'Break-point Checkerboard Plate' for screening of appropriate antibiotic combinations against multidrug-resistant Pseudomonas aeruginosa

Increase of multiple drug resistant Pseudomonas aeruginosa (MDRP) is becoming a serious problem in the clinical setting. Although the checkerboard method to determine FIC index and synergistic effects of antibiotic combinations is useful, it is not well adapted to a routine test, mainly because of its time-consuming and labor-intensive nature. Here we report 'Break-point Checkerboard Plate', in which breakpoint concentrations, such as 'S' (sensitive) and 'I' (intermediate), were combined in a microtiter plate with 8 antibiotics, including carbapenem, aminoglycoside and fluoroquinolone. The results obtained from 12 strains of MDRP demonstrated a strong synergistic effect of some antibiotic combinations at clinically relevant concentrations. Our data suggest a usefulness of 'Break-point Checkerboard Plate' to screen appropriate antibiotic combinations against drug resistant organisms, including MDRP.     

Study of the cases with multidrug-resistant Pseudomonas aeruginosa by sputum culture]

We evaluated the clinical features of multidrug-resistant Pseudomonas aeruginosa cases determined by sputum culture between April, 2005 and December, 2006. The clinical features of most cases were: (1) pneumonia in the elderly with cerebrovascular diseases, (2) previous administration of carbapenems and antipseudomonal cephems, (3) PIPC, CAZ and ISP sensitve MDRP, (4) MRSA was isolated concurrently, (5) not necessary of therapy against MDRP, (6) good outcome.     

Significance of fluoroquinolone-resistant Escherichia coli in urinary tract infections

Antibiotic-resistant urinary tract infections (UTIs) are on the rise. We investigated the recent emergence of representative resistant strains in patients diagnosed with UTIs at Kobe University Hospital between 2000 and 2006, focusing on resistant strains isolated from the urine of UTI patients, especially fluoroquinolone-resistant Escherichia coli (FQRE), multidrug-resistant Pseudomonas aeruginosa (MDRP), and methicillin-resistant Staphylococcus aureus (MRSA). We found 16 MDRP, 108 FQRE, and 251 MRSA UTI cases, reflecting a significant increase in the incidence of FQRE. Our data demonstrated that isolated ratios of FQRE rose as much as 26.3% in 2006 and that there were significantly more isolated cases in 2003 - 2006 than in 2000 - 2002. The data show a significant trend toward FQRE emergence. This trend should be considered when treating UTI.     

多药耐药铜绿假单胞菌院内感染危险因素及预后因素分析

目的 分析多药耐药铜绿假单胞菌(MDRP)产生的危险因素，并探讨影响MDRP院内感染预后的因素。方法 采用病例对照研究方法。收集北京协和医院1999年1月～2002年12月MDRP引起的院内感染44例，并随机选择同时期敏感铜绿假单胞菌院内感染68例作为对照，采用单因素(t检验，χ^2检验)及多因素Logistic回归进行分析。结果 对112例铜绿假单胞菌院内感染单因素分析发现，下列因素与MDRP感染有关：高龄、高APACHE Ⅱ(acute physiology and chronic health evaluation)评分、2种以上细菌混合感染、院内获得性肺炎(HAP)、机械通气、患有慢性阻塞性肺疾病(COPD)、分离出MCIRP前15天用过氟喹喏酮、分离出MDRP前15天用过亚胺培南／美罗培南。但多因素Logistic回归分析仅确定了2项独立危险因素：机械通气[比值比(OR)=8．19]，分离出MDRP前15天用过亚胺培南／美罗培南(OR，44．80)。44例MDRP院内感染，死亡24例，好转20例，病死率为55％。单因素分析发现，下列因素与MDRP感染死亡相关：高APACHEⅡ评分、机械通气、未恢复对抗铜绿假单胞菌抗生素的敏感性。多因素Logistic回归分析发现了1项独立危险因素：未恢复对抗铜绿假单胞菌抗生素的敏感性(OR=10．70)。结论 机械通气，以及亚胺培南／美罗培南的使用是MDRP感染的危险因素。MDRP未恢复对抗铜绿假单胞菌抗生素的敏感性是MDRP感染预后差的危险因素。     

Bacterial interaction and indirect pathogenesis of Pseudomonas aeruginosa at the growth of MRSA

