Jvim_18_101.8_17.tp

Antimicrobial Use in the Treatment of Calf Diarrhea
Calves with diarrhea often have small intestinal overgrowth with Escherichia coli bacteria, regardless of the inciting cause for thediarrhea, and 30% of systemically ill calves with diarrhea have bacteremia, predominantly because of E coli. Antimicrobial treatmentof diarrheic calves should therefore be focused against E coli in the small intestine and blood, the 2 sites of infection. Fecalbacterial culture and antimicrobial susceptibility testing is not recommended in calves with diarrhea because fecal bacterial pop-ulations do not accurately reflect small intestinal or blood bacterial populations and because the break points for susceptibility testresults have not been validated. Antimicrobial efficacy is therefore best evaluated by the clinical response of a number of calvesto treatment, with calves randomly assigned to treatment groups. Amoxicillin, chlortetracycline, neomycin, oxytetracycline, strep-tomycin, sulfachloropyridazine, sulfamethazine, and tetracycline administered PO are currently labeled in the United States for thetreatment of calf diarrhea. On the basis of published evidence for the oral administration of these antimicrobial agents, onlyamoxicillin can be recommended for the treatment of diarrhea. Dosage recommendations are amoxicillin trihydrate (10 mg/kg POq12h) or amoxicillin trihydrate–clavulanate potassium (12.5 mg combined drug/kg PO q12h) for at least 3 days; the latter constitutesextra-label drug use. Parenteral administration of broad-spectrum ␤-lactam antimicrobials—ceftiofur (2.2 mg/kg IM or SC q12h)and amoxicillin or ampicillin (10 mg/kg IM q12h)—or potentiated sulfonamides (25 mg/kg IV or IM q24h) is recommended fortreating calves with diarrhea and systemic illness; both constitute extra-label drug use. In calves with diarrhea and no systemicillness (normal appetite for milk, no fever), it is recommended that the health of the calf be monitored and that oral or parenteralantimicrobials not be administered.
Key words: Antibiotic; Escherichia coli; Salmonella; septicemia; susceptibility.
Calf diarrhea remains the leading cause of mortality in programs, including vaccination and optimizing transfer of
dairy calves1 and an important cause of morbidity and colostral immunity, it has diverted attention from the finding mortality in beef calves.2 Despite the increased availability of numerous studies that calves with diarrhea have coliform of vaccines against enterotoxigenic E coli, rotavirus, and bacterial overgrowth of the small intestine.3–8 coronavirus and continued emphasis on optimizing colostral Studies completed more than 70 years ago documented transfer of passive immunity, improved treatment protocols increased numbers of E coli bacteria in the abomasum, du- for calf diarrhea are required. Although the administration odenum, and jejunum of scouring calves.3,4 Moreover, of intravenous fluids and oral electrolyte solutions plays a calves severely affected with diarrhea had increased num- central role in treatment, the efficacy of antimicrobial bers of E coli bacteria in the anterior portion of their intes- agents in treating calf diarrhea is controversial. The purpose tinal tracts, compared with mildly affected animals.4 More of this article, therefore, is to critically review studies re- recent studies have consistently documented that calves lated to the use of antimicrobials in calves with diarrhea with naturally acquired diarrhea, regardless of age and eti- and to develop evidence-based recommendations for the ologic cause for the diarrhea, have altered small intestinal use of antimicrobials to treat calf diarrhea. Treatment as- bacterial flora.5–7 Specifically, E coli bacterial numbers are pects related to economics, animal welfare, and the poten- increased 5- to 10,000-fold in the duodenum, jejunum, and tial for promoting antimicrobial resistance are also impor- ileum of calves with naturally acquired diarrhea,5–8 even tant but are beyond the scope of this review.
when the diarrhea was not caused by enterotoxigenic strainsof E coli and when rotavirus and coronavirus were identi- Change in Small Intestinal Bacterial Flora in Calves
fied in the feces. The largest increase in E coli bacterial with Diarrhea
numbers occurs in the distal jejunum and ileum,5 whereasthe E coli or coliform bacterial numbers in the colon and There has been a paradigm shift in the last 40 years toward feces are similar or higher for calves with diarrhea than for attributing an episode of calf diarrhea to a specific etiologic calves without diarrhea,5,7 with E coli being more numerous agent, such as rotavirus, coronavirus, cryptosporidia, Sal- in the feces of colostrum-deprived than colostrum-fed monella spp, or enterotoxigenic E coli. Although the etio- calves.5 Small intestinal overgrowth with coliform bacteria logic approach has correctly focused attention on preventive can persist after departure of the initiating enteric patho-gen.7 From the Department of Veterinary Clinical Medicine, University of In calves with naturally acquired diarrhea, increased Illinois at Urbana-Champaign, Urbana, IL small intestinal colonization with E coli has been associated Reprint requests: Dr Peter D. Constable, Department of Veterinary with impaired glucose, xylose, and fat absorption.7 Mixed Clinical Medicine, University of Illinois at Urbana-Champaign, 1008 infections with enteric pathogens are commonly diagnosed West Hazelwood Drive, Urbana, IL 61802; e-mail: p-constable@uiuc. in calves with naturally acquired diarrhea,6,8,9 and the clin- ical signs and pathologic damage associated with rotavirus Submitted February 4, 2003; Revised May 12 and August 4, 2003; infection are more severe when E coli is present than when Copyright ᭧ 2004 by the American College of Veterinary Internal it is absent.8,10–12 Primary viral morphologic damage to the small intestine also facilitates systemic invasion by normal intestinal flora, including E coli.10 Schematic of the distribution and concentration of Escherichia coli bacteria in the intestinal tract of a calf with undifferentiated diarrhea and a similarly aged calf without diarrhea. Adapted from Reisinger.15 The figure indicates that the number of E coli in the large intestine ofdiarrheic and healthy calves is similar but that diarrheic calves have increased E coli numbers in their small intestine, particularly in the distaljejunum and ileum.
