloramphenicol (50 mg/kg PO q8h for >20 days) and resolved (3/5) or were lost to follow-up (2/5), although clinical examination records and radiographs confirmed that they were improving. Only 1 other dog (dog 8), with peritonitis after abdominal surgery, was treated with IV imipenem (5 mg/kg q8h for 9 days) with resolution of the infection.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. References

Extraintestinal infections in both humans and dogs occur through direct patient-to-patient transfer or contact with a contaminated environment, iatrogenically or via endogenous transfer of bacteria that predominate in the patient's fecal microbiota.4,14,15 Previous characterization of rectal and clinical MDR E. coli isolates suggested that endogenous transfer is the major route of infection in this case series, because a high rate of gastrointestinal carriage of MDR E. coli was also demonstrated in hospitalized dogs over the same time period.7,16

Of the major published risk factors for acquiring MDR extraintestinal infection in animals and humans,4 severe underlying illness (97% of dogs), hospitalization for ≥3 days (82%), and surgical intervention (57%) were common in the present study. More specific risk factors could not be established as animal movements within the hospitals, and the number and nature of interactions with veterinary staff could not be clearly determined from the case records. In addition, these factors are confounded by concurrent antimicrobial use.

Antimicrobial treatment selects for resistance in both pathogenic and commensal Enterobacteriaceae, and is considered the most important risk factor for acquiring extraintestinal infection with MDR strains.17 The results from our study suggest that prior antimicrobial treatment with β-lactam/β-lactamase inhibitors, fluoroquinolones, and 1st-generation cephalosporins, either singularly or in combination, may be a risk factor. Interestingly, the predominant E. coli resistance profile changed over time, with resistance profile 1 and 2 strains becoming less prevalent and resistance profiles 3, 4, and 5 more so in later years. Resistance profile 2 isolates correspond to previously described clonal group 2 isolates6 and contain a 93 kb blaCMY−7 plasmid responsible for resistance to 3rd-generation cephalosporins and β-lactam/β-lactamase inhibitors. Resistance profile 3, 4, and 5 strains are probably closely related to resistance profile 2, except that they are sensitive to β-lactams and may have lost or not acquired the AmpC β-lactamase-bearing 93 kb plasmid.5,6 Molecular typing would be required to confirm whether they indeed belong to the same clonal group.18

Surprisingly, MDR infection could be held directly responsible for the euthanasia of only 1 dog that developed sepsis. For the remaining dogs, treatment varied according to the antimicrobial sensitivity profile of the isolate and the site of infection, with the majority of dogs being UTIs. Risk factors for acquiring UTI include poor host defenses, paresis, or urinary stasis requiring catheterization, such as would be expected in cases of intervertebral disk disease.19–21 In these dogs, antimicrobial administration during the period of catheterization is a major risk factor for development of UTI.21 In the current study, all dogs yielding an MDR urine culture were treated by the clinician as UTIs on the basis of clinical history and physical examination, including 3 dogs from which only <103 MDR bacteria per milliliter urine were obtained from samples collected by cystocentesis. Similarly, the remaining samples collected by voiding or catheter yielded moderate to heavy growth of MDR bacteria in pure culture, indicating UTI rather than asymptomatic bacteruria (Table 4).

Fourteen UTIs resolved in association with co-amoxyclavulanate treatment, even though the isolates showed in vitro resistance to this agent. This may be a result of co-amoxyclavulanate undergoing renal elimination; therefore, urine concentration is high. The minimum inhibition concentration (MIC) range of amoxicillin/clavulanic acid for resistance profile 1 and 2 isolates was 32–128 mg/L (J. Gibson, unpublished data). To treat UTIs, it is necessary to maintain urine antimicrobial concentrations at 4 times the MIC of the pathogen.22 The mean urine concentration of co-amoxyclavulanate at 12.5 mg/kg PO q8h is 201 mg/L.22 This indicates that some resistance in profiles 1 and 2 UTIs would not be expected to respond to treatment with co-amoxyclavulanate at the recommended dosage, but as documented in our study, they may resolve at the higher dose of 25 mg/kg.

Interestingly, the postsurgical dogs of MDR osteomyelitis resolved or were improving after antimicrobial treatment and supportive care, even when the prescribed antimicrobial showed in vitro resistance. Three of these dogs were treated with chloramphenicol at 50 mg/kg PO q8h for >20 days, and the bacteria isolated from these dogs were all sensitive to this agent. Chloramphenicol attains therapeutic concentrations in most tissues,23 but it is not an ideal choice because it is bacteriostatic24 and may trigger bone marrow suppression and development of immune-mediated aplastic anemia in some patients.25 The remaining 2 orthopedic dogs yielded isolates with an amoxicillin/clavulanic acid MIC of 64 mg/L (J. Gibson, unpublished data). These were treated with co-amoxyclavulanate at 25 mg/kg PO q12h for >21 days. Whereas this antimicrobial has excellent penetration through bone,26 it could not be determined whether it maintained a therapeutic drug concentration in this site that exceeded the MIC of the MDR isolates between doses. It must also be considered that complete resolution of infection may in part be attributed to supportive treatment and/or the host response.

Imipenem, a carbapenem for IV use, was used only in 2 dogs because it is expensive, requires IV administration, and affects renal and hepatic function. In addition, the carbapenems are a last-line treatment in human medicine for serious MDR Gram-negative infections, and their use in veterinary medicine should be restricted to an absolute last resort. Other dogs resolved after surgical intervention and treatment of the primary condition, including draining of the abscess, castration, and ovariohysterectomy, without the concurrent use of antimicrobials.

Although the dogs' histories suggested that the majority of infections were nosocomial in origin, this could be established only for dog 11. This dog had a rectal swab taken on admission that was negative for MDR E. coli. After bilateral tibial plateau levelling osteotomy, it had a long hospitalization period, was treated with fluoroquinolones for a Pseudomonas postsurgical infection, and, 2 weeks after the negative rectal swab, became colonized with MDR E. coli. Insertion of a urinary catheter presumably predisposed to development of an MDR UTI (profile 2) caused by the same endogenous E. coli strain isolated from the rectal swab. The UTI resolved after treatment with chloramphenicol.

Case series usually provide only limited evidence when assessing putative risk factors for disease development. However, results from case series can be useful as supportive evidence for findings from other study types and for generating new hypotheses. The potential risk factors for dogs acquiring MDR extraintestinal infection suggested by this study were severe underlying illness, prolonged hospitalization, surgical intervention, and prior antimicrobial treatment with β-lactams, fluoroquinolones, or both, which maintains selection pressure for colonization of the hospitalized animal. In terms of treatment options for veterinary clinicians confronting MDR opportunistic infections, determining the relationship between antimicrobial pharmacokinetics/pharmacodynamics and the MIC of the MDR pathogen may be more judicious than reaching for expensive, top-shelf drugs usually reserved for treating human infections.

Footnotes

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. References

aMedvet Diagnostics, Thebarton, SA, Australia

bPanalog Ointment®, Novartis Animal Health Australasia Pty Limited, North Ryde, NSW, Australia

cOtamax®, Schering-Plough Animal Health, Omaha, NE

dCanaural Compositum®, Boehringer Ingelheim Pty Limited, Ingelheim, Germany

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. References
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    National Nosocomial Infections Surveillance (NNIS). System report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004;32:470485.
  • 3
    Prescott JF, Hanna WJ, Reid-Smith R, et al. Antimicrobial drug use and resistance in dogs. Can Vet J 2002;43:107116.
  • 4
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