Bacterial interactions such as methicillin-resistant Staphylococcus aureus (MRSA) growth inhibition or inactivation of anti-MRSA antibiotics by Pseudomonas aeruginosa as an indirect pathogen were tested by in vitro assay. Paired strains, P. aeruginosa and MRSA, used in this experiment were isolated from 63 respiratory samples at Juntendo University Hospital from 2002 to 2003. Growth inhibitory activities against MRSA by P. aeruginosa were tested with reversed agar plate method. Inactivation of anti-MRSA antibiotics by P. aeruginosa were assayed with disk diffusion method using agar over lay technique. Fifty-six (88.9%) out of 63 samples showed the significant MRSA growth inhibitory activity by co-existed P. aeruginosa. Anti-MRSA antibiotics such as trimetoprim-sulfamethoxazole combination (ST), arbekacin (ABK) and minocycline (MINO) except Vancomycin (VCM) and Teicoplanin (TEIC) were inactivated by the co-existed P. aeruginosa. Our data suggests that P. aeruginosa may play not only as a chronic respiratory pathogen but also as an indirect pathogen. Further, the most P. aeruginosa with anti-MRSA activity isolated respiratory sample may play as a modulator of MRSA infection.     

老年病房分离铜绿假单胞菌的耐药性分析

目的分析老年病房分离铜绿假单胞菌对临床常用抗菌药的耐药特征，为临床用药提供参考。方法收集我院老年病房2004年1月至2005年12月的住院患者分离菌株，药敏试验采用K-β扩散法。结果共分离出230株铜绿假单胞菌，其中224株来自痰标本。哌拉西林／他唑巴坦的敏感率最高，为64．8％，其他依次为阿米卡星、环丙沙星、头孢哌酮-舒巴坦；头孢他啶的耐药率最高，为50．9％，其他依次为哌拉西林、头孢吡肟、亚胺培南等。其对头孢他啶、头孢吡肟、亚胺培南的耐药率皆显著高于同期非老年病房分离株（P〈0．01）；多重耐药铜绿假单胞菌（MDRP）105株，占分离菌株的45．6％；71．5％的患者在标本分离的前2月里，接受过多种抗菌药物治疗。结论密切结合药敏试验，合理有序的应用抗生素、减轻抗生素的选择性压力，对于防治铜绿假单胞菌的耐药及传播，控制老年病房的院内感染具有重要意义。     

Factor analysis of outcomes during drug-resistant bacterial infection treatment

Factors related to poor outcome in drug-resistant bacterial infection treatment were analyzed based on surveys at 54 National Hospital Organization facilities. Results showed common etiological causes of Methicillin-resistant Staphylococcus aureus (MRSA) and Penicillin-resistant Streptococcus pneumoniae (PRSP). Specifically, the odds ratio in the elderly, aged 75 years and older, was 1.473 (p=0.006) for MRSA and 6.401 (p=0.0001) for PRSP. Among those undergoing tracheal intubation, the odds ratio was 1.767 (p=0.021) for MRSA and 4.185 (p=0.0001) for PRSP, showing that advanced age and tracheal intubation tended to aggravate disease. MRSA-specific causes were pneumonia with an odds ratio of 2.426 (p=0.0001) and sepsis with one of 1.417 (p=0.013). Causes specific to Multi-drug resistant Pseudomonas aeruginosa (MDRP) were Intravenous hyperalimentation (IVH) with an odds ratio of 2.078 (p=0.0001) and urinary-tract infection with one of 0.566 (p=0.027). The individual roles of these factors in poor outcomes must thus be clarified to develop preventive measures against them.     

铜绿假单胞菌近7年的耐药性变迁及其抗生素应用分析

目的分析铜绿假单胞菌近7年的耐药性变迁情况。方法收集2001年1月至2007年6月我院分离的铜绿假单胞菌1076株,分析其耐药性变迁及临床抗生素的应用情况;结果对铜绿假单胞菌保持抗菌活性较强而耐药率30%的抗菌药物依次为美罗培南、亚胺培南及阿米卡星,对常用抗菌药物的耐药率有普遍增高的趋势;抗铜绿假单胞菌所用抗生素单用455例(44.4%);二联521例(50.9%);三联48例(4.7%)。结论铜绿假单胞菌耐药率高,耐药率有普遍增高的趋势;对严重铜绿假单胞菌感染、多药耐药(MDRP)或泛耐药(PDRP)的治疗,宜采用联合用药,β-内酰胺类+阿米卡星为较优化的组合治疗方案之一。     