In calves with experimentally induced enterotoxigenic E number of calves with severe diarrhea and bacteremia was coli diarrhea, colonization of the small intestine by E coli has been associated with impaired glucose and lactose ab- Lofstedt and her colleagues examined 252 calves Ͻ28 sorption, decreased serum glucose concentration, and pos- days old with diarrhea on Prince Edward Island, Canada.16 sibly increased susceptibility to cryptosporidial infection.13 The feces of diarrheic calves were examined for enteric Calves with diarrhea often have increased coliform bac- pathogens and were positive for coronavirus (39%), entero- terial numbers in the small intestine, regardless of etiology toxigenic E coli (38%), cryptosporidia (33%), and rotavirus (Fig 1),3–8,14 and this colonization is associated with altered (12%). Forty-one percent (103/252) of the calves had fail- small intestinal function, morphologic damage, and in- ure of passive transfer of colostral immunoglobulin, and creased susceptibility to bacteremia. It therefore follows 31% (78/252) of the calves were bacteremic, predominantly that administration of antimicrobial agents that decrease with E coli. Bacteremia was detected in a significantly (P small intestinal coliform bacterial numbers in calves with Ͻ .0001) greater proportion of calves with failure of pas- diarrhea might prevent the development of bacteremia, de- sive transfer (47/103 ϭ 46%) than in calves with adequate crease mortality, and decrease morphologic damage to the passive transfer (21/116 ϭ 18%) and calves Յ5 days old.
small intestine, thereby facilitating digestion and absorption The results of these 2 studies15,16 indicate that veterinar- ians should assume that, on average, 30% of severely illcalves with diarrhea are bacteremic, that the risk of bacter- Incidence of Bacteremia in Calves with Diarrhea
emia is higher in calves with failure of passive transfer thanin calves with adequate passive transfer, and that the risk Calves with diarrhea are more likely to have failure or of bacteremia is higher in calves Յ5 days old. The fre- partial failure of passive transfer, and this group of calves, quency of bacteremia is sufficiently high that treatment of in turn, is more likely to be bacteremic. This is an additional calves with diarrhea that are severely ill (as manifested by reason that antimicrobial agents might be indicated in the reduced suckle reflex, Ͼ6% dehydration, weakness, inabil- treatment of calf diarrhea. Smith reported in 19625 that co- ity to stand, or clinical depression) should include routine lostrum-deprived calves that subsequently developed diar- treatment against bacteremia, with emphasis on treating po- rhea were frequently bacteremic (14/17 ϭ 82%), whereas tential E coli bacteremia. Veterinarians should also assume bacteremia occurred much less frequently in colostrum-fed that 8%15 to 18%16 of diarrheic calves with adequate passive calves that developed diarrhea (0/26 ϭ 0%). Similar results transfer and systemic illness are bacteremic. In the author’s have been observed in 2 recent North American studies.15,16 opinion, the prevalence of bacteremia is sufficiently high in These studies identified bacteremia in calves with a median systemically ill calves that effective antimicrobial treatment age of 8 days15 or a mean age of 9 days16; these results for potential bacteremia should be routinely instituted, re- were at odds with current dogma that calf septicemia and gardless of passive transfer status and treatment cost. With- bacteremia occur most frequently in the 1st few days of holding an effective treatment for a life-threatening condi- tion, such as bacteremia in calves with diarrhea, cannot be Fecteau et al15 examined 169 dairy calves Ͻ20 days old with severe diarrhea or depression on a large Californiacalf-rearing facility; 129 of 169 (76%) of the calves had Safety and Efficacy of Antimicrobials in
failure of passive transfer of colostral immunoglobulin, and Treating Calf Diarrhea
47 of 169 (28%) of the affected calves were bacteremic,predominantly with E coli. Bacteremia was detected in a The appropriate use of antimicrobial agents to treat calf significantly (P ϭ .0010) greater proportion of calves with diarrhea would be facilitated by publication of controlled, failure of passive transfer (44/129 ϭ 34%) than in calves randomized treatment studies in peer-reviewed journals.
with adequate passive transfer (3/40 ϭ 8%); however, the Unfortunately, the majority of the valuable information generated by pharmaceutical companies to support their la- ceptibility testing have traditionally been used to guide bel claim of treating calf diarrhea has not been published treatment decisions; however, susceptibility testing in calf and is therefore unavailable for independent evaluation.
diarrhea probably has clinical relevance only when applied On the basis of the previous discussion, the 2 primary to fecal isolates of enterotoxigenic strains of E coli or path- reasons for administering antimicrobial agents to calves ogenic Salmonella spp and blood culture isolates from with diarrhea are (1) to decrease the number of E coli bac- calves with bacteremia. Validation of susceptibility testing teria in the small intestine and (2) to treat potential E coli as being predictive of treatment outcome for calves with bacteremia. It therefore follows that when antimicrobial agents are administered to calves with diarrhea, the anti- Antimicrobial Susceptibility of Fecal E coli Isolates.
