Med Pediatr Oncol 2003;40:62–63

BRIEF REPORTResistance to a Beta-Lactam Antibiotic Appearing During

Therapy for Enterobacter Cloacae Sepsis in a Child

Miguel Munoz, MD, PhD,1 Catalina Marquez, MD, PhD,2 Macarena Taguas-Casano, MD, PhD,1

Juan A. Soult, MD, PhD,1* Jose D. Lopez-Castilla, MD, PhD,1 andAna M. Alvarez-Silvan, MD, PhD

2

Severe infections cause considerable morbidity andmortality in children receiving cancer chemotherapy.Gram-negative bacterial infections are a leading cause ofdeath in febrile neutropenic patients. Efforts to reducethis mortality by early empiric treatment has led to theuse of broad-spectrum antibiotic regimens, resulting inincreasing exposure to antibiotics. Gram-negative bac-teria have developed resistance to multiple antibioticagents after being classified as sensitive to broad-spectrum cephalosporins. The list includes Pseudomonasaeruginosa, Enterobacter cloacae, Serratia marcescens,and Citrobacter freundii [2]. Enterobacter sp is anaerobic Gram-negative bacillus, producer of induciblechromosomal beta-lactamases. Emergence of Enterobac-teri resistant to beta-lactam antibiotics is related to third-generation cephalosporin or aztreonam exposure [1].These drugs may select derepressed mutants of E.aerogenes, and E. cloacae resistant to all beta-lactams(including inhibitors of beta-lactamases), except carba-penems [2,3].The appearance of resistance to all beta-lactam antibiotics during therapy for Enterobactercloacae sepsis in children is infrequent and thereforelittle appreciated.

Our experience with this problem in a 9-year-old girlwith osteosarcoma is instructive. She had been treatedwith ifosfamide and etoposide 5 days before beingadmitted with fever and a chill. The hematologic studiesshowed: normal white blood (WBC), platelet and hema-tocrit levels. Blood culture was ordered and we startedceftazidime monotherapy. After 48 hr, she was trans-ferred to the pediatric intensive care unit (PICU) becauseof high fever (40.58C) and hypotension (70/30 mmHg)with no response to volume replacement. These and herclinical findings were consist with septic shock. Thehematologic studies then revealed the following values:WBC 32.600 (99% neutrophils), 25.000 plateles/mm3,and hemoglobin 8.1 g/dl. The patient also had both aprolonged PT and PTT, that required transfusion therapy

(fresh frozen plasma, platelets and red blood cells) andcatecholamines. A second blood culture was ordered andtreatment was changed to intravenously administeredmeropenem and vancomycin. Some hours later, the firstblood culture positive for E. cloacae sensitive toceftacidime and carbapenems were received. Two dayslater, the second blood culture revealed an Enterobactercloacae, which was resistant to ceftazidime and otherbeta-lactam antibiotics but still sensitive to carbapenemsand aminoglycosides (Table I). Fever disappeared after 3days, and the patient gradually improved. We dischargedher from PICU 5 days later.

DISCUSSION

Cancer patients receiving chemotherapy may developgram-negative sepsis even when not neutropenic orobviously inmunosupressed. Hematologic studies donot always correlate with the severity of the infection inthese patients. Enterobacter cloacae and other aerobicGram-negative bacilli may produce inducible chromoso-mal beta-lactamases. Treatment with third-generationcephalosporins or aztreonam may select derepressedmutants of E. aerogenes, and E. cloacae resistant to allbeta-lactams except for carbapenems. Emergent resistantstrains that appear during antibiotic treatment mayhave cross-resistance to other betalactams as our caseshows. In our patient the Enterobacter initially isolated

Key words: childhood cancer; sepsis; antibiotic resistance; E. cloacae; ceftazidime;betalactams; carbapenem

——————1Unidad de Cuidados Intensivos Pediatricos, Hospital InfantilUniversitario Virgen del Rocio, Sevilla, Spain

2Unidad de Oncologıa Pediatrica, Hospital Infantil UniversitarioVirgen del Rocio, Sevilla, Spain

*Correspondence to: Juan A. Soult, Hospital Infantil UniversitarioVirgen del Rocıo, Unidad de Cuidados Intensivos Pediatricos,C/Manuel Siurot s/n, 41013-Sevilla, Spain.E-mail: jasoult@terra.es

Received 15 August 2001; Accepted 7 November 2001

� 2003 Wiley-Liss, Inc.DOI 10.1002/mpo.10070

was responsive to ceftazidime and other b-lactamantibiotics. Later on, all b-lactam antibiotic minimalinhibitory concentrations (MIC) except for carbapenemsand aminoglycosides increased considerably (Table I).The rise of resistant species may be secondary to abetalactamase induction in the original bacterial cloneor a selection of a resistant plasmid strain producer.Resistance can be transfered in vivo by cell-to-cellconjugation of genetic transposons [2–5]. Emergence ofresistance from previously susceptible strains appeared tobe more important than horizontal transmission inacquisition of ceftazidime AZ-RGN in a nonoutbreakperiod [6]. Emergence of resistance is related to the MICof the antibiotic and the concentration of antibiotic usedto select for resistance; it is independent of the efficacyof the beta-lactam inducer. Resistant mutants arisethrough both beta-lactamase-dependent and -independentmechanisms [7,8].