In vitro indirect pathogenesis of Pseudomonas aeruginosa against anti MRSA chemotherapy

In the patient with a chronic respiratory disease, both Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) are frequently detected from expectoration. Vancomycin (VCM) and arbekacin (ABK) are both recommended for the chemotherapy of MRSA infection in Japan. Minocycline (MINO) is also selected for the treatment of MRSA infection. While rifampicin (RFP) and a trimetoprim-sulfamethoxazole combination (ST) are also recommended in Europe and USA but not recommended in Japan for the chemotherapy of MRSA infection. It is pointed out that coexistence bacteria affect chemotherapy as an indirect pathogen. Not only an antibacterial action but the immunological action or the metabolic effect against chronic P. aeruginosa infection such as DPB is known by the administration of 14-membered ring macrolides including erythromycin (EM). We considered the influence of P. aeruginosa isolated with MRSA on the activity against anti-MRSA agents by the disk diffusion method with bilayer flat agar in vitro. Moreover, we also examined the influence of EM against the activity of the anti-MRSA agents when P. aeruginosa was coexistence. One strain of MRSA as an indicator strain and 100 strains of P. aeruginosa as test strains, which were obtained from clinical materials, were used for the following experiment. P. aeruginosa was streaked on to the Mueller-Hinton agar culture medium (MHA), and they incubated at 35 degrees C for 24 hours. Then, the blood agar plate was piled up, MRSA was streaked on the blood agar surface, the susceptibility test disks (VCM, ABK, MINO, RFP, ST) were put on it, and incubated at 35 degrees C for a further 24 hours. The diameter of the zone of inhibition around the susceptibility disks against MRSA was measured and compared with P. aeruginosa free experiments. The anti-MRSA activity of MINO, ST and ABK was reduced by coexistence of P. aeruginosa. In RFP and VCM, the anti-MRSA activity was reinforced by coexistence of P. aeruginosa. Although the anti-MRSA activity of ST and ABK has improved by EM addition in the MHA plates, the anti-MRSA activity has not improved in MINO. These results are suggesting that in a MRSA infection, the chemotherapy by anti-MRSA agents were affected by coexistence of P. aeruginosa as an indirect pathogen. The macrolides such as EM may be useful as a modulator for chemotherapy by ST or ABK when MRSA and P. aeruginosa are isolated at the same time from the patient.     

Ventilator-associated pneumonia: impact of organisms on clinical resolution and medical resources utilization

BACKGROUND: Clinical resolution of ventilator-associated pneumonia (VAP) determines the duration of treatment and mechanical ventilation. The aim of this study was to evaluate the influence of organisms and their susceptibility to treatment on outcomes. METHODS: Prospective observational study in three teaching ICUs. Sixty episodes of VAP with appropriate therapy (Haemophilus influenzae, 15 episodes; methicillin-sensitive Staphylococcus aureus [MSSA], 15 episodes; Pseudomonas aeruginosa, 15 episodes; and methicillin-resistant S aureus [MRSA], 15 episodes), and 30 episodes with initial inappropriate therapy, all due to P aeruginosa, were compared. The main outcome measures were clinical resolution variables and, in survivors, length of mechanical ventilation after VAP onset. RESULTS: A significant delay in the resolution of hypoxemia was observed in VAP episodes due to MRSA and P aeruginosa with inappropriate antibiotic therapy (IAT) (median time to resolution, 10 and 8 days, respectively) when compared with the remaining pathogens (median time to resolution, 2 days). A multiple regression model, adjusted for disease severity, confirmed the delayed clinical resolution for MRSA and P aeruginosa with IAT. Similar associations were documented for defervescence. Among survivors, the median duration of mechanical ventilation after VAP onset was significantly longer for MRSA (17 days) and P aeruginosa IAT (11 days) when compared with episodes due to H influenzae or MSSA (6 days). Multiple regression analysis, adjusted for disease severity, confirmed that MRSA required significantly (R(2) = 0.132; p < 0.01) longer respiratory support than other organisms. CONCLUSIONS: When treated promptly, the resolution of VAP due to MSSA, H influenzae, and P aeruginosa was comparable. The resolution of MRSA VAP, regardless of the appropriateness of initial antibiotic therapy, was associated with longer respiratory support.     