microbial should be safe and effective against E coli in both The ability of fecal bacterial culture and antimicrobial sus- the small intestine and blood, which should be regarded as ceptibility testing by the Kirby Bauer technique to guide treatment in calf diarrhea is questionable when applied tofecal E coli isolates that have not been identified as entero- Antimicrobial Safety
toxigenic, although 2 reports concluded that a ‘‘good cor- A number of antimicrobial agents produce deleterious relation’’ existed between in vitro antimicrobial suscepti- effects on small intestinal function and morphology when bility of fecal E coli isolates and clinical response to anti- administered PO to healthy milk-fed dairy calves. The ad- microbial treatment.24,25 In contrast, 3 other studies reported dition to milk replacer powder of potassium penicillin (11 no correlation between in vitro antimicrobial susceptibility mg/kg of milk replacer) and procaine penicillin (2–60 mg/ of fecal E coli and Salmonella spp isolates and clinical kg of milk replacer) increased the incidence and duration response to antimicrobial treatment,26–28 although these of diarrhea and decreased growth rate compared with un- studies did not differentiate enterotoxigenic and nonenter- treated controls in a total of 36 milk-fed calves.17 Admin- otoxigenic strains of E coli. The only study to statistically istration of neomycin sulfate (300 mg PO q24h for the 1st test the predictive ability of fecal antimicrobial susceptibil- 4 days of life) tended (P ϭ .060) to increase the proportion ity results found that the rectal swab was an inaccurate of calves developing diarrhea (99/233 ϭ 43%) compared method of predicting clinical outcome.28 There do not ap- with the proportion in an untreated control group (58/174 pear to be any data demonstrating that fecal bacterial flora ϭ 33%).18 Administration of neomycin sulfate (25 mg/kg is representative of small intestinal bacterial flora, which is PO q6h, n ϭ 10), chloramphenicol (50 mg/kg PO q12h, n the physiologically important site of infection in calf diar- ϭ 6),a ampicillin trihydrate (12 mg/kg PO q8h, n ϭ 6), or rhea. Finally, and most importantly, the predominant strain tetracycline hydrochloride (11 mg/kg PO q12h, n ϭ 6) for of E coli in the feces of a scouring calf can change several 5 days increased the occurrence of diarrhea and decreased times during the diarrhea episode,5,29 and 9 of 20 (45%) glucose absorption through unknown mechanisms com- calves with diarrhea had different strains of E coli isolated pared with untreated controls (n ϭ 6),19 whereas 2 other from the upper and lower small intestine,5 indicating that studies found that tetracycline hydrochloride (40 mg PO fecal E coli strains are not always representative of small q12h; 11 mg/kg PO q12h) did not induce diarrhea or alter glucose absorption.20,21 In a separate study, administration An additional bias present in most antimicrobial suscep- of chloramphenicol (50 mg/kg PO q12h for 3 days) to tibility studies conducted on fecal E coli isolates is that data healthy neonatal calves decreased jejunal villous length and are frequently obtained from dead calves, which are likely D-xylose absorption and increased breath H excretion, in- to be treatment failures. The time since death is also likely dicating small intestinal malabsorption, which was attribut- to be an important determinant of the value of fecal culture ed to a chloramphenicol-induced decrease in intestinal ep- because ‘‘such a rapid proliferation of bacteria occurs in ithelium mitochondrial protein synthesis.22 Other investi- the alimentary tract after death that the results of exami- gators reported that administration of chloramphenicol (50 nations made on dead calves received at the laboratory can mg/kg PO q12h) induced diarrhea in 7 of 8 calves within have little significance.’’5(p147) Calves that die from diarrhea 5 days, although this study did not contain a control are likely to have received multiple antimicrobial treat- group.23 Finally, administration of chloramphenicol (55 mg/ ments, and preferential growth of antimicrobial-resistant E kg PO q12h for 5 days) did not induce diarrhea in 7 calves, coli strains starts within 3 hours of antimicrobial adminis- but delayed glucose absorption.21 The effects of prolonged tration.30 A 3rd concern with fecal susceptibility testing is oral chloramphenicol administration in calves raises the that the Kirby Bauer break points (minimum inhibitory con- question as to whether other antimicrobial agents adminis- centration [MIC]) are not based on typical antimicrobial tered PO induce diarrhea or alter small intestinal function concentrations in the small intestine and blood of calves.
or morphology; such a deleterious effect is less likely to What is urgently needed are studies documenting the anti- occur after administration of antimicrobial agents with high microbial susceptibility of E coli isolates from the small intestine of untreated calves on the basis of achievable drugconcentrations and dosage regimens. Until these data are Antimicrobial Susceptibility
available, it appears that antimicrobial efficacy is best eval- The most important determinant of antimicrobial efficacy uated by the clinical response of a number of calves to in calf diarrhea is obtaining an effective antimicrobial con- treatment, with calves randomly assigned to treatment centration against bacteria at the sites of infection (small groups, rather than the results of in vitro antimicrobial sus- intestine and blood). The results of fecal antimicrobial sus- ceptibility testing performed on fecal E coli isolates.
Antimicrobial Susceptibility of Blood E coli Isolates.
for 3 days) was 45% (10/22), which was significantly (P The Kirby Bauer technique for the antimicrobial suscepti- ϭ .014) higher than the mortality rate (1/15 ϭ 7%) in an- bility test has more clinical relevance for predicting the other group of calves treated with chloramphenicol (500 mg clinical response to antimicrobial treatment when applied PO q24h for 4 days).34 This study was instrumental in pro- to blood isolates than fecal isolates. This is because the moting the use of oral chloramphenicol to treat calf diar- Kirby Bauer break points (MIC) are based on achievable rhea, particularly diarrhea episodes caused by Salmonella antimicrobial concentrations in human plasma and MIC values for human E coli isolates, which provide a reason- A 1959 study in North Carolina involved 63 dairy calves able approximation to achievable MIC values in calf plasma with diarrhea.35 Twice daily administration of neomycin values for bovine E coli isolates. Unfortunately, sulfate (dose unknown) and nifuraldezoneb (dose unknown) susceptibility results are not available for at least 48 hours, PO for 2 days did not alter mortality rate (neomycin, 6/21 and very few studies have documented the antimicrobial ϭ 28%; nifuraldezone, 3/21 ϭ 14%) when compared with susceptibility of blood isolates in calves with diarrhea. In a nonantimicrobial-treated controls (6/21 ϭ 28%). Among 1997 study of dairy calves in California, the antimicrobial surviving calves, the mean duration of diarrhea tended to susceptibility of isolates from the blood of calves with se- be shorter in those treated with neomycin (6.5 days) or vere diarrhea or illness produced the following results— nifuraldezone (6.2 days) when compared with untreated ceftiofur (19/25 ϭ 76% sensitive), potentiated sulfonamides control calves (9.7 days). Furazolidone (15 mg/kg PO (14/25 ϭ 56% sensitive), gentamicin (12/25 ϭ 48% sen- q24h) also had no effect on mortality when compared with sitive), ampicillin (11/25 ϭ 44% sensitive), and tetracycline untreated control calves in a 1971 study completed in Scot- (3/25 ϭ 12% sensitive)—although there was a clinically land on 24 male Ayrshire calves with diarrhea.36 significant year-to-year difference in the results of suscep- One of the seminal studies was conducted on 165 beef tibility testing that might have reflected different antimicro- calves with diarrhea in Saskatchewan, Canada.37 Ampicillin bial administration protocols on the farm.16 (12 mg/kg PO q12h for 3–5 days) had no effect (P ϭ .83)on mortality rate (26/83 ϭ 31% in ampicillin-treated calves; Success of Antimicrobial Therapy
27/82 ϭ 33% in control calves). Lack of treatment success The 4 critical measures of success of antimicrobial ther- in this 1975 study was later attributed to a delay in insti- apy in calf diarrhea are, in decreasing order of importance, tuting antimicrobial treatment38; antimicrobials were not ad- (1) mortality rate, (2) growth rate in survivors, (3) severity ministered until diarrhea had been present for a number of of diarrhea in survivors, and (4) duration of diarrhea in days. In the same year, a large study was conducted in survivors. Because many of the early studies on antimicro- Europe involving 347 male dairy calves with diarrhea.39 bial treatment in calf diarrhea were uncontrolled, this re- Apramycin significantly decreased the mortality rate in view of antimicrobial therapy success has been restricted to calves treated at 20 mg/kg PO q24h for 5 days (mortality studies with adequate numbers, random allocation to 10/118 ϭ 9%, P Ͻ .001) or 40 mg/kg PO q24h (mortality groups, and inclusion of an appropriate control group.