The recommendation to use ceftazidime as the initialmonotherapy for neutropenic fever in cancer patients thatappears in Paediatric Practice Guidelines does not totallyavoid the risk of a severe infection [9]. In our patient, theuse of monotherapy was associated with the emergenceof mutant-selected strains and the development ofsevere sepsis, septic shock, and DIC. Monotherapy withceftazidime can’t compare with imipenem because gram-negative bacilli usually produce beta-lactamases but nocarbapenemases. In our case, we saw no change in MICfor carbapenemases, but cefepime behaved as a classicbetalactam antibiotic.

In our opinion, these practice guidelines should bereviewed because of the possible emergence of antibioticresistance during therapy. Combination therapy is the rulein antibiotic treatment of adults, and the addition of anaminoglycoside seems to decrease mortality in them [2].

The use of combination therapy does not avoid theappearence of antibiotic resistance, but it could improvethe survival in these patients [1].

In the past, we used ceftazidime empirically in febrileneutropenic childhood cancer patients as a single agentfor gram-negative coverage. However, bacteremia withresistant Enterobacter species has emerged and appearsto be related to the repeated use of this agent. We sug-gest the use of combination therapy with a beta-lactamagent and an aminoglycoside or a carbapenem as mono-therapy in the empiric treatment of patients with sepsisor neutropenic fever. In our unit, we now use com-bination therapy with a beta-lactam antibiotic and anaminoglycoside [1,2] or carbapenem monotherapy [10]if there is a severe infection, a positive blood culture fora gram-negative bacillus, or any Enterobacter species isisolated.

REFERENCES

1. Chow JW, Fine MJ, Shlaes DM, et al. Enterobacter bacteriemia:clinical features and emergence of antibiotic resistance duringtherapy. Ann Inter Med 1991;115:585–589.

2. Johnson MP, Ramphal R. Beta-lactam resistant Enterobacterbacteriemia in febrile neutropenic patients receiving monother-apy. J Infect Dis 1990;162:981–983.

3. Naumovski L, Quinn JP, Miyashiro D, et al. Outbreak of ceftazi-dime resistance due to a novel extended-spectrum beta-lactamasein isolates from cancer patients. Antimicrob Agents Chemother1992;36:1991–1996.

4. Quinn JP, DiVincenzo CA, Foster J. Emergence of resistance toceftazidime during therapy for Enterobacter cloacae infections.J Infect Dis 1987;155:942–947.

5. Rice LB, Willey SH, Papanicolau GA, et al. Outbreak ofceftazidime resistance caused by extended-spectrum beta-lacta-mases at aMassachusetts chronic-care facility. Antimicrob AgentsChemother 1990;34:2193–2199.

6. D’Agata E, Venkataraman L, DeGirolami P, Samore M. Mole-cular epidemiology of acquisition of ceftazidime-resistant gram-negative bacilli in a nonoutbreak setting. J Clin Microbiol 1997;35:2602–2605.

7. Aronoff SC, Shlaes DM. Factors that influence the evolution ofbeta-lactam resistance in beta-lactamase-inducible strains ofEnterobacter cloacae and Pseudomonas aeruginosa. J Infect Dis1987;155:936–941.

8. Higashitani F, Nishida K, Hyodo A, et al. Effects of tazobactamon the frequency of the emergence of resistant strains fromEnterobacter cloacae, Citrobacter freundii, and Proteus vulgaris(beta-lactamase derepressed mutants). J Antibiot (Tokyo) 1995;48:1027–1033.

9. Hughes WT, Armstrong D, Bodey GP, et al. guidelines for the useof antimicrobial agents in neutropenic patients with unexplainedfever. Clin Infect Dis 1997;25:551–573.

10. Paterson DL. Recomendations for treatment of severe infectionscaused by Enterobacteriaceae producing extended-spectrumbeta-lactamases (ESBLs). Clin Microbiol Infect 2000;6:460–463.

TABLE I. Minimal Inhibitory Concentration (MIC) Obtainedfor Enterobacter cloacae Strain Isolated From Two Different BloodCultures

Antibiotics

MIC (mg/ml)

1st Culture 2nd Culture

Ceftazidime � 8 (S) > 16 (R)Cefepime � 8 (S) 16 (I)Aztreonam � 8 (S) 16 (I)Piperacillin-Tazobactam � 16/4 (S) > 128/4 (R)Ampicillin-Sulbactam 16/4 (I) > 32/16 (R)Meropenem � 4 (S) � 4 (S)Imipenem � 4 (S) � 4 (S)Tobramycin � 4 (S) � 4 (S)Amikacin � 16 (S) � 16 (S)

Beta-Lactam Resistance 63