多耐药铜绿假单胞菌下呼吸道感染临床分析

目的　分析耐亚胺培南和头孢他啶铜绿假单胞菌下呼吸道感染的临床特点和治疗对策。方法　对2 0 0 1年 1月至 2 0 0 3年 12月收住我院的 15例耐亚胺培南和头孢他啶的铜绿假单胞菌下呼吸道感染患者的临床表现及治疗进行回顾性分析。结果　 15例均患有基础疾病 ,以支气管扩张最多见 ,临床特点有发热 ,咳黄色粘稠痰 ,胸部 X线表现为小斑片状浸润阴影。 6株对亚胺培南、头孢他啶、环丙沙星和哌拉西林均耐药。 15例患者 2例治愈 ,5例好转 ,其治疗选用抗生素药物有亚胺培南 ,头孢他啶 ,头孢哌酮 舒巴坦 ,哌拉西林 舒巴坦 ,环丙沙星等 ,均为联合使用 ;2例无明显改善 ;6例患者死亡。结论　多药耐药铜绿假单胞菌 (MDRP)下呼吸道感染大多合并基础疾病 ;有住院时间长 ,反复多次住院 ,曾使用多种广谱抗生素的特点 ;治疗困难 ,病死率高 ,预后差。抗生素药物选择应避免选用亚胺培南。     

Growth inhibitory activity of clinical isolates of Pseudomonas aeruginosa against Staphylococcus aureus (MRSA and MSSA)]

Anti staphylococcal activity by clinical isolates of Pseudomonas aeruginosa was tested by the reversed agar plate and the filter paper stamp methods. Almost 40% of Pseudomonas aeruginosa inhibited the growth of both Methicillin resistant Staphylococcus aureus (MRSA) and Methicillin sensitive Staphylococcus aureus (MSSA). Green pigment (Pyocyanin) produced strains showed a strong inhibitory effect against MRSA and MSSA respectively. But some other pigment (Yellow, Red) strains also showed anti staphylococcal activity. These data suggest the colonization of Pseudomonas aeruginosa with anti staphylococcal activity may not be eradicated by the anti pseudomonic antibiotics.     

Successful combination therapy by meropenem and colistin for multi-drug-resistant Pseudomonas aeruginosa infection after allogeneic bone marrow transplantation

A 66-year-old male with acute type adult T-cell leukemia that was refractory to chemotherapy underwent unrelated allogeneic bone marrow transplantation after non-myeloablative conditioning with fludarabine, busulfan and total body irradiation. During an episode of neutropenia on day 12 after transplantation, pneumonia and sepsis due to multi-drug resistant Pseudomonas aeruginosa developed. Drug susceptibility tests demonstrated resistance to all kinds of intravenous antibiotics available for P. aeruginosa in Japan. Multi-drug susceptibility tests by the breakpoint-checkerboard plate method were then performed and combination therapy with meropenem hydrate and colistin was started based on the test results. After starting treatment, clinical symptoms and laboratory data immediately improved and engraftment of neutrophils was achieved on day 18. Infections with multi-drug-resistant P. aeruginosa are often critical for patients after hematopoietic stem cell transplantation and are difficult to control. In this paper, we report a case of severe multi-drug-resistant P. aeruginosa infection that was successfully treated by combination therapy selected using the breakpoint-checkerboard plate method.     

Health care-associated pneumonia (HCAP): empiric antibiotics targeting methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa predict optimal outcome

Inappropriate initial antimicrobial therapy (IIAT) has been associated with decreased survival in patients with health care-associated pneumonia (HCAP). We performed a study to determine whether empiric HCAP antibiotic regimens targeting methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are associated with greater appropriate therapy. A retrospective cohort study of culture-positive HCAP over 6 years (January 2003-December 2008) was performed at Barnes-Jewish Hospital, a 1200-bed urban teaching hospital. We identified 757 consecutive patients with HCAP. IIAT was administered to 213 (28%) patients. The pathogens most frequently associated with IIAT included P. aeruginosa (n=60, 28%), MRSA (n=58, 27%), and Acinetobacter species (n=32, 15%).Multivariate logistic regression analysis demonstrated that empiric anti-pseudomonal antibiotics (adjusted odds ratio [AOR], 1.75; 95% confidence interval [CI], 1.34-2.29; p=0.036), empiric anti-MRSA antibiotics (AOR, 1.71; 95% CI, 1.36-2.14; p=0.018), infection with Streptococcus pneumoniae (AOR, 2.82; 95% CI, 2.03-3.91; p=0.002), absence of Acinetobacter species infection (AOR, 10.57; 95% CI, 7.29-15.33; p<0.001), absence of P. aeruginosa infection (AOR, 1.69; 95% CI, 1.36-2.05; p=0.014), and absence of Stenotrophomonas maltophilia infection (AOR, 20.43; 95% CI, 9.35-44.66; p<0.001) are independent predictors of appropriate therapy for HCAP. Our study suggests that initial therapy for HCAP should include antibiotics targeting MRSA and P. aeruginosa in order to provide appropriate initial therapy. However, the selection of individual antibiotic agents should be based on local patterns of infection and adjusted when microbiology results become available.     