6/108 ϭ 6%, P Ͻ .001) when compared with untreated Success of antimicrobial therapy can vary with the route controls (mortality 36/121 ϭ 30%). Apramycin administra- of administration and whether the antimicrobial is dissolved tion PO also increased growth rate in survivors. Apramycin in milk, oral electrolyte solutions, or water.31,32 Oral anti- is an aminocyclitol antimicrobial with a predominantly microbials administered as a bolus or contained in a gelatin capsule are deposited into the rumen and therefore have a One hundred fifty-three dairy calves with diarrhea in Ar- different serum concentration-time profile to antimicrobial kansas were administered a potentiated sulfonamide or sul- agents dissolved in milk replacer that are suckled by the famethazine and neomycin.40 Administration of a potenti- calf or administered as an oral drench at the back of the ated sulfonamide (5 mg/kg PO q24h trimethoprim; 25 mg/ pharynx.24,30,31,33 Antimicrobial agents that bypass the rumen kg PO q24h sulfadiazine) for 3–5 days had no effect (P ϭ are not thought to alter rumen microflora, potentially per- .17) on the proportion of calves returning to normal fecal mitting bacterial recolonization of the small intestine from consistency (recovery rate 88/101 ϭ 87%) when compared the rumen.30 Finally, when oral antimicrobial agents are ad- with a combined treatment of 87 mg/kg PO q12h sulfa- ministered to calves with diarrhea, the antimicrobial con- methazine and 11 mg/kg PO q12h neomycin sulfate (re- centration in the small intestinal lumen is lower and the rate covery rate 62/78 ϭ 80%) or with an untreated control of antimicrobial elimination faster than in healthy calves.30 group (recovery rate 23/31 ϭ 74%, P ϭ .097).
Amoxicillin, chlortetracycline, neomycin, oxytetracy- In a 1998 European study, 174 beef and dairy diarrheic cline, streptomycin, sulfachloropyridazine, sulfamethazine, calves Ͻ5 days old were randomly assigned to treatment and tetracycline administered PO are currently labeled in with fluoroquinolone marbofloxacinc (1 mg/kg PO q24h for the United States for the treatment of calf diarrhea. No par- 3 days) or amoxicillin-clavulanic acid (12.5 mg/kg PO enteral antimicrobial agents have a label claim in the United q12h) as a positive control.41 Marbofloxacin treatment pro- duced a significantly (P Ͻ .05) faster return to normal feces Success of Oral Antimicrobials in Treating Naturally
(30% by day 1; 73% by day 3) than did amoxicillin-cla- Acquired Diarrhea. The studies are summarized in chro-
vulanic acid (10% by day 1; 58% by day 3). E coli K99 nological order. A 1954 study in California involved 37 was isolated from the feces in 51% of the calves, and the dairy calves with Salmonella enterica serotype Bredeney superior response to marbofloxacin was similar whether en- diarrhea.34 The mortality rate in calves treated with strep- terotoxigenic E coli was detected or not detected in the tomycin (500 mg IM and PO once, then 750 mg PO q24h Oral administration of chloramphenicol was effective in or oral electrolyte solution and amoxicillin (2.3 Ϯ 1.5 days) treating S enterica serotype Bredeney diarrhea, and apra- than in untreated control calves (4.6 Ϯ 2.3 days).
mycin and marbofloxacin administered PO were effective In a study of forty-three 1-day-old calves with experi- in treating undifferentiated diarrhea. Although chloram- mentally induced enterotoxigenic E coli diarrhea, oral ad- phenicol and marbofloxacin have demonstrated efficacy, ministration of cephamycin C, a broad-spectrum ␤-lactam their listing does not condone, support, or suggest that these antimicrobial that is ␤-lactamase resistant and not absorbed therapies should be used in the United States.
from the intestine, caused a significant (P Ͻ .0001) de- Efficacy of Oral Antimicrobials in Treating Experimen-
crease in mortality (3/22 ϭ 14%) in treated calves com- tally Induced Diarrhea. Diarrhea was experimentally in-
pared with control calves (19/21 ϭ 90% mortality) and duced by intraduodenal inoculation with S enterica serotype greatly decreased fecal E coli bacterial concentrations.47 Dublin in 54 dairy calves aged 1–2 weeks.42 Treatment be- In a related study in thirty-one 1–3-day-old calves with gan when calves had profuse diarrhea and fever and con- experimentally induced enterotoxigenic E coli diarrhea, oral sisted of administration of 30 mg/kg chloramphenicol, 500 administration of L-640,876, a broad-spectrum, potent ␤- mg furazolidone, 75 mg/kg sulphamethylphenasole, or 500 lactam antimicrobial, caused a significant (P Ͻ .01) de- mg neomycin sulfate PO q12h. Compared with an untreated crease in mortality (1/9 ϭ 11%) in treated calves compared control group (16/20 ϭ 80% died), the mortality rate was with control calves (9/11 ϭ 82% mortality) and greatly significantly lower in calves treated with chloramphenicol decreased fecal E coli bacterial concentrations.48 (1/9 ϭ 11% died, P ϭ .0009), furazolidone (2/10 ϭ 20% In a 1998 study, enterotoxigenic E coli diarrhea was ex- died, P ϭ .0041), and sulphamethylphenasole (3/9 ϭ 33% perimentally induced in 30 calves (Ͻ1 day old), and calves died, P ϭ .032). The mortality rate in the untreated control were randomly assigned to treatment with fluoroquinolone group was similar to that obtained in calves treated with enrofloxacin (5 mg/kg PO q24h for 3 days) or no treat- neomycin sulfate (3/6 ϭ 50% died, P ϭ .29).
ment.49 Oral administration of enrofloxacin significantly de- Diarrhea was experimentally induced by oral inoculation creased the mortality rate (7/15 ϭ 47% versus 13/15 ϭ with S enterica serotype Dublin in 35 dairy calves aged 2– 3 weeks.43 Daily administration of trimethoprim, sulfadia- Oral administration of chloramphenicol, furazolidone, zine, or both (in 1 : 5 ratio) was started 24 hours after in- sulphamethylphenasole, broad-spectrum ␤-lactam antimi-crobials (amoxicillin, cephamycin C, L-640,876), and en- oculation, at which time the calves were slightly subdued rofloxacin was effective in treating experimentally induced but otherwise clinically normal,44 and continued for 5 days.
enterotoxigenic E coli or S enterica serotype Dublin diar- Compared with an untreated control group (5/7 ϭ 71% rhea. Although chloramphenicol, furazolidone, and enro- died), the mortality rate tended to be lower in calves treated floxacin have demonstrated efficacy, their listing here does with trimethoprim/sulfadiazine boluses (5 mg/kg trimetho- not condone, support, or suggest that these therapies should prim and 25 mg/kg sulfadiazine; 1/7 ϭ 14% died, P ϭ .10).
Similar mortality rates were observed in control calves and Efficacy of Parenteral Antimicrobials in Treating Nat-
calves treated with a lower dose of trimethoprim/sulfadia- urally Acquired Diarrhea. Chloramphenicol (15 mg/kg IM
zine (2.5 mg/kg trimethoprim and 12.5 mg/kg sulfadiazine; q24h) had no effect on mortality when compared with un- 4/7 ϭ 57% died, P ϭ 1.00), trimethoprim (10 mg/kg; 4/7 treated control calves in a 1971 study in Scotland involving 57% died, P ϭ 1.00), or sulfadiazine (50 mg/kg; 6/7 ϭ 20 male Ayrshire calves with diarrhea.36 Administration of chloramphenicol (20 mg/kg IV q12h) combined with ni- Enterotoxigenic E coli diarrhea was experimentally in- furaldezone (60 mg/kg initially, then 30 mg/kg PO q12h duced in 40 calves 5–10 days old, and treatment was ad- for 3 days) also had no effect (P ϭ .13) on mortality rate ministered immediately after diarrhea was detected.45 The (20/89 ϭ 22% in antimicrobial-treated calves; 27/82 ϭ mortality rate was significantly (P Ͻ .05) lower in calves 33% in control calves) in a study involving 171 diarrheic administered amoxicillin trihydrate in milk replacer (at ϳ10 mg/kg PO q12h for 4 days; 1/20 ϭ 5%) than in untreated In a 1975 study conducted in Europe involving 181 male control calves (6/20 ϭ 30%). The duration of diarrhea was dairy calves with diarrhea,39 injection of apramycin (20 mg/ significantly (P Ͻ .01) shorter in calves administered amox- kg q24h, unstated route, for 5 days) significantly (P ϭ .030) icillin (3.9 Ϯ 0.1 days) than in untreated control calves (5.7 decreased the mortality rate (5/90 ϭ 6%) compared with untreated controls (14/91 ϭ 15%). Apramycin injection Diarrhea was experimentally induced in 82 calves by ad- also increased the growth rate in survivors.39 A study in- ministering an enterotoxigenic strain of E coli, although volving 25 male Holstein calves with diarrhea was con- rotavirus was frequently isolated from calves with diar- ducted in the same year in the United States.50 Ampicillin rhea.46 Treatment was administered immediately after di- trihydrate (400 mg/kg IM q24h) combined with nitrofura- arrhea was detected. The mortality rate tended to be lower zone ([2 oz] 57 g PO q24h) for 5 days improved (P Ͻ .05) in calves administered amoxicillin (as amoxicillin trihy- the general appearance (assessed subjectively by appetite, drate, 10 mg/kg PO q12h for 2 days; 1/21 ϭ 5%), oral coat condition, morbidity) on day 5 and day 12 when com- electrolyte solution (1/20 ϭ 5%), or oral electrolyte solu- pared with nonantimicrobial-treated control calves.