Respiratory tract infections in the elderly, advances and limitations in the diagnosis and treatment]

Advances and limitations in the diagnosis and treatment of respiratory tract infections were discussed in relation to the prognosis of the elderly patients. Haemophilus influenzae and Streptococcus pneumoniae are the major pathogens in the community-acquired respiratory tract infections. On the other hand, methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are the major pathogens in the nosocomial respiratory tract infections. Detection of MRSA-PBP genes and antibiotic sensitivity tests are important for the diagnosis of MRSA. Vancomycin or arbekacin is the first-choice antibiotic for the treatment of severe infection caused by MRSA, and a combination therapy using one of the above agents and a partner antibiotic is necessary in some cases of MRSA infections. Reports concerning the significance of anaerobic bacteria in respiratory tract infections in Japan have been rare, presumably because procedures to recover anaerobic bacteria from specimens other than sputum, for example transtrancheal aspiration (TTA), bronchoscopic procedure and transcutaneous lung biopsy, are required for the diagnosis of the anaerobic respiratory tract infections. Nowadays, identification of cytomegalovirus (CMV) is a prerequisit for the rapid diagnosis of CMV infection. Therefore attempts are being made to detect a specific substance, for example messenger RNA during the stage of reactivation of CMV. Prophylaxis as well as treatment is necessary for the control of acute exacerbation of chronic respiratory tract infections. In this regard, long-term administration of a small dose of erythromycin or new-quinolone is promising.     

Mortality of COPD Patients Infected with Multi-Resistant Pseudomonas aeruginosa : A Case and Control Study

Abstract Background:   The incidence of infections caused by multiresistant Pseudomonas aeruginosa (MDRP) is increasing, especially in critically ill patients. The relevance of MDRP in the prognosis of chronic obstructive pulmonary disease (COPD) acute exacerbation in patients admitted to the hospital’s general ward is not well known. Patients and Methods:   Case and control study. Cases were patients admitted for COPD acute exacerbation in which a MDRP was isolated from spontaneous sputum. MDRP was defined as the absence of susceptibility to three or more antibiotic families (betalactams, quinolones, carbapenems and aminoglycosides). Patients currently or previously admitted to the intensive care unit (ICU), who had a recent surgery, neoplasia or immunosuppressive treatment were excluded from the study. Patients from the control group were admitted for COPD acute exacerbation and matched 1:1 with each case-patient in terms of age, sex, date of admission and degree of airway obstruction. Pseudomonas aeruginosa susceptible to all antimicrobials or other microorganisms was isolated from sputum. Results:   During the study period (2000–2005), 50 casepatients and 50 controls were included. Crude mortality at 2 years was 60% for the case-patients and 28% for the control group. In the logistic regression analysis adjusted for age, FEV₁ and number of previous hospital admissions, MDRP infection was associated to an increased mortality in comparison to patients without MDRP (OR = 6.2; IC 95%: 1.7–22.1; p < 0.01). Conclusions:   In COPD patients admitted to the general ward, acute exacerbation with MDRP in sputum was associated with higher mortality.     