tion and amoxicillin (0/20 ϭ 0%) than in untreated control Twenty diarrheic calves were treated with oral, subcu- calves (4/21 ϭ 19%). The duration of diarrhea was signif- taneous, and intravenous fluids and trimethoprim/sulfon- icantly (P Ͻ .05) shorter in calves administered amoxicillin amide (IM at ‘‘the recommended dose’’ for up to 7 days) (3.1 Ϯ 1.9 days), oral electrolyte solution (3.1 Ϯ 1.1 days), or no treatment (controls) in a 1980 study conducted in Scotland.51 No difference in mortality rate was detected be- suggest that this therapy should be used in the United tween antimicrobial-treated (6/10 ϭ 60%) and control (4/10 Another seminal study was conducted in 1987 at multiple Evidenced-Based Recommendations for
locations in Europe involving 318 diarrheic calves.38 Calves Antimicrobial Administration
were randomly assigned to 1 of 3 treatment groups: sul-bactam-ampicillin (9.9 mg/kg IM q24h; 10/105 ϭ 10% The current recommendation by some veterinarians that mortality), ampicillin (6.6 mg/kg IM q24h; 15/107 ϭ 14% oral or parenteral antimicrobials should not be used for mortality), or untreated control (28/106 ϭ 26% mortality).
treating calf diarrhea is not supported by a critical evi- Treatment was instituted immediately on detection of di- denced-based review of the literature. The arguments used arrhea. This study indicated a lower mortality rate in calves to support a nonantimicrobial treatment approach are that treated with sulbactam-ampicillin (P ϭ .0014) or ampicillin (1) antimicrobials administered PO alter intestinal flora and (P ϭ .024) and provided strong support for the routine function and thereby induce diarrhea, which has been doc- parenteral administration of broad-spectrum ␤-lactam anti- umented on more than 1 occasion with chlorampheni- microbials in the treatment of undifferentiated calf diarrhea.
col,20,22–24 neomycin,19,20 and penicillin18,53; (2) antimicrobi- The study also indicated that administration of sulbactam als harm the ‘‘good’’ bacteria more than the ‘‘bad’’ bacteria (penicillinic acid sulfone), which is a potent irreversible in the small intestine (an undocumented claim in the calf); inhibitor of ␤-lactamase, increased the treatment efficacy of (3) antimicrobials are not effective (a statement that is clearly not supported by the results of some published peer- Parenteral administration of apramycin or the ␤-lactam reviewed studies); and (4) antimicrobial administration pro- antimicrobial ampicillin was effective in treating naturally motes the selection of antimicrobial resistance in enteric acquired diarrhea, and treatment efficacy of ampicillin was increased with ␤-lactamase inhibition.
Oxytetracycline and sulfachloropyridiazine administered Efficacy of Parenteral Antimicrobials in Treating Ex-
parenterally and amoxicillin, chlortetracycline, neomycin, perimentally Induced Diarrhea. A study was conducted in
oxytetracycline, streptomycin, sulfachloropyridazine, sul- 38 male dairy calves aged 1–2 weeks with experimentally famethazine, and tetracycline administered PO are currently induced enterotoxigenic E coli diarrhea.52 After diarrhea in- labeled in the United States for the treatment of calf diar- duction, calves were randomized into 3 treatment groups rhea. Of the 8 antimicrobials administered PO, only amox- consisting of danofloxacin,c a fluoroquinolone antimicrobial icillin has been shown to be efficacious in studies that were (1.25 mg/kg IM q24h for 3 days), a positive control ba- conducted with appropriate control groups and published in quiloprim/sulphadimidine (10 mg/kg IM q24h for 3 days), peer-reviewed journals. In general, the 2 parenteral and 8 or untreated controls. Although most calves developed only oral antimicrobials have been labeled by the U.S. Food and mild diarrhea and did not become severely ill (all calves Drug Administration for the treatment and aid in the control survived), danofloxacin decreased the time taken to recover of bacterial enteritis (scours, colibacillosis) caused by E coli to a normal demeanor and prevented development of mild bacteria susceptible to the antimicrobial. Unfortunately, metabolic acidosis. Compared with potentiated sulfon- data supporting the efficacy of parenteral oxytetracycline amide–treated calves, danofloxacin increased weight gain.
and sulfachloropyridiazine and of oral amoxicillin, chlor- Diarrhea was experimentally induced by oral inoculation tetracycline, neomycin, oxytetracycline, streptomycin, sul- with S enterica serotype Dublin in 58 dairy calves aged 2– fachloropyridazine, sulfamethazine, and tetracycline in 3 weeks.43 Daily administration of trimethoprim/sulfadia- treating calves with naturally acquired diarrhea do not ap- zine (in a 1 : 5 ratio) was started 24 hours after inoculation, pear to have been published in peer-reviewed journals, and at which time the calves were slightly subdued but other- the Freedom of Information summary (www.fda.gov/cvm/ wise clinically normal,44 and continued for 5 days. Com- efoi) does not supply sufficient information for an indepen- pared with untreated controls (19/22 ϭ 86% died), the mor- dent conclusion of efficacy to be made. Chlortetracycline, tality rate was significantly lower in calves treated with tri- neomycin, oxytetracycline, and tetracycline were originally methoprim/sulfadiazine (20 mg/kg sulfadiazine and 4 mg/ approved as safe for use in the 1950s. Subsequently, the kg trimethoprim IV; 2/14 ϭ 14% died, P Ͻ .0001), National Academy of Sciences/National Research Council trimethoprim/sulfadiazine (20 mg/kg sulfadiazine and 4 mg/ reviewed the available data from 1969 to 1971 and con- kg trimethoprim IM; 1/14 ϭ 7% died, P Ͻ .0001), or a cluded that chlortetracycline, neomycin, oxytetracycline, lower dose of trimethoprim/sulfadiazine (10 mg/kg sulfa- and tetracycline were probably effective for oral treatment diazine and 2 mg/kg trimethoprim IV; 1/7 ϭ 14% died, P of animal diseases when such diseases were caused by path- ϭ .0011). Administration of either sulfadiazine or trimeth- ogenic microorganisms sensitive to the drug (www.fda.gov/ oprim alone was associated with high mortality rates, dem- onstrating marked synergism of trimethoprim and sulfadi- Oral amoxicillin has documented efficacy in the treat- ment of experimentally induced diarrhea,45,46 but amoxicil- Early IV or IM administration of trimethoprim/sulfadia- lin administered PO was not efficacious in the treatment of zine was effective in treating experimentally induced S en- naturally acquired diarrhea in beef calves.37 Extra-label an- terica serotype Dublin diarrhea, and danofloxacin was ef- timicrobial use (excluding prohibited antimicrobials) is fective in treating experimentally induced mild enterotoxi- therefore justified in treating calf diarrhea because of the genic E coli diarrhea. Although danofloxacin has demon- apparent lack of published studies documenting clinical ef- strated efficacy, its listing does not condone, support, or ficacy of antimicrobials with a label claim and because the health of the animal is threatened and suffering or death hydrate for oral administration in calves because it is la- might result from failure to treat systemically ill calves.
beled for the treatment of calf diarrhea in the United States Because the 2 sites of infection in calf diarrhea are the and is absorbed to a much greater extent.32,55,57 However, a small intestine and blood, administered antimicrobials field study comparing amoxicillin (400 mg PO q12h) and should have both local (small intestinal) and systemic ef- ampicillin (400 mg PO q12h) treatments for diarrhea re- fects. In addition, the antimicrobial must reach therapeutic ported similar proportions of calves with a good to excel- concentrations at the site of infection for a long enough lent clinical response (49/62 ϭ 79% for amoxicillin bolus, period and, ideally, have only a narrow gram-negative spec- 59/74 ϭ 80% for amoxicillin powder, 47/65 ϭ 65% for trum of activity to minimize collateral damage to other en- ampicillin bolus, P Ͼ .30 for all comparisons).58 The ad- teric bacteria.15 In general, oral and parenteral administra- dition of clavulanate potassium to amoxicillin trihydrate is tion of broad-spectrum ␤-lactam and fluoroquinolone anti- recommended because clavulanate potassium is a potent ir- microbials have proven efficacy in treating naturally ac- reversible inhibitor of ␤-lactamase, increasing the antimi- quired and experimentally induced diarrhea; parenteral administration of trimethoprim/sulfadiazine has proven ef- Oral administration of potentiated sulfonamides is not ficacy in treating experimentally induced S enterica sero- recommended for treating calf diarrhea because of the lack type Dublin (although efficacy has only been demonstrated of efficacy studies. No other antimicrobial administered PO when antimicrobial administration starts before diarrhea is currently available in the United States is likely to be ef- present); and oral administration of the predominantly fective in treating calves with diarrhea, even though gen- gram-negative antimicrobial apramycin has proven efficacy tamicin (50 mg/calf PO q12h) markedly decreased E coli in treating naturally acquired diarrhea. Because use of fluo- bacterial concentrations in the feces of healthy calves.59 De- roquinolone antimicrobials in an extra-label manner is il- spite 1 study that reported gentamicin (40–80 mg q12h for legal in the United States and apramycin is an aminocyclitol 3 days, route not stated but presumed to be oral) improved antimicrobial that is poorly absorbed after oral administra- stool consistency in calves with experimentally induced E tion (oral bioavailability Ͻ15%) and has relatively high coli diarrhea,60 administration of gentamicin PO is not rec- MIC values against Salmonella spp and E coli (MIC ommended because antimicrobial agents administered to ␮g/mL) in the calf,54 treatment recommendations will focus calves with diarrhea should have both local and systemic on the use of broad-spectrum ␤-lactam antimicrobials such effects and gentamicin administered PO is poorly absorbed.
as amoxicillin, ampicillin, ceftiofur, and potentiated sulfon- An additional problem with gentamicin is the prolonged withdrawal time for slaughter, even after oral administra-tion.
Administration of Oral Antimicrobials to Treat E coli
Fluoroquinolones clearly have proven efficacy in treating Overgrowth of the Small Intestine
calf diarrhea, and a label indication exists in Europe fororal and parenteral enrofloxacin and oral marbofloxacin for In enteric infections, it is desirable that high intestinal the treatment of calf diarrhea. In those countries where their luminal antimicrobial concentrations are maintained with administration is permitted to treat calf diarrhea, oral fluo- some degree of drug penetration through the intestinal roquinolones are recommended because of their high oral wall.55 Accordingly, in preruminant calves with diarrhea bioavailability. However, it must be emphasized that extra- and mild systemic illness (defined as depressed suckling but label use of the fluoroquinolone class of antimicrobials in normal rectal temperature, hydration status, and heart rate), food-producing animals in the United States is illegal and the veterinarian should continue to monitor the calf’s health or administer amoxicillin trihydrate (10 mg/kg PO q12h) or In calves with diarrhea and no systemic illness (normal amoxicillin trihydrate-clavulanate potassium (12.5 mg com- appetite for milk or milk replacer, no fever), the author bined drug/kg PO q12h) for at least 3 days; the latter con- recommends that the clinician monitor the health of the calf stitutes extra-label drug use. Amoxicillin trihydrate (10 mg/ and not administer oral antimicrobials.