Bacteremia in narcotic addicts at the Detroit Medical Center. I. Microbiology, epidemiology, risk factors, and empiric therapy

The changing microbiology of bacteremia among narcotic addicts in Detroit raised concerns about current presumptive antimicrobial therapy. In a one-year study of incidence, microbiology, sites, and risk factors, 180 bacteremic addicts (15% of addict-related admissions) were followed prospectively. Cases of bacteremia were caused by methicillin-sensitive Staphylococcus aureus (33%), methicillin-resistant S. aureus (MRSA, 24%), streptococci (20%), mixed organisms (11%), Pseudomonas aeruginosa (9%), and miscellaneous other single organisms (3%). Endocarditis (41%) and abscess or cellulitis (34%) were usually found. Multivariate analysis of host factors and addiction habits yielded results predictive of bacterial species but not of infection sites. Previous hospitalization, long-term addiction, and nonprescribed antibiotic use were associated with MRSA acquisition (odds ratio, 8.6:1). All addicts with polymicrobial or P. aeruginosa bacteremia abused pentazocine and tripelennamine (P = .05). Many of the addicts with streptococcal bacteremia were women who did not abuse antibiotics (odds ratio, 20.7:1). Physicians inappropriately prescribed empiric antibiotics for 67 of 72 addicts with MRSA, P. aeruginosa, or polymicrobial infection. The results of regression analysis suggest that, guided by the patient's history, the physician can prescribe appropriate empiric antimicrobial therapy for bacteremia in the febrile addict in Detroit.     

Clinical features and etiology of community-acquired pneumonia at a general hospital between 1994 and 1997]

To characterize the clinical features and etiology of recently encountered cases of community-acquired pneumonia (CAP), we carried out a hospital-based retrospective study of 120 episodes of CAP (115 patients) at Tagami Hospital, Nagasaki City between 1994 and 1997. We identified the causative pathogens in 55 episodes (50 patients) by sputum Gram stain and quantitative culture, for a determination rate of 45.8%. Streptococcus pneumoniae (17 episodes) and Haemophilus influenzae (15 episodes) were the primary causative organisms. It is noteworthy that two major nosocomial pathogens, Pseudomonas aeruginosa (P. aeruginosa; 5 episodes) and Methicillin-resistant Staphylococcus aureus (MRSA; 2 episodes), were also identified as causative agents of CAP. These two pathogens were isolated from patients with severe underlying diseases and patients who had been repeatedly hospitalized. The incidence of CAP due to P. aeruginosa and MRSA is increasing because patients with respiratory colonization by these nosocomial pathogens are often followed up on an outpatient basis.     

Pneumogene Sepsis

The lung is the most important site for septic infections with a remarkable morbidity and mortality. Early diagnosis and early initial antibiotic therapy is the key factor for patient outcome. In patients with community-acquired pneumonia, Streptococcus pneumoniae is the most relevant pathogen. Beta-lactam/macrolide combination therapy is recommended. In patients with sepsis due to nosocomial pneumonia, Staphylococcus aureus, Enterobacteriaceae and Pseudomonas aeruginosa play a role. Broad-spectrum, high-dose antibiotic treatment is necessary. Combination therapy for these patients is discussed controversially. Glycopeptides and linezolid are the treatment of choice for septic MRSA pneumonia. A protective ventilation strategy with low tidal volume (4–6 ml/kg body weight) and moderate PEEP (12–15 cm H₂O) is recommended for patients who need mechanical ventilation. High-frequency oscillation or extracorporeal lung assist could be alternatives in highly experienced centres.     

Antimicrobial therapy of febrile complications after high-dose chemo-/radiotherapy and autologous hematopoietic stem cell transplantation--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

Infectious complications occur in 60-100% of patients following high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (HSCT), and are commonly caused by Gram-negative aerobic bacteria (such as Pseudomonas aeruginosa and enterobacteriacea e) and Gram-positive cocci (such as enterococci, streptococci and staphylococci), which should be covered by empiric first-line antibiotic therapy. Less frequently, infections are caused by fungi and anaerobic bacteria, and initial therapy does not necessarily have to cover coagulase-negative staphylococci, oxacillin-resistant S. aureus (MRSA), anaerobic bacteria and fungi. Patients who already receive antibiotics and develop pulmonary infiltrates should immediately be treated with systemic antifungals. Patients with fever and diarrhea or other signs and symptoms of gastrointestinal or perianal infection should be treated with antibiotics covering anaerobic bacteria and enterococci. Clinically stable patients with skin infections or central venous catheter-related infections can be treated with standard empiric antibiotic therapy including a beta-lactam active against Pseudomonas aeruginosa with or without an aminoglycoside, and should only receive glycopeptides if they do not respond to first-line therapy within 72 hours, become clinically unstable, have severe mucositis, or when resistance against the empiric antibiotics is demonstrated. Recombinant hematopoietic growth factors should not be added routinely but may be considered in life-threatening situations such as invasive pulmonary mycoses or sepsis.