kg PO q12h in milk replacer) was efficacious in decreasingmortality rate and duration of diarrhea in 2 studies in which Administration of Parenteral Antimicrobials to Treat
diarrhea was experimentally induced with enterotoxigenic E coli Bacteremia
E coli bacteria.45,46 Amoxicillin trihydrate is 30% absorbedfrom the calf small intestine, with absorption being similar In calves with diarrhea and moderate to severe systemic in milk-fed and fasted calves.55 After administration of illness, the positive predictive value (.65) of clinical tests amoxicillin trihydrate (7 mg/kg PO in milk replacer), high (sensitivity [Se] ϭ .39, specificity [Sp] ϭ .91) and the pos- antimicrobial concentrations are present in the bile and in- itive predictive value (.77) of clinicopathologic tests (Se ϭ testinal contents, with lower antimicrobial concentrations in .40, Sp ϭ .95) for detecting bacteremia are too low assum- serum,45 although serum amoxicillin concentration exceed- ing reasonable estimates for the prevalence of bacteremia ed 0.5 ␮g/mL for the duration of treatment.55 Concurrent (30%).17 Accordingly, it is recommended that clinicians feeding of milk and amoxicillin does not change the bio- routinely assume 30% of ill calves with diarrhea are bac- availability of amoxicillin, although it is absorbed faster teremic and that bacteremia constitutes a threat to the life when dissolved in an oral electrolyte solution than in milk of the calf. Parenteral antimicrobial treatment is required replacer32 and absorption is slowed during endotoxemia, presumably because of a decrease in the abomasal emptying The most logical parenteral treatment is ceftiofur (2.2 rate.56 Amoxicillin trihydrate is preferred to ampicillin tri- mg/kg IM/SC q12h) for at least 3 days. Ceftiofur is the most appropriate antimicrobial because it is a broad-spec- In the past, gentamicin has been ‘‘considered an appro- trum ␤-lactam antimicrobial that is resistant to the action priate alternative drug for use in calf diarrheas and pneu- of ␤-lactamase; the MIC for E coli is Ͻ0.25 ␮g/mL61; the monias when other antimicrobial agents are unsatisfacto- recommended dosage schedule maintains free plasma ␤- ry.’’66(p2461) Parenteral administration of gentamicin and oth- lactam antimicrobial concentrations at the desired 4 times er aminoglycosides (amikacin, kanamycin) cannot currently value for the duration of treatment in 7- be recommended as part of the treatment for calf diarrhea day-old calves; and 30% of the active metabolite of cef- because of the lack of published efficacy studies; prolonged tiofur (desfuroylceftiofur) is excreted into the intestinal tract slaughter withdrawal times (15–18 months); potential for of cattle,62 providing antimicrobial activity in both blood nephrotoxicity in dehydrated animals; and availability of and small intestine. Moreover, ceftiofur hydrochloride (2 ceftiofur, amoxicillin, and ampicillin.
mg/kg IM once and 0.5 mg/kg PO once) decreased the A label indication exists in Europe for parenteral enro- mortality rate and the severity of diarrhea in pigs with ex- floxacin in the treatment of calf diarrhea. In those countries perimentally induced enteric colibacillosis, although these where administration is permitted to treat calves with di- pigs were not suspected to be bacteremic.63 The beneficial arrhea, parenteral fluoroquinolones are recommended be- effects of parenteral ceftiofur in these pigs was attributed cause of their broad-spectrum bactericidal activity, partic- to decreasing intestinal luminal concentration of pathogenic ularly against gram-negative bacteria. However, it must be E coli.63 Ceftiofur sodium (Ͻ5 mg/kg PO q24h) was also emphasized that extra-label use of the fluoroquinolone class effective in treating mice with experimentally induced en- of antimicrobials in food-producing animals in the United teric colibacillosis.61 Administration of ceftiofur to treat States is illegal and obviously not recommended.
bacteremia and diarrhea in calves constitutes extra-label Chloramphenicol had proven efficacy in treating calf di- drug use, and ceftiofur should not be administered to calves arrhea due to S enterica serotype Bredeney and Dublin,34,42 although its use is now illegal in the United States. The Another recommended treatment is parenteral amoxicil- related antimicrobial florfenicol achieves high concentra- lin trihydrate or ampicillin trihydrate (10 mg/kg IM q12h) tions in the small intestinal lumen and is 89% absorbed for at least 3 days. Although parenteral ampicillin has prov- when administered PO to milk-fed calves67; however, flor- en efficacy in treating naturally acquired diarrhea,38 whereas fenicol is not the most appropriate antimicrobial for treating ceftiofur has unproven efficacy, the broad-spectrum ␤-lac- tam antimicrobials amoxicillin and ampicillin are theoreti- 25 ␮g/mL,68 and florfenicol (11 mg/kg PO or 20 mg/kg cally inferior to ceftiofur because parenterally administered ampicillin and amoxicillin reach lower plasma concentra- florfenicol (11–20 mg/kg IV) only exceeded the MIC val- tions, require a higher MIC than ceftiofur, and are not ␤- lactamase resistant.61 Amoxicillin or ampicillin should be In calves with diarrhea and no systemic illness (normal injected into the neck musculature because this site pro- appetite for milk or milk replacer, no fever), the author vides the greatest absorption62 and minimizes damage to recommends that the clinician monitor the health of the calf more valuable areas of the carcass. Amoxicillin and ampi- and not administer parenteral antimicrobials.
cillin should not be administered subcutaneously becausethe rate and extent of absorption is reduced relative to in-tramuscular injection.64 Footnotes
A 3rd recommended treatment is parenteral potentiated sulfonamides (20 mg/kg sulfadiazine with 5 mg/kg trimeth- a The use of chloramphenicol in food-producing animals in the United oprim IV or IM, depending on the formulation character- States is prohibited by law because of the occurrence of non–dose- istics, q24h for 5 days). Efficacy of potentiated sulfon- related aplastic anemia in 1 in 10,000–50,000 exposed humans.
amides has only been proven when treatment began before b The administration of nifuraldezone and furazolidone in food-pro- clinical signs of diarrhea were present.43,44 It is therefore ducing animals in the United States is prohibited by law because of unknown whether potentiated sulfonamides are efficacious concerns regarding nitrofuran-induced mutagenicity and carcinoge-nicity.
when administered to calves with diarrhea and depression, c Extra-label administration of fluoroquinolones in food-producing an- although it is likely that potentiated sulfonamides are effi- imals in the United States is prohibited by law because of concerns cacious in the treatment of salmonellosis.
regarding facilitating the emergence of bacteria with multiple anti- Oral administration of potentiated sulfonamides and microbial resistance, particularly pathogenic enteric bacteria in hu- apramycin is not recommended for the treatment of bacter- emia because of poor oral bioavailability. Oxytetracyclineor chlortetracycline also are not recommended for the treat-ment of bacteremia, although tetracyclines might have some References
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